Methotrexate Nanoparticles Prepared with Codendrimer from Polyamidoamine (PAMAM) and Oligoethylene Glycols (OEG) Dendrons: Antitumor Efficacy in Vitro and in Vivo

PubMed Central

Zhao, Yanna; Guo, Yifei; Li, Ran; Wang, Ting; Han, Meihua; Zhu, Chunyan; Wang, Xiangtao

2016-01-01

The novel methotrexate-loaded nanoparticles (MTX/PGD NPs) prepared with amphiphilic codendrimer PGD from polyamidoamine and oligothylene glycol dendrons were obtained via antisolvent precipitation method augmented by ultrasonication. Based on the excellent hydrophility of PGD, the drug-loaded nanoparticles could be investigated easily with the high drug-loading content (~85.2%, w/w). The MTX/PGD NPs possessed spherical morphology, nanoscaled particle size (approximately 182.4 nm), and narrow particle size distribution. Release of MTX from MTX/PGD NPs showed a sustained release manner and completed within 48 h. Hemolytic evaluation indicated MTX/PGD NPs presented good blood compatibility, and the cytotoxicity of nanoparticles against breast cancer cells in vitro, biodistribution in tumor tissue, and antitumor efficacy in vivo were enhanced significantly compared to MTX injection. According to the higher drug-loading content, enhanced antitumor efficacy, and appropriate particle size, MTX/PGD NPs as the drug delivery systems could have potential application for cancer chemotherapy in clinic. PMID:27388443

Addressing the risk of bacterial contamination in platelets: a hospital economic perspective.

PubMed

Li, Justin W; Brecher, Mark E; Jacobson, Jessica L; Harm, Sarah K; Chen, Dorothy; El-Gamil, Audrey; Dobson, Al; Mintz, Paul D

2017-10-01

Bacterially contaminated platelets (PLTs) remain a serious risk. The Food and Drug Administration has issued draft guidance recommending hospitals implement secondary testing or transfuse PLTs that have been treated with pathogen reduction technology (PRT). The cost implications of these approaches are not well understood. We modeled incurred costs when hospitals acquire, process, and transfuse PLTs that are PRT treated with INTERCEPT (Cerus Corp.) or secondary tested with the PLT PGD Test (Verax Biomedical). Hospitals will spend $221.27 (30.0%) more per PRT-treated apheresis PLT unit administered compared to a Zika-tested apheresis PLT unit that is irradiated and PGD tested in hospital. This difference is reflected in PRT PLT units having: 1) a higher hospital purchase price ($100.00 additional charge compared to an untreated PLT); 2) lower therapeutic effectiveness than untreated PLTs among hematologic-oncologic patients, which contributes to additional transfusions ($96.05); or 3) fewer PLT storage days, which contributes to higher outdating cost from expired PLTs ($67.87). Only a small portion of the incremental costs for PRT-treated PLTs are offset by costs that may be avoided, including primary bacterial culture, secondary bacterial testing ($26.65), hospital irradiation ($8.50), Zika testing ($4.47), and other costs ($3.03). The significantly higher cost of PRT-treated PLTs over PGD-tested PLTs should interest stakeholders. For hospitals that outdate PLTs, savings associated with expiration extension to 7 days by adding PGD testing will likely be substantially greater than the cost of implementing PGD-testing. Our findings might usefully inform a hospital's decision to select a particular blood safety approach. © 2017 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

America's Overseas School System.

ERIC Educational Resources Information Center

Walling, Donovan R.

1985-01-01

Describes the history, size, location, administrative structure, curricula, accreditation, teacher and student characteristics, test administration and results, problems, and future expectations of the school system operated by the United States Department of Defense for 149,000 children of military personnel based outside the United States. (PGD)

Reproductive Endocrinologists’ Utilization of Genetic Counselors for Oncofertility and Preimplantation Genetic Diagnosis (PGD) Treatment of BRCA1/2 Mutation Carriers

PubMed Central

Goetsch, Allison L.; Wicklund, Catherine; Clayman, Marla L.; Woodruff, Teresa K.

2016-01-01

Genetic counselors believe fertility preservation and preimplantation genetic diagnosis (PGD) discussions to be a part of their role when counseling BRCA1/2 mutation-positive patients. This study is the first to explore reproductive endocrinologists’ (REI) practices and attitudes regarding involvement of genetic counselors in the care of BRCA1/2 mutation carriers seeking fertility preservation and PGD. A survey was mailed to 1000 REIs from Reproductive Endocrinology & Infertility (SREI), an American Society for Reproductive Medicine (ASRM) affiliate group. A 14.5 % response rate was achieved; data was analyzed using SPSS software. The majority of participating REIs were found to recommend genetic counseling to cancer patients considering fertility preservation (82 %) and consult with a genetic counselor regarding PGD for hereditary cancer syndromes (92 %). Additionally, REIs consult genetic counselors regarding PGD patient counseling (88 %), genetic testing (78 %), and general genetics questions (66 %). Two areas genetic counselors may further aid REIs are: elicitation of family history, which is useful to determine fertility preservation and PGD intervention timing (32 % of REIs utilize a cancer family history to determine intervention timing); and, interpretation of variants of uncertain significance (VOUS) as cancer panel genetic testing becomes more common (36 % of REIs are unfamiliar with VOUS). Given our findings, the Oncofertility Consortium® created an online resource for genetic counselors focused on fertility preservation education and communication strategies. PMID:26567039

A Qualitative Inquiry of the Financial Concerns of Couples Opting to Use Preimplantation Genetic Diagnosis to Prevent the Transmission of Known Genetic Disorders

PubMed Central

Drazba, Kathryn T.; Kelley, Michele A.; Hershberger, Patricia E.

2013-01-01

Preimplantation genetic diagnosis (PGD) is an innovative prenatal testing option because the determination of whether a genetic disorder or chromosomal abnormality is evident occurs prior to pregnancy. However, PGD is not covered financially under the majority of private and public health insurance institutions in the United States, leaving couples to decide whether PGD is financially feasible. The aim of this qualitative study was to understand the role of finances in the decision-making process among couples who were actively considering PGD. In-depth, semi-structured interviews were completed with 18 genetic high-risk couples (36 individual partners). Grounded theory guided the analysis, whereby three themes emerged: 1) Cost is salient, 2) Emotions surrounding affordability, and 3) Financial burden and sacrifice. Ultimately, couples determined that the opportunity to avoid passing on a genetic disorder to a future child was paramount to the cost of PGD, but expressed financial concerns and recognized financial access as a major barrier to PGD utilization. PMID:23949612

Developmental neuropsychological assessment of 4- to 5-year-old children born following Preimplantation Genetic Diagnosis (PGD): A pilot study.

PubMed

Sacks, Gilat Chaya; Altarescu, Gheona; Guedalia, Judith; Varshaver, Irit; Gilboa, Tal; Levy-Lahad, Ephrat; Eldar-Geva, Talia

2016-01-01

The purpose of this pilot study was to evaluate developmental neuropsychological profiles of 4- to 5-year-old children born after Preimplantation Genetic Diagnosis (PGD). Twenty-seven participants received a neurological examination and a battery of neuropsychological assessments including Wechsler Preschool & Primary Scale of Intelligence - Third Edition (WPPSI-III; cognitive development), Preschool Language Scale, Fourth Edition (PLS-4; language development), Wide Range Assessment of Visual Motor Abilities (visual motor abilities), Childhood Autism Rating Scales II (a screening test for autistic spectrum disorders), and the Miles ABC Test (ocular dominance). Parental questionnaires included the Behavior Rating Inventory of Executive Function Preschool Version (BRIEF-P; executive function), Child Behavior Checklist (CBCL) and the Carey Temperament Scales Behavioral Style Questionnaire (socioemotional development and temperament), and the Vineland Adaptive Behavior Scales, Interview Edition, Second Edition (general adaptive behavior). Subjects' tests results were compared to each test's norms. Children born after PGD demonstrated scores within the normal or above-normal ranges for all developmental outcomes (mean ± SD): WPPSI-III-VIQ 107.4 ± 14.4 (p = .013), PLS-4-Total 113.2 ± 12.4, p < .001), CBCL-Total 41.1 ± 8.6 (p < .001), BRIEF-P-Global Executive Composite 44.8 ± 9.5 (p = .009). Twelve (44%) of the PGD children had a significant difference between their VIQ and PIQ scores (compared to 27% in the general population). One subject was found to show possible signs of autistic spectrum disorder, although a family history of autism was noted. In conclusion, in this pilot study, children assessed at age 4-5 years and conceived after PGD displayed developmental neuropsychological outcomes within normal limits as compared to their chronologic peers. A larger study is needed to evaluate and follow the neuropsychological development of children born after PGD.

High-risk individuals' perceptions of reproductive genetic testing for CDH1 mutations.

PubMed

Hallowell, Nina; Badger, Shirlene; Richardson, Sue; Caldas, Carlos; Hardwick, Richard H; Fitzgerald, Rebecca C; Lawton, Julia

2017-10-01

Reproductive genetic testing- PreNatal Diagnosis (PND) and Preimplantation Genetic Diagnosis (PGD)-for CDH1 mutations associated with Hereditary Diffuse Gastric Cancer (HDGC)is available in the UK. This qualitative interview study examined high-risk individuals' (n = 35) views of CDH1 reproductive genetic testing. Interviewees generally regarded reproductive genetic testing as an acceptable form of HDGC risk management. However, some were concerned that their genetic risks required them to plan reproduction and anticipated difficulties communicating this to reproductive partners. Individuals had a preference for PGD over PND because it avoided the need for a termination of pregnancy. However, those who had not yet had children expressed concerns about having to undergo IVF procedures and worries about their effectiveness and the need for embryo selection in PGD. It is suggested that high-risk individuals are provided with access to reproductive genetic counselling.

Defects in Peroxisomal 6-Phosphogluconate Dehydrogenase Isoform PGD2 Prevent Gametophytic Interaction in Arabidopsis thaliana1[OPEN

PubMed Central

Hölscher, Christian; Meyer, Tanja; Fischer, Kerstin

2016-01-01

We studied the localization of 6-phosphogluconate dehydrogenase (PGD) isoforms of Arabidopsis (Arabidopsis thaliana). Similar polypeptide lengths of PGD1, PGD2, and PGD3 obscured which isoform may represent the cytosolic and/or plastidic enzyme plus whether PGD2 with a peroxisomal targeting motif also might target plastids. Reporter-fusion analyses in protoplasts revealed that, with a free N terminus, PGD1 and PGD3 accumulate in the cytosol and chloroplasts, whereas PGD2 remains in the cytosol. Mutagenesis of a conserved second ATG enhanced the plastidic localization of PGD1 and PGD3 but not PGD2. Amino-terminal deletions of PGD2 fusions with a free C terminus resulted in peroxisomal import after dimerization, and PGD2 could be immunodetected in purified peroxisomes. Repeated selfing of pgd2 transfer (T-)DNA alleles yielded no homozygous mutants, although siliques and seeds of heterozygous plants developed normally. Detailed analyses of the C-terminally truncated PGD2-1 protein showed that peroxisomal import and catalytic activity are abolished. Reciprocal backcrosses of pgd2-1 suggested that missing PGD activity in peroxisomes primarily affects the male gametophyte. Tetrad analyses in the quartet1-2 background revealed that pgd2-1 pollen is vital and in vitro germination normal, but pollen tube growth inside stylar tissues appeared less directed. Mutual gametophytic sterility was overcome by complementation with a genomic construct but not with a version lacking the first ATG. These analyses showed that peroxisomal PGD2 activity is required for guided growth of the male gametophytes and pollen tube-ovule interaction. Our report finally demonstrates an essential role of oxidative pentose-phosphate pathway reactions in peroxisomes, likely needed to sustain critical levels of nitric oxide and/or jasmonic acid, whose biosynthesis both depend on NADPH provision. PMID:26941195

Single-cell high resolution melting analysis: A novel, generic, pre-implantation genetic diagnosis (PGD) method applied to cystic fibrosis (HRMA CF-PGD).

PubMed

Destouni, A; Poulou, M; Kakourou, G; Vrettou, C; Tzetis, M; Traeger-Synodinos, J; Kitsiou-Tzeli, S

2016-03-01

Institutions offering CF-PGD face the challenge of developing and optimizing single cell genotyping protocols that should cover for the extremely heterogeneous CF mutation spectrum. Here we report the development and successful clinical application of a generic CF-PGD protocol to facilitate direct detection of any CFTR nucleotide variation(s) by HRMA and simultaneous confirmation of diagnosis through haplotype analysis. A multiplex PCR was optimized supporting co-amplification of any CFTR exon-region, along with 6 closely linked STRs. Single cell genotypes were established through HRM analysis following melting of the 2nd round PCR products and were confirmed by STR haplotype analysis of the 1st PCR products. The protocol was validated pre-clinically, by testing 208 single lymphocytes, isolated from whole blood samples from 4 validation family trios. Fifteen PGD cycles were performed and 103 embryos were biopsied. In 15 clinical PGD cycles, genotypes were achieved in 88/93 (94.6%) embryo biopsy samples, of which 57/88 (64.8%) were deemed genetically suitable for embryo transfer. Amplification failed at all loci for 10/103 blastomeres biopsied from poor quality embryos. Six clinical pregnancies were achieved (2 twin, 4 singletons). PGD genotypes were confirmed following conventional amniocentesis or chorionic villus sampling in all achieved pregnancies. The single cell HRMA CF-PGD protocol described herein is a flexible, generic, low cost and robust genotyping method, which facilitates the analysis of any CFTR genotype combination. Single-cell HRMA can be beneficial to other clinical settings, for example the detection of single nucleotide variants in single cells derived from clinical tumor samples. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Preimplantation genetic diagnosis for Duchenne muscular dystrophy by multiple displacement amplification.

PubMed

Ren, Zi; Zeng, Hai-tao; Xu, Yan-wen; Zhuang, Guang-lun; Deng, Jie; Zhang, Cheng; Zhou, Can-quan

2009-02-01

To evaluate the use of multiple displacement amplification (MDA) in preimplantation genetic diagnosis (PGD) for female carriers with Duchenne muscular dystrophy (DMD). MDA was used to amplify a whole genome of single cells. Following the setup on single cells, the test was applied in two clinical cases of PGD. One mutant exon, six short tandem repeats (STR) markers within the dystrophin gene, and amelogenin were incorporated into singleplex polymerase chain reaction (PCR) assays on MDA products of single blastomeres. Center for reproductive medicine in First Affiliated Hospital, Sun Yat-sen University, China. Two female carriers with a duplication of exons 3-11 and a deletion of exons 47-50, respectively. The MDA of single cells and fluorescent PCR assays for PGD. The ability to analyze single blastomeres for DMD using MDA. The protocol setup previously allowed for the accurate diagnosis of each embryo. Two clinical cases resulted in a healthy girl, which was the first successful clinical application of MDA in PGD for DMD. We suggest that this protocol is reliable to increase the accuracy of the PGD for DMD.

Attitudes to reproductive genetic testing in women who had a positive BRCA test before having children: a qualitative analysis

PubMed Central

Ormondroyd, Elizabeth; Donnelly, Louise; Moynihan, Clare; Savona, Cornelie; Bancroft, Elizabeth; Evans, D Gareth; Eeles, Rosalind; Lavery, Stuart; Watson, Maggie

2012-01-01

The scope of conditions for which preimplantation genetic diagnosis (PGD) is licensed has recently been expanded in the United Kingdom to include genetic predisposition to adult-onset cancer. This qualitative interview study explores reproductive decision making, knowledge of and attitudes to reproductive genetic testing (prenatal diagnosis and PGD) with 25 women aged 18–45 years who received a positive BRCA test in the United Kingdom before having children. In this cohort of younger women, BRCA testing was motivated by risk management decisions; for some, BRCA status has affected their later decisions about having children. The perceived severity of hereditary breast/ovarian cancer (HBOC) influences thoughts about passing on the mutation to children and willingness to consider reproductive genetic testing, but most participants do not believe HBOC is a condition for which pregnancy termination is justified. PGD is considered more acceptable and advantageous because it would prevent transmission to future generations, but women have concerns about selecting embryos and the fact that they and affected family members would not have been selected. Women would also be deterred by the need to undergo in vitro fertilisation (IVF) and ovarian stimulation for PGD. Awareness of reproductive testing options was very variable among the cohort. The findings highlight the complexities of reproductive decision making for young women who knowingly carry a BRCA mutation, and the dilemmas inherent to reproductive genetic testing when the condition being tested for also affects a prospective parent. Counselling and psychological support for BRCA-positive women and couples concerning reproductive options are strongly indicated. PMID:21811309

Choosing between possible lives: legal and ethical issues in preimplantation genetic diagnosis.

PubMed

Scott, Rosamund

2006-01-01

This article critically appraises the current legal scope of the principal applications of preimplantation genetic diagnosis (PGD). This relatively new technique, which is available to some parents undergoing in vitro fertilization (IVF) treatment, aims to ensure that a child is not born with a seemingly undesirable genetic condition. The question addressed here is whether there should be serious reasons to test for genetic conditions in embryos in order to be able to select between them. The Human Fertilisation and Embryology Authority and the Human Genetics Commission have decided that there should be such reasons by broadly aligning the criteria for PGD with those for selective abortion. This stance is critically explored, as are its implications for the possible use of PGD to select either against or for marginal features or for significant traits. The government is currently reviewing the legal scope and regulation of PGD.

ESHRE PGD Consortium data collection XIV-XV: cycles from January 2011 to December 2012 with pregnancy follow-up to October 2013.

PubMed

De Rycke, M; Goossens, V; Kokkali, G; Meijer-Hoogeveen, M; Coonen, E; Moutou, C

2017-10-01

How does the data collection XIV-XV of the European Society of Human Reproduction and Embryology (ESHRE) PGD Consortium compare with the cumulative data for data collections I-XIII? The 14th and 15th retrospective collection represents valuable data on PGD/PGS cycles, pregnancies and children: the main trend observed is the increased application of array technology at the cost of FISH testing in PGS cycles and in PGD cycles for chromosomal abnormalities. Since 1999, the PGD Consortium has collected, analysed and published 13 previous data sets and an overview of the first 10 years of data collections. Data were collected from each participating centre using a FileMaker Pro database (versions 5-12). Separate predesigned FileMaker Pro files were used for the cycles, pregnancies and baby records. The study documented cycles performed during the calendar years 2011 and 2012 and follow-up of the pregnancies and babies born which resulted from these cycles (until October 2013). Data were submitted by 71 centres (full PGD Consortium members). Records with incomplete or inconsistent data were excluded from the calculations. Corrections, calculations and tables were made by expert co-authors. For data collection XIV-XV, 71 centres reported data for 11 637 cycles with oocyte retrieval (OR), along with details of the follow-up on 2147 pregnancies and 1755 babies born. A total of 1953 cycles to OR were reported for chromosomal abnormalities, 144 cycles to OR for sexing for X-linked diseases, 3445 cycles to OR for monogenic diseases, 6095 cycles to OR for PGS and 38 cycles to OR for social sexing. From 2010 until 2012, the use of arrays for genetic testing increased from 4% to 20% in PGS and from 6% to 13% in PGD cycles for chromosomal abnormalities; the uptake of biopsy at the blastocyst stage (from <1% up to 7%) was only observed in cycles for structural chromosomal abnormalities, alongside the application of array comparative genomic hybridization. The findings apply to the 71 participating centres and may not represent worldwide trends in PGD. The annual data collections provide an important resource for data mining and for following trends in PGD/PGS practice. None. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Dexamethasone Protects Neonatal Hypoxic-Ischemic Brain Injury via L-PGDS-Dependent PGD2-DP1-pERK Signaling Pathway

PubMed Central

Gonzalez-Rodriguez, Pablo J.; Li, Yong; Martinez, Fabian; Zhang, Lubo

2014-01-01

Background and Purpose Glucocorticoids pretreatment confers protection against neonatal hypoxic-ischemic (HI) brain injury. However, the molecular mechanism remains poorly elucidated. We tested the hypothesis that glucocorticoids protect against HI brain injury in neonatal rat by stimulation of lipocalin-type prostaglandin D synthase (L-PGDS)-induced prostaglandin D2 (PGD2)-DP1-pERK mediated signaling pathway. Methods Dexamethasone and inhibitors were administered via intracerebroventricular (i.c.v) injections into 10-day-old rat brains. Levels of L-PGD2, D prostanoid (DP1) receptor, pERK1/2 and PGD2 were determined by Western immunoblotting and ELISA, respectively. Brain injury was evaluated 48 hours after conduction of HI in 10-day-old rat pups. Results Dexamethasone pretreatment significantly upregulated L-PGDS expression and the biosynthesis of PGD2. Dexamethasone also selectively increased isoform pERK-44 level in the neonatal rat brains. Inhibitors of L-PGDS (SeCl4), DP1 (MK-0524) and MAPK (PD98059) abrogated dexamethasone-induced increases in pERK-44 level, respectively. Of importance, these inhibitors also blocked dexamethasone-mediated neuroprotective effects against HI brain injury in neonatal rat brains. Conclusion Interaction of glucocorticoids-GR signaling and L-PGDS-PGD2-DP1-pERK mediated pathway underlies the neuroprotective effects of dexamethasone pretreatment in neonatal HI brain injury. PMID:25474649

6-Phosphogluconate dehydrogenase regulates tumor cell migration in vitro by regulating receptor tyrosine kinase c-Met

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chan, Barden, E-mail: cchan@bidmc.harvard.edu; VanderLaan, Paul A.; Sukhatme, Vikas P.

2013-09-20

Highlights: •Expression of 6PGD positively correlates with advancing stage of lung carcinoma. •Knockdown of 6PGD by shRNA potently inhibits c-Met tyrosine phosphorylation. •Exogenous HGF fails to restore c-Met phosphorylation in cells with 6PGD knocked down. •6PGD knockdown results in inhibition of cell migration in vitro. •Constitutively active TPR-cMet significantly restores migration of cells without 6PGD. -- Abstract: 6-Phosphogluconate dehydrogenase (6PGD) is the third enzyme in the oxidative pentose phosphate pathway (PPP). Recently, we reported that knockdown of 6PGD inhibited lung tumor growth in vitro and in a xenograft model in mice. In this study, we continued to examine the functionalmore » role of 6PGD in cancer. We show that 6PGD expression positively correlates with advancing stage of lung carcinoma. In search of functional signals related to 6PGD, we discovered that knockdown of 6PGD significantly inhibited phosphorylation of c-Met at tyrosine residues known to be critical for activity. This downregulation of c-Met phosphorylation correlated with inhibition of cell migration in vitro. Overexpression of a constitutively active c-Met specifically rescued the migration but not proliferation phenotype of 6PGD knockdown. Therefore, 6PGD appears to be required for efficient c-Met signaling and migration of tumor cells in vitro.« less

Preimplantation diagnosis for neurofibromatosis.

PubMed

Verlinsky, Yury; Rechitsky, Svetlana; Verlinsky, Oleg; Chistokhina, Anna; Sharapova, Tatyana; Masciangelo, Christina; Levy, Michael; Kaplan, Brian; Lederer, Kevin; Kuliev, Anver

2002-01-01

Preimplantation genetic diagnosis (PGD) has recently been performed for inherited cancer predisposition determined by p53 tumour suppressor gene mutations, suggesting the usefulness of PGD for late onset disorders with genetic predisposition, including those caused by the germline mutations of other tumour suppressor genes. Here PGD was performed for two couples, one at risk for producing a child with maternally derived neurofibromatosis type I (NF1), and the other with paternally derived neurofibromatosis type II (NF2). The procedure involved a standard IVF protocol, combined with testing of oocytes or embryos prior to their transfer back to the patients. Maternal mutation Trp-->Ter (TGG-->TGA) in exon 29 of the NF1 gene was tested by sequential PCR analysis of the first and second polar bodies, and paternal L141P mutation in exon 4 of the NF2 gene by embryo biopsy at the cleavage stage. In both cases, multiplex nested PCR was applied, involving NF1 and NF2 mutation analysis simultaneously with the 3 and 2 linked markers, respectively. Of 57 oocytes tested in four PGD cycles for NF1 mutation, 26 mutation-free oocytes were detected, from which eight were preselected for transfer, two in each cycle. These produced two clinical pregnancies, one confirmed to be mutation free by chorionic villus sampling but ending in a stillbirth, and the other still ongoing. Of 18 embryos analysed in a cycle performed for NF2 mutation, eight mutation-free embryos were detected, three of which were transferred back to the patient, resulting in a singleton pregnancy and the birth of a mutation-free child. This suggests that PGD is a useful approach for avoiding the birth of children with inherited cancer predisposition, determined by NF1 and NF2 gene mutations.

Effects of Common Pesticides on Prostaglandin D2 (PGD2) Inhibition in SC5 Mouse Sertoli Cells, Evidence of Binding at the COX-2 Active Site, and Implications for Endocrine Disruption.

PubMed

Kugathas, Subramaniam; Audouze, Karine; Ermler, Sibylle; Orton, Frances; Rosivatz, Erika; Scholze, Martin; Kortenkamp, Andreas

2016-04-01

There are concerns that diminished prostaglandin action in fetal life could increase the risk of congenital malformations. Many endocrine-disrupting chemicals have been found to suppress prostaglandin synthesis, but to our knowledge, pesticides have never been tested for these effects. We assessed the ability of pesticides that are commonly used in the European Union to suppress prostaglandin D2 (PGD2) synthesis. Changes in PGD2 secretion in juvenile mouse Sertoli cells (SC5 cells) were measured using an ELISA. Coincubation with arachidonic acid (AA) was conducted to determine the site of action in the PGD2 synthetic pathway. Molecular modeling studies were performed to assess whether pesticides identified as PGD2-active could serve as ligands of the cyclooxygenase-2 (COX-2) binding pocket. The pesticides boscalid, chlorpropham, cypermethrin, cyprodinil, fenhexamid, fludioxonil, imazalil (enilconazole), imidacloprid, iprodione, linuron, methiocarb, o-phenylphenol, pirimiphos-methyl, pyrimethanil, and tebuconazole suppressed PGD2 production. Strikingly, some of these substances-o-phenylphenol, cypermethrin, cyprodinil, linuron, and imazalil (enilconazole)-showed potencies (IC50) in the range between 175 and 1,500 nM, similar to those of analgesics intended to block COX enzymes. Supplementation with AA failed to reverse this effect, suggesting that the sites of action of these pesticides are COX enzymes. The molecular modeling studies revealed that the COX-2 binding pocket can accommodate most of the pesticides shown to suppress PGD2 synthesis. Some of these pesticides are also capable of antagonizing the androgen receptor. Chemicals with structural features more varied than previously thought can suppress PGD2 synthesis. Our findings signal a need for in vivo studies to establish the extent of endocrine-disrupting effects that might arise from simultaneous interference with PGD2 signaling and androgen action. Kugathas S, Audouze K, Ermler S, Orton F, Rosivatz E, Scholze M, Kortenkamp A. 2016. Effects of common pesticides on prostaglandin D2 (PGD2) inhibition in SC5 mouse Sertoli cells, evidence of binding at the COX-2 active site, and implications for endocrine disruption. Environ Health Perspect 124:452-459; http://dx.doi.org/10.1289/ehp.1409544.

Effects of Common Pesticides on Prostaglandin D2 (PGD2) Inhibition in SC5 Mouse Sertoli Cells, Evidence of Binding at the COX-2 Active Site, and Implications for Endocrine Disruption

PubMed Central

Kugathas, Subramaniam; Audouze, Karine; Ermler, Sibylle; Orton, Frances; Rosivatz, Erika; Scholze, Martin; Kortenkamp, Andreas

2015-01-01

Background: There are concerns that diminished prostaglandin action in fetal life could increase the risk of congenital malformations. Many endocrine-disrupting chemicals have been found to suppress prostaglandin synthesis, but to our knowledge, pesticides have never been tested for these effects. Objectives: We assessed the ability of pesticides that are commonly used in the European Union to suppress prostaglandin D2 (PGD2) synthesis. Methods: Changes in PGD2 secretion in juvenile mouse Sertoli cells (SC5 cells) were measured using an ELISA. Coincubation with arachidonic acid (AA) was conducted to determine the site of action in the PGD2 synthetic pathway. Molecular modeling studies were performed to assess whether pesticides identified as PGD2-active could serve as ligands of the cyclooxygenase-2 (COX-2) binding pocket. Results: The pesticides boscalid, chlorpropham, cypermethrin, cyprodinil, fenhexamid, fludioxonil, imazalil (enilconazole), imidacloprid, iprodione, linuron, methiocarb, o-phenylphenol, pirimiphos-methyl, pyrimethanil, and tebuconazole suppressed PGD2 production. Strikingly, some of these substances—o-phenylphenol, cypermethrin, cyprodinil, linuron, and imazalil (enilconazole)—showed potencies (IC50) in the range between 175 and 1,500 nM, similar to those of analgesics intended to block COX enzymes. Supplementation with AA failed to reverse this effect, suggesting that the sites of action of these pesticides are COX enzymes. The molecular modeling studies revealed that the COX-2 binding pocket can accommodate most of the pesticides shown to suppress PGD2 synthesis. Some of these pesticides are also capable of antagonizing the androgen receptor. Conclusions: Chemicals with structural features more varied than previously thought can suppress PGD2 synthesis. Our findings signal a need for in vivo studies to establish the extent of endocrine-disrupting effects that might arise from simultaneous interference with PGD2 signaling and androgen action. Citation: Kugathas S, Audouze K, Ermler S, Orton F, Rosivatz E, Scholze M, Kortenkamp A. 2016. Effects of common pesticides on prostaglandin D2 (PGD2) inhibition in SC5 mouse Sertoli cells, evidence of binding at the COX-2 active site, and implications for endocrine disruption. Environ Health Perspect 124:452–459; http://dx.doi.org/10.1289/ehp.1409544 PMID:26359731

Parental mosaicism is a pitfall in preimplantation genetic diagnosis of dominant disorders.

PubMed

Steffann, Julie; Michot, Caroline; Borghese, Roxana; Baptista-Fernandes, Marcia; Monnot, Sophie; Bonnefont, Jean-Paul; Munnich, Arnold

2014-05-01

PCR amplification on single cells is prone to allele drop-out (PCR failure of one allele), a cause of misdiagnosis in preimplantation genetic diagnosis (PGD). Owing to this error risk, PGD usually relies on both direct and indirect genetic analyses. When the affected partner is the sporadic case of a dominant disorder, building haplotypes require spermatozoon or polar body testing prior to PGD, but these procedures are cost and time-consuming. A couple requested PGD because the male partner suffered from a dominant Cowden syndrome (CS). He was a sporadic case, but the couple had a first unaffected child and the non-mutated paternal haplotype was tentatively deduced. The couple had a second spontaneous pregnancy and the fetus was found to carry the at-risk haplotype but not the PTEN mutation. The mutation was present in blood from the affected father, but at low level, confirming the somatic mosaicism. Ignoring the possibility of mosaicism in the CS patient would have potentially led to selection of affected embryos. This observation emphasizes the risk of PGD in families at risk to transmit autosomal-dominant disorder when the affected partner is a sporadic case.

[Preimplantation genetic diagnosis and monogenic inherited eye diseases].

PubMed

Hlavatá, L; Ďuďáková, Ľ; Trková, M; Soldátová, I; Skalická, P; Kousal, B; Lišková, P

Preimplantation genetic diagnosis (PGD) is an established application of genetic testing in the context of in vitro fertilization. PGD is an alternative method to prenatal diagnosis which aims to prevent the transmission of an inherited disorder to the progeny by implanting only embryos that do not carry genetic predisposition for a particular disease. The aim of this study is to provide an overview of eye disorders for which PGD has been carried out. The European literature search focused on best practices, ethical issues, risks and results of PGD for inherited eye disorders. PGD is performed for a number of ocular disorders; a prerequisite for its application is however, the knowledge of a disease-causing mutation(s). The main advantage of this method is that the couple is not exposed to a decision of whether or not to undergo an abortion. Qualified counselling must be provided prior to the PGD in order to completely understand the risk of disability in any child conceived, consequences of disease manifestation, and advantages as well as limitations of this method. In the group of non-syndromic eye diseases and diseases in which ocular findings dominate, PGD has been performed in European countries for aniridia, choroideremia, congenital fibrosis of extraocular muscles, Leber congenital amaurosis, ocular albinism, retinitis pigmentosa, X-linked retinoschisis, Stargardt disease, blepharophimosis-ptosis-inverse epicanthus syndrome and retinoblastoma. Sexing for X-linked or mitochondrial diseases has been carried out for blue cone monochromatism, choroideremia, familial exudative vitreoretinopathy, Leber hereditary optic neuropathy, macular dystrophy (not further specified), Norrie disease, X-linked congenital stationary night blindness, X-linked retinoschisis and nystagmus (not further specified). In recent years, there has been an increase in potential to use PGD. The spectrum of diseases for this method has widened to include severe inherited eye diseases.Key words: preimplantation genetic diagnosis; monogenic eye diseases; in vitro fertilization.

De Novo Paternal FBN1 Mutation Detected in Embryos Before Implantation.

PubMed

Wang, Shuling; Niu, Ziru; Wang, Hui; Ma, Minyue; Zhang, Wei; Fang Wang, Shu; Wang, Jun; Yan, Hong; Liu, Yifan; Duan, Na; Zhang, Xiandong; Yao, Yuanqing

2017-06-26

BACKGROUND Marfan syndrome (MFS) is an autosomal dominant disease caused by mutations in the Fibrillin (FBN)1 gene and characterized by disorders in the cardiovascular, skeletal, and visual systems. The diversity of mutations and phenotypic heterogeneity of MFS make prenatal molecular diagnoses difficult. In this study, we used pre-implantation genetic diagnosis (PGD) to identify the pathogenic mutation in a male patient with MFS and to determine whether his offspring would be free of the disease. MATERIAL AND METHODS The history and pedigree of the proband were analyzed. Mutation analysis was performed on the couple and immediate family members. The couple chose IVF treatment and 4 blastocysts were biopsied. PGD was carried out by targeted high-throughput sequencing of the FBN1 gene in the embryos, along with single-nucleotide polymorphism haplotyping. Sanger sequencing was used to confirm the causative mutation. RESULTS c.2647T>C (p.Trp883Arg) was identified as the de novo likely pathogenic mutation in the proband. Whole-genome amplification and sequencing of the 3 embryos revealed that they did not carry the mutation, and 1 blastocyst was transferred back to the uterus. The amniocentesis test result analyzed by Sanger sequencing confirmed the PGD. A premature but healthy infant free of heart malformations was born. CONCLUSIONS The de novo mutation c.2647T>C (p.Trp883Arg) in FBN1 was identified in a Chinese patient with MFS. Embryos without the mutation were identified by PGD and resulted in a successful pregnancy.

Access to a simulator is not enough: the benefits of virtual reality training based on peer-group-derived benchmarks--a randomized controlled trial.

PubMed

von Websky, Martin W; Raptis, Dimitri A; Vitz, Martina; Rosenthal, Rachel; Clavien, P A; Hahnloser, Dieter

2013-11-01

Virtual reality (VR) simulators are widely used to familiarize surgical novices with laparoscopy, but VR training methods differ in efficacy. In the present trial, self-controlled basic VR training (SC-training) was tested against training based on peer-group-derived benchmarks (PGD-training). First, novice laparoscopic residents were randomized into a SC group (n = 34), and a group using PGD-benchmarks (n = 34) for basic laparoscopic training. After completing basic training, both groups performed 60 VR laparoscopic cholecystectomies for performance analysis. Primary endpoints were simulator metrics; secondary endpoints were program adherence, trainee motivation, and training efficacy. Altogether, 66 residents completed basic training, and 3,837 of 3,960 (96.8 %) cholecystectomies were available for analysis. Course adherence was good, with only two dropouts, both in the SC-group. The PGD-group spent more time and repetitions in basic training until the benchmarks were reached and subsequently showed better performance in the readout cholecystectomies: Median time (gallbladder extraction) showed significant differences of 520 s (IQR 354-738 s) in SC-training versus 390 s (IQR 278-536 s) in the PGD-group (p < 0.001) and 215 s (IQR 175-276 s) in experts, respectively. Path length of the right instrument also showed significant differences, again with the PGD-training group being more efficient. Basic VR laparoscopic training based on PGD benchmarks with external assessment is superior to SC training, resulting in higher trainee motivation and better performance in simulated laparoscopic cholecystectomies. We recommend such a basic course based on PGD benchmarks before advancing to more elaborate VR training.

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy.

PubMed

Sykes, David A; Bradley, Michelle E; Riddy, Darren M; Willard, Elizabeth; Reilly, John; Miah, Asadh; Bauer, Carsten; Watson, Simon J; Sandham, David A; Dubois, Gerald; Charlton, Steven J

2016-05-01

Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. [(3)H]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 ± 0.44 nM) expressed in Chinese hamster ovary cells, the binding being reversible and competitive with the native agonist prostaglandin D2(PGD2). The binding kinetics of QAW039 determined directly using [(3)H]-QAW039 revealed mean kinetic on (kon) and off (koff) values for QAW039 of 4.5 × 10(7)M(-1)min(-1)and 0.048 minute(-1), respectively. Importantly, thekoffof QAW039 (half-life = 14.4 minutes) was >7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD2-stimulated [(35)S]-GTPγS activation, and its effects were not fully reversed by increasing concentrations of PGD2after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for >180 minutes. All CRTh2 antagonists tested inhibited PGD2-stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD2-induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD2concentrations, which may be clinically relevant. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Attitudes Toward Pre-implantation Genetic Diagnosis (PGD) for Genetic Disorders Among Potential Users in Malaysia.

PubMed

Olesen, Angelina Patrick; Nor, Siti Nurani Mohd; Amin, Latifah

2016-02-01

While pre-implantation genetic diagnosis (PGD) is available and legal in Malaysia, there is an ongoing controversy debate about its use. There are few studies available on individuals' attitudes toward PGD, particularly among those who have a genetic disease, or whose children have a genetic disease. To the best of our knowledge, this is, in fact, the first study of its kind in Malaysia. We conducted in-depth interviews, using semi-structured questionnaires, with seven selected potential PGD users regarding their knowledge, attitudes and decisions relating to the use PGD. The criteria for selecting potential PGD users were that they or their children had a genetic disease, and they desired to have another child who would be free of genetic disease. All participants had heard of PGD and five of them were considering its use. The participants' attitudes toward PGD were based on several different considerations that were influenced by various factors. These included: the benefit-risk balance of PGD, personal experiences of having a genetic disease, religious beliefs, personal values and cost. The study's findings suggest that the selected Malaysian participants, as potential PGD users, were supportive but cautious regarding the use of PGD for medical purposes, particularly in relation to others whose experiences were similar. More broadly, the paper highlights the link between the participants' personal experiences and their beliefs regarding the appropriateness, for others, of individual decision-making on PGD, which has not been revealed by previous studies.

Conversion and non-conversion approach to preimplantation diagnosis for chromosomal rearrangements in 475 cycles.

PubMed

Kuliev, Anver; Janzen, Jeanine Cieslak; Zlatopolsky, Zev; Kirillova, Irina; Ilkevitch, Yury; Verlinsky, Yury

2010-07-01

Due to the limitations of preimplantation genetic diagnosis (PGD) for chromosomal rearrangements by interphase fluorescent in-situ hybridization (FISH) analysis, a method for obtaining chromosomes from single blastomeres was introduced by their fusion with enucleated or intact mouse zygotes, followed by FISH analysis of the resulting heterokaryons. Although this allowed a significant improvement in the accuracy of testing of both maternally and paternally derived translocations, it is still labour intensive and requires the availability of fertilized mouse oocytes, also creating ethical issues related to the formation of interspecies heterokaryons. This method was modified with a chemical conversion procedure that has now been clinically applied for the first time on 877 embryos from PGD cycles for chromosomal rearrangements and has become the method of choice for performing PGD for structural rearrangements. This is presented within the context of overall experience of 475 PGD cycles for translocations with pre-selection and transfer of balanced or normal embryos in 342 (72%) of these cycles, which resulted in 131 clinical pregnancies (38%), with healthy deliveries of 113 unaffected children. The spontaneous abortion rate in these cycles was as low as 17%, which confirms an almost five-fold reduction of spontaneous abortion rate following PGD for chromosomal rearrangements. 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Inhibition of soluble epoxide hydrolase limits niacin-induced vasodilation in mice

PubMed Central

Inceoglu, A. B.; Clifton, H.L.; Yang, J.; Hegedus, C.; Hammock, B. D.; Schaefer, S.

2012-01-01

Background The use of niacin in the treatment of dyslipidemias is limited by the common side effect of cutaneous vasodilation, commonly termed flushing. Flushing is thought to be due to release of the vasodilatory prostanoids PGD2 and PGE2 from arachidonic acid metabolism through the cyclooxygenase (COX) pathway. Arachidonic acid is also metabolized by the cytochrome P450 system which is regulated, in part, by the enzyme soluble epoxide hydrolase (sEH). Methods: These experiments used an established murine model in which ear tissue perfusion was measured by laser Doppler to test the hypothesis that inhibition of sEH would limit niacin-induced flushing. Results: Niacin-induced flushing was reduced from 506 ± 126 to 213 ± 39 % in sEH knockout animals. Pharmacologic treatment with 3 structurally distinct sEH inhibitors similarly reduced flushing in a dose dependent manner, with maximal reduction to 143±15% of baseline flow using a concentration of 1 mg/kg TPAU (1-trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl) urea). Systemically administered PGD2 caused ear vasodilation which was not changed by either pharmacologic sEH inhibition or by sEH gene deletion. Conclusions: Inhibition of sEH markedly reduces niacin-induced flushing in this model without an apparent effect on the response to PGD2. sEH inhibition may be a new therapeutic approach to limit flushing in humans. PMID:22526297

Exogenous fatty acids and niacin on acute prostaglandin D2 production in human myeloid cells.

PubMed

Montserrat-de la Paz, Sergio; Bermudez, Beatriz; Lopez, Sergio; Naranjo, Maria C; Romero, Yolanda; Bando-Hidalgo, Maria J; Abia, Rocio; Muriana, Francisco J G

2017-01-01

Niacin activates HCA 2 receptor that results in the release of PGD 2 . However, little is known on PGD 2 -producing cells and the role of fatty acids. Notably M-CSF macrophages exhibited a timely dependent PGD 2 production upon niacin challenge. Short pretreatment of M-CSF macrophages with autologous postprandial TRLs induced the down-regulation of HCA 2 gene and up-regulation of genes encoding COX1 and COX2 enzymes in a fatty acid-dependent manner. These effects were paralleled by a higher PGD 2 production with postprandial TRL-SFAs. The niacin-mediated transcriptional activity of all genes involved in PGD 2 biosynthesis was desensitized in a time-dependent manner by postprandial TRLs, leading to a decreased PGD 2 release. In vivo, the net excursions of PGD 2 in plasma followed similar fatty acid-dependent patterns as those found for PGD 2 release in vitro. The predominant fatty acid class in the diet acutely modulates PGD 2 biosynthetic pathway both in vitro and in vivo. Copyright © 2016 Elsevier Inc. All rights reserved.

Excitotoxicity-induced prostaglandin D2 production induces sustained microglial activation and delayed neuronal death.

PubMed

Iwasa, Kensuke; Yamamoto, Shinji; Yagishita, Sosuke; Maruyama, Kei; Yoshikawa, Keisuke

2017-04-01

Excitotoxicity is the pivotal mechanism of neuronal death. Prostaglandins (PGs) produced during excitotoxicity play important roles in neurodegenerative conditions. Previously, we demonstrated that initial burst productions of PGD 2 , PGE 2 , and PGF 2α are produced by cyclooxygenase-2 (COX-2) in the hippocampus following a single systemic kainic acid (KA) administration. In addition, we showed that blocking of all PG productions ameliorated hippocampal delayed neuronal death at 30 days after KA administration. To investigate the role of individual PGs in the delayed neuronal death, we performed intracerebroventricular injection of PGD 2 , PGE 2 , or PGF 2α in rats whose hippocampal PG productions were entirely blocked by pretreatment of NS398, a COX-2 selective inhibitor. Administration of PGD 2 and PGF 2α had a latent contribution to the delayed neuronal death, sustained over 30 days after a single KA treatment. Furthermore, PGD 2 enhanced microglial activation, which may be involved in the delayed neuronal death in the hippocampus. These findings suggest that excitotoxic delayed neuronal death is mediated through microglia activated by PGD 2 . Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Preimplantation genetic diagnosis: a systematic review of litigation in the face of new technology.

PubMed

Amagwula, Tochi; Chang, Peter L; Hossain, Amjad; Tyner, Joey; Rivers, Aimée L; Phelps, John Y

2012-11-01

To study legal cases against IVF facilities pertaining to preimplantation genetic diagnosis (PGD) misdiagnosis. Systematic case law review. University medical center using US legal databases. The IVF recipients using PGD services. Lawsuits pertaining to PGD against IVF facilities. Lawsuits, court rulings, damage awards, and settlements pertaining to PGD after the birth of a child with a genetic defect. Causes of action pertaining to PGD arise from negligence in performing the procedure as well as failure to properly inform patients of key information, such as inherent errors associated with the PGD process, a facility's minimal experience in performing PGD, and the option of obtaining PGD. Courts have sympathized with the financial burden involved in caring for children with disabilities. Monetary damage awards are based on the costs of caring for children with debilitating defects, including lifetime medical and custodial care. Facilities offering PGD services expose themselves to a new realm of liability in which damage awards can easily exceed the limits of a facility's insurance policy. Competent laboratory personnel and proper informed consent--with particular care to inform patients of the inherent inaccuracies of PGD--are crucial in helping deter liability. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation

PubMed Central

Luna-Gomes, Tatiana; Magalhães, Kelly G; Mesquita-Santos, Fabio P.; Bakker-Abreu, Ilka; Samico, Rafaela F.; Molinaro, Raphael; Calheiros, Andrea S.; Diaz, Bruno L.; Bozza, Patrícia T.

2011-01-01

Prostaglandin (PG)D2 is a key mediator of allergic inflammatory diseases that is mainly synthesized by mast cells, which constitutively express high levels of the terminal enzyme involved in PGD2 synthesis, the hematopoietic PGD synthase (H-PGDS). Here, we investigated whether eosinophils are also able to synthesize, and therefore, supply biologically active PGD2. PGD2 synthesis was evaluated within human blood eosinophils, in vitro-differentiated mouse eosinophils, and eosinophils infiltrating inflammatory site of mouse allergic reaction. Biological function of eosinophil-derived PGD2 was studied by employing inhibitors of synthesis and activity. Constitutive expression of H-PGDS was found within non-stimulated human circulating eosinophils. Acute stimulation of human eosinophils with A23187 (0.1 – 5 μM) evoked PGD2 synthesis, which was located at the nuclear envelope and was inhibited by pre-treatment with HQL-79 (10 μM), a specific H-PGDS inhibitor. Pre-stimulation of human eosinophils with arachidonic acid (AA; 10 μM) or human eotaxin (6 nM) also enhanced HQL-79-sensitive PGD2 synthesis, which, by acting on membrane-expressed specific receptors (DP1 and DP2), displayed an autocrine/paracrine ability to trigger leukotriene (LT)C4 synthesis and lipid body biogenesis, hallmark events of eosinophil activation. In vitro-differentiated mouse eosinophils also synthesized paracrine/autocrine active PGD2 in response to AA stimulation. In vivo, at late time point of the allergic reaction, infiltrating eosinophils found at the inflammatory site appeared as an auxiliary PGD2-synthesizing cell population. Our findings reveal that eosinophils are indeed able to synthesize and secrete PGD2, hence representing during allergic inflammation an extra cell source of PGD2, which functions as an autocrine signal for eosinophil activation. PMID:22102725

Rates and risks for prolonged grief disorder in a sample of orphaned and widowed genocide survivors.

PubMed

Schaal, Susanne; Jacob, Nadja; Dusingizemungu, Jean-Pierre; Elbert, Thomas

2010-07-06

The concept of Prolonged Grief Disorder (PGD) has been defined in recent years by Prigerson and co-workers, who have developed and empirically tested consensus and diagnostic criteria for PGD. Using these most recent criteria defining PGD, the aim of this study was to determine rates of and risks for PGD in survivors of the 1994 Rwandan genocide who had lost a parent and/or the husband before, during or after the 1994 events. The PG-13 was administered to 206 orphans or half orphans and to 194 widows. A regression analysis was carried out to examine risk factors of PGD. 8.0% (n = 32) of the sample met criteria for PGD with an average of 12 years post-loss. All but one person had faced multiple losses and the majority indicated that their grief-related loss was due to violent death (70%). Grief was predicted mainly by time since the loss, by the violent nature of the loss, the severity of symptoms of posttraumatic stress disorder (PTSD) and the importance given to religious/spiritual beliefs. By contrast, gender, age at the time of bereavement, bereavement status (widow versus orphan), the number of different types of losses reported and participation in the funeral ceremony did not impact the severity of prolonged grief reactions. A significant portion of the interviewed sample continues to experience grief over interpersonal losses and unresolved grief may endure over time if not addressed by clinical intervention. Severity of grief reactions may be associated with a set of distinct risk factors. Subjects who lose someone through violent death seem to be at special risk as they have to deal with the loss experience as such and the traumatic aspects of the loss. Symptoms of PTSD may hinder the completion of the mourning process. Religious beliefs may facilitate the mourning process and help to find meaning in the loss. These aspects need to be considered in the treatment of PGD.

Preimplantation genetic diagnosis for cancer predisposition.

PubMed

Rechitsky, Svetlana; Verlinsky, Oleg; Chistokhina, Anna; Sharapova, Tatyana; Ozen, Seckin; Masciangelo, Christina; Kuliev, Anver; Verlinsky, Yury

2002-01-01

Preimplantation genetic diagnosis (PGD) has recently been offered for couples with an inherited predisposition for late onset disorders. This paper presents the results of PGD for a group of couples at risk for producing children with cancer predisposition. Using a standard IVF procedure, oocytes or embryos were tested for different mutations predisposing to cancer, preselecting and transferring only mutation-free embryos back to the patients. The procedure was performed for patients with predisposition to familial adenomatous polyposis coli (FAP), Von Hippel-Lindau syndrome (VHL), retinoblastoma, Li-Fraumeni syndrome, determined by p53 tumour suppressor gene mutations, neurofibromatosis types I and II and familial posterior fossa brain tumour (hSNF5). Overall, 20 PGD cycles were performed for 10 couples, resulting in preselection and transfer of 40 mutation-free embryos, which resulted in five unaffected clinical pregnancies and four healthy children born by the present time. Despite the controversy of PGD use for late onset disorders, the data demonstrate the usefulness of this approach as the only acceptable option for at-risk couples to avoid the birth of children with an inherited predisposition to cancer, and to have a healthy child.

The reproductive outcome of female patients with myotonic dystrophy type 1 (DM1) undergoing PGD is not affected by the size of the expanded CTG repeat tract

PubMed Central

Seneca, Sara; De Rademaeker, Marjan; Sermon, Karen; De Rycke, Martine; De Vos, Michel; Haentjens, Patrick; Devroey, Paul; Liebaers, Ingeborg

2010-01-01

Purpose This study aims to analyze the relationship between trinucleotide repeat length and reproductive outcome in a large cohort of DM1 patients undergoing ICSI and PGD. Methods Prospective cohort study. The effect of trinucleotide repeat length on reproductive outcome per patient was analyzed using bivariate analysis (T-test) and multivariate analysis using Kaplan-Meier and Cox regression analysis. Results Between 1995 and 2005, 205 cycles of ICSI and PGD were carried out for DM1 in 78 couples. The number of trinucleotide repeats does not have an influence on reproductive outcome when adjusted for age, BMI, basal FSH values, parity, infertility status and male or female affected. Cox regression analysis indicates that cumulative live birth rate is not influenced by the number of trinucleotide repeats. The only factor with a significant effect is age (p < 0.05). Conclusion There is no evidence of an effect of trinucleotide repeat length on reproductive outcome in patients undergoing ICSI and PGD. PMID:20221684

Induction of apoptosis in non-small cell lung carcinoma A549 cells by PGD₂ metabolite, 15d-PGJ₂.

PubMed

Wang, Jun-Jie; Mak, Oi-Tong

2011-11-01

PGD2 (prostaglandin D2) is a mediator in various pathophysiological processes, including inflammation and tumorigenesis. PGD2 can be converted into active metabolites and is known to activate two distinct receptors, DP (PGD2 receptor) and CRTH2/DP2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). In the past, PGD2 was thought to be involved principally in the process of inflammation. However, in recent years, several studies have shown that PGD2 has anti-proliferative ability against tumorigenesis and can induce cellular apoptosis via activation of the caspase-dependent pathway in human colorectal cancer cells, leukaemia cells and eosinophils. In the lung, where PGD2 is highly released when sensitized mast cells are challenged with allergen, the mechanism of PGD2-induced apoptosis is unclear. In the present study, A549 cells, a type of NSCLC (non-small cell lung carcinoma), were treated with PGD2 under various conditions, including while blocking DP and CRTH2/DP2 with the selective antagonists BWA868C and ramatroban respectively. We report here that PGD2 induces A549 cell death through the intrinsic apoptotic pathway, although the process does not appear to involve either DP or CRTH2/DP2. Similar results were also found with H2199 cells, another type of NSCLC. We found that PGD2 metabolites induce apoptosis effectively and that 15d-PGJ2 (15-deoxy-Δ12,14-prostaglandin J2) is a likely candidate for the principal apoptotic inducer in PGD2-induced apoptosis in NSCLC A549 cells.

Parental bonding in subjects with pathological gambling disorder compared with healthy controls.

PubMed

Villalta, Laia; Arévalo, Rubén; Valdepérez, Ana; Pascual, Juan C; de los Cobos, J Pérez

2015-03-01

The new Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-V) includes pathological gambling disorder (PGD) in the subgroup of "Addiction and Related Disorders" due to the similarities between PGD and substance-based addictions in neurobiological, psychological, and social risk factors. Family factors as parental rearing attitudes play a crucial role in the development of substance use disorders and PGD. The aim of the present study was to assess the parental bonding during childhood perceived for adults with PGD compared with healthy controls. Twenty males with PGD and 20 control subjects answered the parental bonding instrument, which measures subjects' recollections of parenting on dimensions of care and protection. Subjects with PGD showed significantly lower maternal and paternal care (p = 0.016 and p = 0.031, respectively) than controls, and higher paternal protection (p = 0.003). The most common parental pattern for PGD subjects was the affectionless control (50% for the father and 60% for the mother). Preliminary results suggest that, as previously reported for substance use disorders, an affectionless control parenting style is associated with PGD.

Providing preimplantation genetic diagnosis in the United Kingdom, The Netherlands and Germany: a comparative in-depth analysis of health-care access.

PubMed

Aarden, Erik; Van Hoyweghen, Ine; Vos, Rein; Horstman, Klasien

2009-07-01

In recent years, preimplantation genetic diagnosis (PGD) has developed into a routine diagnostic procedure in health care. Although during this process, several initiatives have been employed to regulate the procedure, access to PGD may be hampered by the diversity in health-care arrangements or therapeutic cultures in different countries. This article demonstrates how PGD provision practices depend on much more than regulation alone, by providing an in-depth comparative analysis of the provision of PGD in Britain, the Netherlands and Germany. In analysing regulation, organization, selection of indications, and mechanisms and criteria for reimbursement, differences between these countries can be identified. This is important, since differences in PGD provision can have enormous consequences for the access of individual patients in different countries. Somewhat paradoxically, this article concludes that even though differences in access do have serious consequences, they also serve the establishment of PGD. Developing access to PGD in national 'therapeutic cultures' can contribute to making PGD routine health care in a way that may not be achievable by harmonizing regulation.

Assessment and associated features of prolonged grief disorder among Chinese bereaved individuals.

PubMed

Li, Jie; Prigerson, Holly G

2016-04-01

Most research on the assessment and characteristics of prolonged grief disorder (PGD) has been conducted in Western bereaved samples. Limited information about PGD in Chinese samples exists. This study aims to validate the Chinese version of the Inventory of Complicated grief (ICG), examine the distinctiveness of PGD symptoms from symptoms of bereavement-related depression and anxiety, and explore the prevalence of PGD in a Chinese sample. Responses from 1358 bereaved Chinese adults were collected through an on-line survey. They completed the Chinese version of ICG and a questionnaire measuring depression and anxiety symptoms. The findings indicate that Chinese ICG has sound validity and high internal consistency. The ICG cut-off score for PGD "caseness"in this large Chinese sample was 48. The distinctiveness of PGD symptoms from those of depression and anxiety was supported by the results of the confirmatory factor analysis and the fact that PGD occurred in isolation in the studied sample. The prevalence of PGD was13.9%. ICG is a valid instrument for use in the Chinese context. Several key characteristics of PGD in Chinese, either different from or comparable to findings in Western samples, may stimulate further research and clinical interest in the concept by providing empirical evidence from an large and influential Eastern country. Copyright © 2015 Elsevier Inc. All rights reserved.

Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation.

PubMed

Sayah, David M; Mallavia, Beñat; Liu, Fengchun; Ortiz-Muñoz, Guadalupe; Caudrillier, Axelle; DerHovanessian, Ariss; Ross, David J; Lynch, Joseph P; Saggar, Rajan; Ardehali, Abbas; Ware, Lorraine B; Christie, Jason D; Belperio, John A; Looney, Mark R

2015-02-15

Primary graft dysfunction (PGD) causes early mortality after lung transplantation and may contribute to late graft failure. No effective treatments exist. The pathogenesis of PGD is unclear, although both neutrophils and activated platelets have been implicated. We hypothesized that neutrophil extracellular traps (NETs) contribute to lung injury in PGD in a platelet-dependent manner. To study NETs in experimental models of PGD and in lung transplant patients. Two experimental murine PGD models were studied: hilar clamp and orthotopic lung transplantation after prolonged cold ischemia (OLT-PCI). NETs were assessed by immunofluorescence microscopy and ELISA. Platelet activation was inhibited with aspirin, and NETs were disrupted with DNaseI. NETs were also measured in bronchoalveolar lavage fluid and plasma from lung transplant patients with and without PGD. NETs were increased after either hilar clamp or OLT-PCI compared with surgical control subjects. Activation and intrapulmonary accumulation of platelets were increased in OLT-PCI, and platelet inhibition reduced NETs and lung injury, and improved oxygenation. Disruption of NETs by intrabronchial administration of DNaseI also reduced lung injury and improved oxygenation. In bronchoalveolar lavage fluid from human lung transplant recipients, NETs were more abundant in patients with PGD. NETs accumulate in the lung in both experimental and clinical PGD. In experimental PGD, NET formation is platelet-dependent, and disruption of NETs with DNaseI reduces lung injury. These data are the first description of a pathogenic role for NETs in solid organ transplantation and suggest that NETs are a promising therapeutic target in PGD.

Public Perceptions of Ethical, Legal and Social Implications of Pre-implantation Genetic Diagnosis (PGD) in Malaysia.

PubMed

Olesen, Angelina P; Mohd Nor, Siti Nurani; Amin, Latifah; Che Ngah, Anisah

2017-12-01

Pre-implantation genetic diagnosis (PGD) became well known in Malaysia after the birth of the first Malaysian 'designer baby', Yau Tak in 2004. Two years later, the Malaysian Medical Council implemented the first and only regulation on the use of Pre-implantation Genetic Diagnosis in this country. The birth of Yau Tak triggered a public outcry because PGD was used for non-medical sex selection thus, raising concerns about PGD and its implications for the society. This study aims to explore participants' perceptions of the future implications of PGD for the Malaysian society. We conducted in-depth interviews with 21 participants over a period of one year, using a semi-structured questionnaire. Findings reveal that responses varied substantially among the participants; there was a broad acceptance as well as rejection of PGD. Contentious ethical, legal and social issues of PGD were raised during the discussions, including intolerance to and discrimination against people with genetic disabilities; societal pressure and the 'slippery slope' of PGD were raised during the discussions. This study also highlights participants' legal standpoint, and major issues regarding PGD in relation to the accuracy of diagnosis. At the social policy level, considerations are given to access as well as the impact of this technology on families, women and physicians. Given these different perceptions of the use of PGD, and its implications and conflicts, policies and regulations of the use of PGD have to be dealt with on a case-by-case basis while taking into consideration of the risk-benefit balance, since its application will impact the lives of so many people in the society.

Opposing roles of PGD2 in GBM.

PubMed

Ferreira, Matthew Thomas; Gomes, Renata Nascimento; Panagopoulos, Alexandros Theodoros; de Almeida, Fernando Gonçalves; Veiga, José Carlos Esteves; Colquhoun, Alison

2018-01-01

The World Health Organization classifies glioblastoma (GBM) as a grade IV astrocytoma. Despite the advances in chemotherapy, surgery, and radiation treatments that improve a patient's length of survival, the overall trajectory of the disease remains unchanged. GBM cells produce significant levels of various types of bioactive lipids. Prostaglandin D 2 (PGD 2 ) influences both pro- and anti-tumorigenic activities in the cell; however, its role in GBM is unclear. Therefore, this study aimed to identify the impact of PGD 2 on GBM cell activities in vitro. First we looked to identify the presence of the PGD 2 synthesis pathway through RT-PCR, immunohistochemistry, and HPLC-MS/MS in three GBM cell lines. Then, to observe PGD 2 's effects on cell count and apoptosis/mitosis (Hoechst 33342 stain), and migration (Transwell Assay), the cells were treated in vitro with physiological (<1μM) and/or supraphysiological (>1μM) concentrations of PGD 2 over 72h. HPLC-MS/MS was used to identify the lipid composition of patients with either Grade II/III gliomas or GBM. We identified the presence of endogenous PGD 2 with its corresponding enzymes and receptors. Exogenous PGD 2 both increased cell count (<1μM) and decreased cell count (10μM) in a concentration-dependent manner. There were no significant effects on apoptosis. A significant decrease in mitotic activity was seen only in U251MG, and a significant increase was seen in migration with 5μM PGD 2 treatments. A very significant increase of PGD 2 was seen from Grade II/III gliomas to GBM. Our study demonstrates that prostaglandin D 2 possesses a dynamic, concentration-dependent effect in GBM cell activities. The increase of PGD 2 production in GBM patients suggests a pro-tumorigenic role of PGD 2 in glioma growth and invasion. Therefore, prostaglandin signaling in GBM requires further investigation to identify new targets for more effective therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Ninety-day mortality and major complications are not affected by use of lung allocation score.

PubMed

McCue, Jonathan D; Mooney, Josh; Quail, Jacob; Arrington, Amanda; Herrington, Cynthia; Dahlberg, Peter S

2008-02-01

In May 2005 the Organ Procurement Transplant Network (OPTN) and United Network for Organ Sharing (UNOS) implemented the donor lung allocation score (LAS) system to prioritize organ allocation among prospective transplant recipients. The purpose of our study was to determine the impact of LAS implementation on 90-day survival, early complications and incidence of severe primary graft dysfunction (PGD) after the transplant procedure. Early outcomes among 78 patients receiving transplants after the initiation of the scoring system were compared with those of the 78 previous patients. Survival rates at 90 days and 1 year were the primary end-points of the study. Arterial blood-gas measurements were collected for all patients at the time of ICU arrival and at 12, 24 and 48 hours after surgery to determine the distribution of International Society of Heart and Lung Transplant (ISHLT) PGD grade. Major complications within 30 days post-transplant were recorded. We found a small but significant 1-year survival advantage among post-LAS implementation patients, which was largely due to decreased early mortality in comparison to the control cohort. The incidence of ISHLT Grade 3 PGD measured within the first 24 hours after transplant did not differ between groups, nor was there an increase in the rate of major post-operative complications. Implementation of the LAS system has not been associated with an increase in early mortality, immediate PGD or major complications.

The expression pattern of the Picea glauca Defensin 1 promoter is maintained in Arabidopsis thaliana, indicating the conservation of signalling pathways between angiosperms and gymnosperms.

PubMed

Germain, Hugo; Lachance, Denis; Pelletier, Gervais; Fossdal, Carl Gunnar; Solheim, Halvor; Séguin, Armand

2012-01-01

A 1149 bp genomic fragment corresponding to the 5' non-coding region of the PgD1 (Picea glauca Defensin 1) gene was cloned, characterized, and compared with all Arabidopsis thaliana defensin promoters. The cloned fragment was found to contain several motifs specific to defence or hormonal response, including a motif involved in the methyl jasmonate reponse, a fungal elicitor responsive element, and TC-rich repeat cis-acting element involved in defence and stress responsiveness. A functional analysis of the PgD1 promoter was performed using the uidA (GUS) reporter system in stably transformed Arabidopsis and white spruce plants. The PgD1 promoter was responsive to jasmonic acid (JA), to infection by fungus and to wounding. In transgenic spruce embryos, GUS staining was clearly restricted to the shoot apical meristem. In Arabidopsis, faint GUS coloration was observed in leaves and flowers and a strong blue colour was observed in guard cells and trichomes. Transgenic Arabidopsis plants expressing the PgD1::GUS construct were also infiltrated with the hemibiotrophic pathogen Pseudomonas syringae pv. tomato DC3000. It caused a suppression of defensin expression probably resulting from the antagonistic relationship between the pathogen-stimulated salicylic acid pathway and the jasmonic acid pathway. It is therefore concluded that the PgD1 promoter fragment cloned appears to contain most if not all the elements for proper PgD1 expression and that these elements are also recognized in Arabidopsis despite the phylogenetic and evolutionary differences that separates them.

Ethics of PGD: thoughts on the consequences of typing HLA in embryos.

PubMed

Edwards, R G

2004-08-01

As with so many fields of study associated with assisted human reproduction, many ethical issues are raised by the practice of preimplantation diagnosis of inherited disease (PGD). Some are part and parcel of assisted conception, e.g.the rights of human embryos in vitro and of embryologists to establish them, carry out research and discard them. Others unique to clinical PGD were discussed at an earlier meeting on PGD (Edwards et al., 2003). Recent developments in PGD are discussed briefly in this Commentary, especially the ethics of designer babies.

Neutrophil Extracellular Traps Are Pathogenic in Primary Graft Dysfunction after Lung Transplantation

PubMed Central

Mallavia, Beñat; Liu, Fengchun; Ortiz-Muñoz, Guadalupe; Caudrillier, Axelle; DerHovanessian, Ariss; Ross, David J.; Lynch III, Joseph P.; Saggar, Rajan; Ardehali, Abbas; Ware, Lorraine B.; Christie, Jason D.; Belperio, John A.; Looney, Mark R.

2015-01-01

Rationale: Primary graft dysfunction (PGD) causes early mortality after lung transplantation and may contribute to late graft failure. No effective treatments exist. The pathogenesis of PGD is unclear, although both neutrophils and activated platelets have been implicated. We hypothesized that neutrophil extracellular traps (NETs) contribute to lung injury in PGD in a platelet-dependent manner. Objectives: To study NETs in experimental models of PGD and in lung transplant patients. Methods: Two experimental murine PGD models were studied: hilar clamp and orthotopic lung transplantation after prolonged cold ischemia (OLT-PCI). NETs were assessed by immunofluorescence microscopy and ELISA. Platelet activation was inhibited with aspirin, and NETs were disrupted with DNaseI. NETs were also measured in bronchoalveolar lavage fluid and plasma from lung transplant patients with and without PGD. Measurements and Main Results: NETs were increased after either hilar clamp or OLT-PCI compared with surgical control subjects. Activation and intrapulmonary accumulation of platelets were increased in OLT-PCI, and platelet inhibition reduced NETs and lung injury, and improved oxygenation. Disruption of NETs by intrabronchial administration of DNaseI also reduced lung injury and improved oxygenation. In bronchoalveolar lavage fluid from human lung transplant recipients, NETs were more abundant in patients with PGD. Conclusions: NETs accumulate in the lung in both experimental and clinical PGD. In experimental PGD, NET formation is platelet-dependent, and disruption of NETs with DNaseI reduces lung injury. These data are the first description of a pathogenic role for NETs in solid organ transplantation and suggest that NETs are a promising therapeutic target in PGD. PMID:25485813

Psychosocial development of full term singletons, born after preimplantation genetic diagnosis (PGD) at preschool age and family functioning: a prospective case-controlled study and multi-informant approach.

PubMed

Winter, C; Van Acker, F; Bonduelle, M; Desmyttere, S; Nekkebroeck, J

2015-05-01

Do full term singletons born after preimplantation genetic diagnosis (PGD) differ in their psychosocial functioning from children born after intracytoplasmic sperm injection (ICSI) and spontaneous conceived controls (SC)? The psychosocial maturation process of 5-6-year-old PGD children is comparable between the three conception groups (PGD, ICSI and SC). In general, a lot of research has been published regarding follow-up of children born after artificial reproductive technologies (ART), which mainly is reassuring. But the ART population itself is marked by broad diversity [IVF, ICSI, gamete donation, preimplantation genetic screening (PGS) or PGD] which complicates comparisons. Some literature concerning the socio-emotional development of PGD/PGS children is available and it suggests a normal maturation process. However, the complex reality of PGD families (e.g. safety of the technique and psychological burden of genetic histories) asks for an exclusive PGD sample with matched control groups and a multi-informant approach. Between April 2011 and May 2013, the psychosocial wellbeing of preschoolers and their families born after PGD was assessed in a prospective case-controlled, matched follow-up study, with a multi-informant approach. A group of 47 PGD, 50 ICSI and 55 SC 5-6-year-old children participated in a follow-up study performed at the Centre for Medical Genetics of the Universitair Ziekenhuis Brussel (UZ Brussel). Assessments took place in the hospital and in kindergartens. Children performed the Bene-Anthony family relations test (FRT), yielding their perceptions upon family relationships. Parents and teachers completed the child behaviour checklist (CBCL) and Caregiver Teacher Report Form (C-/TRF), respectively. Parental and family functioning were measured by the NEO-FFi, the parenting stress index (PSI), the Greenberger Work-Parenting Investment Questionnaire and the Marlowe-Crowne Social Desirability Scale (MCSDS). Statistical analysis was performed by using analysis of covariance (ANCOVA). No differences were detected between the psychosocial development of PGD children and the control groups. Parents did not differ in reporting problem behaviour and they were stricter than teachers. Concerning family functioning the ART parents scored comparable with each other. PGD and ICSI mothers were emotionally more stable [NEO-FFi Neuroticism/emotionality: P = 0.013, η(2) = 0.066; 95% confidence interval (CI) 95% (0.003;0.148)]. They experienced less parental stress in general [PSI, Total stress: P = 0.001, η(2) = 0.102, 95% CI (0.02;0.192)] and on different sublevels opposed to their SC counterparts. Yet ART mothers presented higher ratings on the NEO-FFi Conscientiousness [P = 0.011, η(2) = 0.064; 95% CI (0.003;0.144)] indicating a higher feeling of competence and goal directedness. Mediation analysis confirmed: PGD and ICSI mothers who experienced less family stress were emotionally more stable. A power analysis indicated that a sample with 152 children is sufficient to detect a medium size effect with 80% power using ANCOVA. The current sample comprised only Dutch speaking Caucasians, hence conclusions should be drawn cautiously. Future research should include larger groups, prematures, multiples and children from different cultural backgrounds. This current research is the first to compare PGD preschoolers with matched controls. Concerns about the behavioural effects on the offspring should not inhibit the use of PGD. Furthermore, our findings suggest that on the long run ART procedures might enhance personal resources of women to cope with family stress. These findings are reassuring for women who might feel insecure and anxious during their ART trajectory. This research project gained funding from the OZR (a grant by the Research group of the Vrije Universiteit Brussel), the FWO (Fonds Wetenschappelijk Onderzoek) and the Wetenschappelijk Fonds Willy Gepts. The UZ Brussel and the Centre of Medical Genetics received funding from pharmaceutical firms for data collection. UZ Brussel and the Centre for Medical Genetics have received many educational grants for organizing the data collection, from IBSA, Ferring, Organon, Shering-Plough, Merck and Merck Belgium. M.B. has received consultancy and speaker's fees from Organon, Serono Symposia and Merck. The other authors have no competing interests. not applicable. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Serum tryptase level is a better predictor of systemic side effects than prostaglandin D2 metabolites during venom immunotherapy in children.

PubMed

Cichocka-Jarosz, E; Sanak, M; Szczeklik, A; Brzyski, P; Gielicz, A; Pietrzyk, J J

2011-01-01

We performed a prospective study to analyze mast cell mediators as predictors of systemic adverse reactions during rush venom-specific immunotherapy (VIT) in children. Nineteen children aged 5-17 years received VIT with Venomenhal (HALAllergy). We analyzed serum tryptase (CAP, Phadia), plasma prostaglandin (PG) D2 metabolites (9alpha, 11beta-PGF2), and urine PGD2 metabolites (9alpha, 11beta-PGF2, tetranor-PGD-M) using gas chromatography mass spectrometry before and after the rush protocol. Three boys with high baseline serum tryptase values (>7.76 g/L) (P < .001) and low 9alpha, 11beta-PGF2 concentrations developed grade III systemic adverse reactions during VIT. Baseline serum tryptase was lowest in children who had a Mueller grade II reaction (1.93 [0.36]) before VIT and highest in children with a Mueller grade III reaction (6.31 [4.80]) (P = .029). Repeated measures analysis of variance confirmed that, in children who developed systemic adverse reactions during VIT, serum tryptase was higher both before and after desensitization and increased significantly following the procedure. Analysis of PGD2 metabolites in the prediction of systemic adverse reactions during VIT was inadequate (sensitivity 67% and specificity 0.53%), whilst prediction based on serum tryptase was accurate. In children with severe systemic adverse reactions to Hymenoptera sting, the evaluation of baseline tryptase levels should be a standard procedure. Children with Apis mellifera venom allergy and baseline tryptase levels higher than 7.75 g/L are at risk of anaphylaxis during buildup. Lower baseline values of plasma and urinary PGD2 metabolite concentration in patients with systemic adverse reaction during VIT suggest that prostaglandin catabolism is altered.

Preimplantation genetic diagnosis with HLA matching.

PubMed

Rechitsky, Svetlana; Kuliev, Anver; Tur-Kaspa, Illan; Morris, Randy; Verlinsky, Yury

2004-08-01

Preimplantation genetic diagnosis (PGD) has recently been offered in combination with HLA typing, which allowed a successful haematopoietic reconstitution in affected siblings with Fanconi anaemia by transplantation of stem cells obtained from the HLA-matched offspring resulting from PGD. This study presents the results of the first PGD practical experience performed in a group of couples at risk for producing children with genetic disorders. These parents also requested preimplantation HLA typing for treating the affected children in the family, who required HLA-matched stem cell transplantation. Using a standard IVF procedure, oocytes or embryos were tested for causative gene mutations simultaneously with HLA alleles, selecting and transferring only those unaffected embryos, which were HLA matched to the affected siblings. The procedure was performed for patients with children affected by Fanconi anaemia (FANC) A and C, different thalassaemia mutations, Wiscott-Aldrich syndrome, X-linked adrenoleukodystrophy, X-linked hyperimmunoglobulin M syndrome and X-linked hypohidrotic ectodermal displasia with immune deficiency. Overall, 46 PGD cycles were performed for 26 couples, resulting in selection and transfer of 50 unaffected HLA-matched embryos in 33 cycles, yielding six HLA-matched clinical pregnancies and the birth of five unaffected HLA-matched children. Despite the controversy of PGD use for HLA typing, the data demonstrate the usefulness of this approach for at-risk couples, not only to avoid the birth of affected children with an inherited disease, but also for having unaffected children who may also be potential HLA-matched donors of stem cells for treatment of affected siblings.

Elevated rates of prolonged grief disorder in African Americans.

PubMed

Goldsmith, B; Morrison, R S; Vanderwerker, L C; Prigerson, H G

2008-01-01

The prevalence of Prolonged Grief Disorder (PGD) in non-Whites is currently unknown. This study was performed to explore the prevalence of PGD in African Americans (AAs). Multivariable analysis of two studies of recently bereaved individuals found AAs to have significantly higher rates of PGD than Whites (21% [14 of 66] vs. 12% [55 of 471], respectively; p = 0.03). Experiencing a loved one's death as sudden or unexpected was also significantly associated with PGD over and above the effects of race/ethnicity. AAs may be at increased risk for the development of PGD. The development of effective interventions to treat PGD highlights the need to identify high-risk individuals and refer them to therapy and suggests the potential need for such therapies to adopt culturally sensitive approaches to care.

Rates and risks for prolonged grief disorder in a sample of orphaned and widowed genocide survivors

PubMed Central

2010-01-01

Background The concept of Prolonged Grief Disorder (PGD) has been defined in recent years by Prigerson and co-workers, who have developed and empirically tested consensus and diagnostic criteria for PGD. Using these most recent criteria defining PGD, the aim of this study was to determine rates of and risks for PGD in survivors of the 1994 Rwandan genocide who had lost a parent and/or the husband before, during or after the 1994 events. Methods The PG-13 was administered to 206 orphans or half orphans and to 194 widows. A regression analysis was carried out to examine risk factors of PGD. Results 8.0% (n = 32) of the sample met criteria for PGD with an average of 12 years post-loss. All but one person had faced multiple losses and the majority indicated that their grief-related loss was due to violent death (70%). Grief was predicted mainly by time since the loss, by the violent nature of the loss, the severity of symptoms of posttraumatic stress disorder (PTSD) and the importance given to religious/spiritual beliefs. By contrast, gender, age at the time of bereavement, bereavement status (widow versus orphan), the number of different types of losses reported and participation in the funeral ceremony did not impact the severity of prolonged grief reactions. Conclusions A significant portion of the interviewed sample continues to experience grief over interpersonal losses and unresolved grief may endure over time if not addressed by clinical intervention. Severity of grief reactions may be associated with a set of distinct risk factors. Subjects who lose someone through violent death seem to be at special risk as they have to deal with the loss experience as such and the traumatic aspects of the loss. Symptoms of PTSD may hinder the completion of the mourning process. Religious beliefs may facilitate the mourning process and help to find meaning in the loss. These aspects need to be considered in the treatment of PGD. PMID:20604936

PGD for inherited cardiac diseases.

PubMed

Kuliev, Anver; Pomerantseva, Ekaterina; Polling, Dana; Verlinsky, Oleg; Rechitsky, Svetlana

2012-04-01

Preimplantation genetic diagnosis (PGD) has been applied for more than 200 different inherited conditions, with expanding application to common disorders with genetic predisposition. One of the recent indications for PGD has been inherited cardiac disease, for which no preclinical diagnosis and preventive management may exist and which may lead to premature or sudden death. This paper presents the first, as far as is known, cumulative experience of PGD for inherited cardiac diseases, including familial hypertrophic and dilated cardiomyopathy, cardioencephalomyopathy and Emery-Dreifuss muscular dystrophy. A total of 18 PGD cycles were performed, resulting in transfer in 15 of them, which yielded nine unaffected pregnancies and the births of seven disease- or disease predisposition-free children. The data open the prospect of PGD for inherited cardiac diseases, allowing couples carrying cardiac disease predisposing genes to reproduce without much fear of having offspring with these genes, which are at risk for premature or sudden death. Preimplantation genetic diagnosis (PGD) is currently an established clinical procedure in assisted reproduction and genetic practices. Its application has been expanding beyond traditional indications of prenatal diagnosis and currently includes common disorders with genetic predisposition, such as inherited forms of cancer. This applies also to the diseases with no current prospect of treatment, which may manifest despite presymptomatic diagnosis and follow up, when PGD may provide the only relief for the at-risk couples to reproduce. One of the recent indications for PGD has been inherited cardiac disease, for which no preclinical diagnosis and preventive management may exist and which may lead to premature or sudden death. We present here our first cumulative experience of PGD for inherited cardiac diseases, including familial hypertrophic and dilated cardiomyopathy, cardioencephalomyopathy and Emery-Dreifuss muscular dystrophy. A total of 18 PGD cycles for these disorders was performed, resulting in transfer in 15 of them, which yielded nine unaffected pregnancies and birth of seven disease- or disease predisposition-free children. The data open the prospect of PGD for inherited cardiac diseases, allowing couples carrying cardiac disease predisposing genes to reproduce without much fear of having offspring with these genes at risk for premature or sudden death. Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Graft dysfunction immediately after reperfusion predicts short-term outcomes in living-donor lobar lung transplantation but not in cadaveric lung transplantation

PubMed Central

Mizota, Toshiyuki; Miyao, Mariko; Yamada, Tetsu; Sato, Masaaki; Aoyama, Akihiro; Chen, Fengshi; Date, Hiroshi; Fukuda, Kazuhiko

2016-01-01

OBJECTIVES Primary graft dysfunction (PGD) is a major cause of early morbidity and mortality after cadaveric lung transplantation (CLT). This study examined the incidence, time course and predictive value of PGD after living-donor lobar lung transplantation (LDLLT). METHODS We retrospectively investigated 75 patients (42 with LDLLT and 33 with CLT) who underwent lung transplantation from January 2008 to December 2013. Patients were assigned PGD grades at six time points, as defined by the International Society for Heart and Lung Transplantation: immediately after final reperfusion, upon arrival at the intensive care unit (ICU), and 12, 24, 48 and 72 h after ICU admission. RESULTS The incidence of severe (Grade 3) PGD at 48 or 72 h after ICU admission was similar for LDLLT and CLT patients (16.7 vs 12.1%; P = 0.581). The majority of the LDLLT patients having severe PGD first developed PGD immediately after reperfusion, whereas more than half of the CLT patients first developed severe PGD upon ICU arrival or later. In LDLLT patients, severe PGD immediately after reperfusion was significantly associated with fewer ventilator-free days during the first 28 postoperative days [median (interquartile range) of 0 (0–10) vs 21 (13–25) days, P = 0.001], prolonged postoperative ICU stay [median (interquartile range) of 20 (16–27) vs 12 (8–14) days, P = 0.005] and increased hospital mortality (27.3 vs 3.2%, P = 0.02). Severe PGD immediately after reperfusion was not associated with ventilator-free days during the first 28 postoperative days, time to discharge from ICU or hospital, or hospital mortality in CLT patients. CONCLUSIONS Postoperative incidence of severe PGD was not significantly different between LDLLT and CLT patients. In LDLLT patients, the onset of severe PGD tended to be earlier than that in CLT patients. Severe PGD immediately after reperfusion was a significant predictor of postoperative morbidity and mortality in LDLLT patients but not in CLT patients. PMID:26705301

Graft dysfunction immediately after reperfusion predicts short-term outcomes in living-donor lobar lung transplantation but not in cadaveric lung transplantation.

PubMed

Mizota, Toshiyuki; Miyao, Mariko; Yamada, Tetsu; Sato, Masaaki; Aoyama, Akihiro; Chen, Fengshi; Date, Hiroshi; Fukuda, Kazuhiko

2016-03-01

Primary graft dysfunction (PGD) is a major cause of early morbidity and mortality after cadaveric lung transplantation (CLT). This study examined the incidence, time course and predictive value of PGD after living-donor lobar lung transplantation (LDLLT). We retrospectively investigated 75 patients (42 with LDLLT and 33 with CLT) who underwent lung transplantation from January 2008 to December 2013. Patients were assigned PGD grades at six time points, as defined by the International Society for Heart and Lung Transplantation: immediately after final reperfusion, upon arrival at the intensive care unit (ICU), and 12, 24, 48 and 72 h after ICU admission. The incidence of severe (Grade 3) PGD at 48 or 72 h after ICU admission was similar for LDLLT and CLT patients (16.7 vs 12.1%; P = 0.581). The majority of the LDLLT patients having severe PGD first developed PGD immediately after reperfusion, whereas more than half of the CLT patients first developed severe PGD upon ICU arrival or later. In LDLLT patients, severe PGD immediately after reperfusion was significantly associated with fewer ventilator-free days during the first 28 postoperative days [median (interquartile range) of 0 (0-10) vs 21 (13-25) days, P = 0.001], prolonged postoperative ICU stay [median (interquartile range) of 20 (16-27) vs 12 (8-14) days, P = 0.005] and increased hospital mortality (27.3 vs 3.2%, P = 0.02). Severe PGD immediately after reperfusion was not associated with ventilator-free days during the first 28 postoperative days, time to discharge from ICU or hospital, or hospital mortality in CLT patients. Postoperative incidence of severe PGD was not significantly different between LDLLT and CLT patients. In LDLLT patients, the onset of severe PGD tended to be earlier than that in CLT patients. Severe PGD immediately after reperfusion was a significant predictor of postoperative morbidity and mortality in LDLLT patients but not in CLT patients. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Influence of right ventricular function on the development of primary graft dysfunction after lung transplantation.

PubMed

Pérez-Terán, Purificación; Roca, Oriol; Rodríguez-Palomares, José; Sacanell, Judit; Leal, Sandra; Solé, Joan; Rochera, María I; Román, Antonio; Ruiz-Rodríguez, Juan C; Gea, Joaquim; Evangelista, Arturo; Masclans, Joan R

2015-11-01

Primary graft dysfunction (PGD) remains a significant cause of lung transplant postoperative morbidity and mortality. The underlying mechanisms of PGD development are not completely understood. This study analyzed the effect of right ventricular function (RVF) on PGD development. A retrospective analysis of a prospectively assessed cohort was performed at a single institution between July 2010 and June 2013. The primary outcome was development of PGD grade 3 (PGD3). Conventional echocardiographic parameters and speckle-tracking echocardiography, performed during the pre-transplant evaluation phase up to 1 year before surgery, were used to assess preoperative RVF. Included were 120 lung transplant recipients (LTr). Systolic pulmonary arterial pressure (48 ± 20 vs 41 ± 18 mm Hg; p = 0.048) and ischemia time (349 ± 73 vs 306 ± 92 minutes; p < 0.01) were higher in LTr who developed PGD3. Patients who developed PGD3 had better RVF estimated by basal free wall longitudinal strain (BLS; -24% ± 9% vs -20% ± 6%; p = 0.039) but had a longer intensive care unit length of stay and mechanical ventilation and higher 6-month mortality. BLS ≥ -21.5% was the cutoff that best identified patients developing PGD3 (area under the receiver operating characteristic curve, 0.70; 95% confidence interval, 0.54-0.85; p = 0.020). In the multivariate analysis, a BLS ≥ -21.5% was an independent risk factor for PGD3 development (odds ratio, 4.56; 95% confidence interval, 1.20-17.38; p = 0.026), even after adjusting for potential confounding. A better RVF, as measured by BLS, is a risk factor for severe PGD. Careful preoperative RVF assessment using speckle-tracking echocardiography may identify LTrs with the highest risk of developing PGD. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Lung size mismatch and primary graft dysfunction after bilateral lung transplantation *

PubMed Central

Eberlein, Michael; Reed, Robert M.; Bolukbas, Servet; Wille, Keith M.; Orens, Jonathan B.; Brower, Roy G.; Christie, Jason D.

2014-01-01

BACKGROUND Donor to recipient lung size matching at lung transplantation (LTx) can be estimated by the predicted total lung capacity (pTLC)ratio (donor pTLC/recipient pTLC). We aimed to determine whether the pTLC-ratio is associated with the risk of primary graft dysfunction (PGD) after bilateral LTx (BLT). METHODS We calculated the pTLC-ratio for 812 adult BLTs from the Lung Transplant Outcomes Group between 3/2002-12/2010. Patients were stratified by pTLC-ratio>1.0 (“oversized”) and pTLC-ratio≤1.0 (“undersized”). PGD was defined as any ISHLT grade 3 PGD within 72 hours of reperfusion (PGD 3). We analyzed the association between risk factors and PGD using multivariable conditional logistic regression. As transplant diagnoses can influence the size matching decisions and also modulate the risk for PGD, we performed pre-specified analyses by assessing the impact of lung size mismatch within diagnostic categories. RESULTS In univariate analyses oversizing was associated with a 39% lower odds of PGD3 (OR 0.61, 95% CI, p=0.003). In a multivariate model accounting for center effects and known PGD risks, oversizing remained independently associated with a decreased odds of PGD3 (OR 0.58, 95% CI 0.38-0.88, p=0.01). The risk adjusted point estimate was similar for the non-COPD diagnoses groups (OR 0.52, 95%CI 0.32-0.86, p=0.01); however there was no detected association within the COPD group (OR 0.72, 95% CI 0.29-1.78, p=0.5). CONCLUSION Oversized allografts are associated with a decreased risk of PGD3 after BLT; this effect appears most apparent in non-COPD patients. PMID:25447586

An analysis of US fertility centre educational materials suggests that informed consent for preimplantation genetic diagnosis may be inadequate.

PubMed

LaBonte, Michelle Lynne

2012-08-01

The use of preimplantation genetic diagnosis (PGD) has expanded both in number and scope over the past 2 decades. Initially carried out to avoid the birth of children with severe genetic disease, PGD is now used for a variety of medical and non-medical purposes. While some human studies have concluded that PGD is safe, animal studies and a recent human study suggest that the embryo biopsy procedure may result in neurological problems for the offspring. Given that the long-term safety of PGD has not been clearly established in humans, this study sought to determine how PGD safety is presented to prospective patients by means of a detailed website analysis. The websites of 262 US fertility centres performing PGD were analysed and comments about safety and risk were catalogued. Results of the analysis demonstrated that 78.2% of centre websites did not mention safety or risk of PGD at all. Of the 21.8% of centres that did contain safety or risk information about PGD, 28.1% included statements highlighting the potential risks, 38.6% presented information touting the procedure as safe and 33.3% included statements highlighting potential risks and the overall safety of the procedure. Thus, 86.6% of PGD-performing centres state that PGD is safe and/or fail to disclose any risks on their websites despite the fact that the impact of the procedure on the long-term health of offspring is unproven. This lack of disclosure suggests that informed consent is inadequate; this study examines numerous factors that are likely to inhibit comprehensive discussions of safety.

Comparative preimplantation genetic diagnosis policy in Europe and the USA and its implications for reproductive tourism

PubMed Central

Bayefsky, Michelle J

2017-01-01

Unlike many European nations, the USA has no regulations concerning the use of preimplantation genetic diagnosis (PGD), a technique employed during some fertility treatments to select embryos based on their genes. As such, PGD can and is used for a variety of controversial purposes, including sex selection, selection for children with disabilities such as deafness, and selection for ‘saviour siblings’ who can serve as tissue donors for sick relatives. The lack of regulation, which is due to particular features of the US political and economic landscape, has ethical and practical implications for patients seeking PGD around the world. This paper contrasts the absence of PGD oversight in the USA with existing PGD policies in Switzerland, Italy, France and the UK. The primary reasons why PGD is not regulated in the USA are addressed, with consideration of factors such as funding for assisted reproductive technology treatmemt and the proximity of PGD to the contentious abortion debate. The obstacles that would need to be overcome in the USA for PGD to be regulated in the future are outlined. Then, the significance of the current divergence in PGD policy for patients around the world are discussed. Regulatory differences create opportunities for reproductive tourism, which result in legal, health and moral challenges. The paper concludes with comments on the need for policymakers around the world to balance respect for the characters and constitutions of their individual countries with appreciation of the needs of infertile patients across the globe. PMID:28959787

Primary Cardiac Allograft Dysfunction-Validation of a Clinical Definition.

PubMed

Dronavalli, Vamsidhar B; Rogers, Chris A; Banner, Nicholas R

2015-09-01

Heart transplantation is an established treatment for advanced heart failure. Primary allograft dysfunction (PGD) is reported in up to 40% of transplants and is associated with a poor outcome. As part of Heart Evaluation and Retrieval for Transplantation study, an investigation of the assessment of donor hearts for transplantation, we proposed a clinical definition for cardiac PGD comprising severely impaired systolic function affecting one or both ventricles accompanied by hypotension, low cardiac output, and high filling pressures occurring in the first 72 hours (in the absence of hyper acute rejection and technical surgical factors, such as cardiac tamponade). Here, we examine the prospective application of this definition to 290 heart transplants. We compared the clinical outcome of PGD and non-PGD cases. Ninety-four of 290 transplants developed PGD (32.4%). Inotrope use (score) was higher in the PGD group at 24, 48, and 72 hours after transplantation (P < 0.01). In the PGD group, there was a greater requirement for, intra-aortic balloon pump (50% vs 15%, P < 0.01), mechanical support (27% vs 0%, P < 0.01), and renal replacement therapy (61% vs 26%, P < 0.01). Intensive care stay was longer for recipients with PGD (median 14 vs 5 days, P < 0.01) and early mortality was higher (37% vs 4% at 30 days, 42% vs 8% at 1 year, P < 0.01). In conclusion, our definition of PGD could be applied in a national multicenter study, and the cases it defined had more frequent complications and higher mortality.

Factors Influencing the Decision-Making Process and Long-Term Interpersonal Outcomes for Parents Who Undergo Preimplantation Genetic Diagnosis for Fanconi Anemia: a Qualitative Investigation.

PubMed

Haude, K; McCarthy Veach, P; LeRoy, B; Zierhut, H

2017-06-01

Fanconi anemia (FA) is characterized by congenital malformations, progressive bone marrow failure, and predisposition to malignancy. Hematopoietic stem cell transplantation is used to treat FA, and best results are attained with sibling donors who are human leukocyte antigen (HLA) identical matches. Preimplantation genetic diagnosis (PGD) offers parents of an affected child the opportunity to have an unaffected child who is an HLA match. While some research has investigated parents' experiences during the PGD process, no published studies specifically address factors influencing their decision-making process and long-term interpersonal outcomes. The aims of this study are to: (1) examine parents' expectations and the influence of media, bioethics, and religion on their decision to undergo PGD; (2) examine parents' social support and emotional experiences during their PGD process; and (3) characterize long-term effects of PGD on relationship dynamics (partner, family, friends), others' attitudes, and parental regret. Nine parents participated in semi-structured interviews. Thematic analysis revealed their decision to use PGD was variously influenced by media, bioethics, and religion, in particular, affecting parents' initial confidence levels. Moreover, the PGD process was emotionally complex, with parents desiring varying amounts and types of support from different sources at different times. Parents reported others' attitudes towards them were similar or no different than before PGD. Parental regret regarding PGD was negligible. Results of this study will promote optimization of long-term care for FA families.

Comparative preimplantation genetic diagnosis policy in Europe and the USA and its implications for reproductive tourism.

PubMed

Bayefsky, Michelle J

2016-12-01

Unlike many European nations, the USA has no regulations concerning the use of preimplantation genetic diagnosis (PGD), a technique employed during some fertility treatments to select embryos based on their genes. As such, PGD can and is used for a variety of controversial purposes, including sex selection, selection for children with disabilities such as deafness, and selection for 'saviour siblings' who can serve as tissue donors for sick relatives. The lack of regulation, which is due to particular features of the US political and economic landscape, has ethical and practical implications for patients seeking PGD around the world. This paper contrasts the absence of PGD oversight in the USA with existing PGD policies in Switzerland, Italy, France and the UK. The primary reasons why PGD is not regulated in the USA are addressed, with consideration of factors such as funding for assisted reproductive technology treatmemt and the proximity of PGD to the contentious abortion debate. The obstacles that would need to be overcome in the USA for PGD to be regulated in the future are outlined. Then, the significance of the current divergence in PGD policy for patients around the world are discussed. Regulatory differences create opportunities for reproductive tourism, which result in legal, health and moral challenges. The paper concludes with comments on the need for policymakers around the world to balance respect for the characters and constitutions of their individual countries with appreciation of the needs of infertile patients across the globe.

Lipocalin-type prostaglandin D synthase-derived PGD2 attenuates malignant properties of tumor endothelial cells.

PubMed

Omori, Keisuke; Morikawa, Teppei; Kunita, Akiko; Nakamura, Tatsuro; Aritake, Kosuke; Urade, Yoshihiro; Fukayama, Masashi; Murata, Takahisa

2018-01-01

Endothelial cells (ECs) are a key component of the tumor microenvironment. They have abnormal characteristics compared to the ECs in normal tissues. Here, we found a marked increase in lipocalin-type prostaglandin D synthase (L-PGDS) mRNA (Ptgds) expression in ECs isolated from mouse melanoma. Immunostaining of mouse melanoma revealed expression of L-PGDS protein in the ECs. In situ hybridization also showed L-PGDS (PTGDS) mRNA expression in the ECs of human melanoma and oral squamous cell carcinoma. In vitro experiments showed that stimulation with tumor cell-derived IL-1 and TNF-α increased L-PGDS mRNA expression and its product prostaglandin D 2 (PGD 2 ) in human normal ECs. We also investigated the contribution of L-PGDS-PGD 2 to tumor growth and vascularization. Systemic or EC-specific deficiency of L-PGDS accelerated the growth of melanoma in mice, whereas treatment with an agonist of the PGD 2 receptor, DP1 (BW245C, 0.1 mg/kg, injected intraperitoneally twice daily), attenuated it. Morphological and in vivo studies showed that endothelial L-PGDS deficiency resulted in functional changes of tumor ECs such as accelerated vascular hyperpermeability, angiogenesis, and endothelial-to-mesenchymal transition (EndMT) in tumors, which in turn reduced tumor cell apoptosis. These observations suggest that tumor cell-derived inflammatory cytokines increase L-PGDS expression and subsequent PGD 2 production in the tumor ECs. This PGD 2 acts as a negative regulator of the tumorigenic changes in tumor ECs. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Delta 12-prostaglandin J2, a plasma metabolite of prostaglandin D2, causes eosinophil mobilization from the bone marrow and primes eosinophils for chemotaxis.

PubMed

Heinemann, Akos; Schuligoi, Rufina; Sabroe, Ian; Hartnell, Adele; Peskar, Bernhard A

2003-05-01

PGD(2), a major mast cell mediator, is a potent eosinophil chemoattractant and is thought to be involved in eosinophil recruitment to sites of allergic inflammation. In plasma, PGD(2) is rapidly transformed into its major metabolite delta(12)-PGJ(2), the effect of which on eosinophil migration has not yet been characterized. In this study we found that delta(12)-PGJ(2) was a highly effective chemoattractant and inducer of respiratory burst in human eosinophils, with the same efficacy as PGD(2), PGJ(2), or 15-deoxy-delta(12,14)-PGJ(2). Moreover, pretreatment of eosinophils with delta(12)-PGJ(2) markedly enhanced the chemotactic response to eotaxin, and in this respect delta(12)-PGJ(2) was more effective than PGD(2). delta(12)-PGJ(2)-induced facilitation of eosinophil migration toward eotaxin was not altered by specific inhibitors of intracellular signaling pathways relevant to the chemotactic response, phosphatidylinositol 3-kinase (LY-294002), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (U-0126), or p38 mitogen-activated protein kinase (SB-202190). Desensitization studies using calcium flux suggested that delta(12)-PGJ(2) signaled through the same receptor, CRTH2, as PGD(2). Finally, delta(12)-PGJ(2) was able to mobilize mature eosinophils from the bone marrow of the guinea pig isolated perfused hind limb. Given that delta(12)-PGJ(2) is present in the systemic circulation at relevant levels, a role for this PGD(2) metabolite in eosinophil release from the bone marrow and in driving eosinophil recruitment to sites of inflammation appears conceivable.

Successful application of preimplantation genetic diagnosis for Leigh syndrome.

PubMed

Unsal, Evrim; Aktaş, Yasemin; Uner, Ozge; BaltacI, Aysun; Ozcan, Sarp; Turhan, Feriba; Baltaci, Volkan

2008-11-01

To perform preimplantation genetic diagnosis (PGD) for a SURF1 gene mutation of the Leigh syndrome to transfer unaffected or carrier embryo/embryos. Case report. Clinical IVF laboratory. A couple carrying an nt769 G/A mutation that is associated with Leigh syndrome. Oocytes were fertilized by means of intracytoplasmic sperm injection. The resulting embryos were biopsied 3 days after fertilization. One blastomere was taken and whole-genome amplification was performed. Amplification of the mutation site was achieved by polymerase chain reaction (PCR) and restriction digestion was completed. Gel Imager was used to measure the digests of normal and mutant load. Embryo testing by means of PGD-PCR and pregnancy. Successful preimplantation genetic diagnosis for a SURF1 gene mutation and transfer of healthy or carrier embryos. Successful singleton pregnancy resulting in the delivery of healthy baby girl. We report the first case of successful PGD for Leigh syndrome resulting in delivery of a healthy newborn.

PGD to reduce reproductive risk: the case of mitochondrial DNA disorders.

PubMed

Bredenoord, A L; Dondorp, W; Pennings, G; De Die-Smulders, C E M; De Wert, G

2008-11-01

This paper discusses the pros and cons of introducing PGD for mitochondrial DNA (mtDNA) disorders such as NARP (Neurogenic muscle weakness, Ataxia, Retinis Pigmentosa)/Leigh, MELAS (Mitochondrial myopathy, Encephalopathy, Lactic acidosis, and Stroke-like episodes), private mtDNA mutations and LHON (Leber Hereditary Optic Neuropathy). Although there is little experience with PGD for mtDNA disorders, it is reasonable to assume that in many cases, the best one can achieve is the selection of the 'least' affected embryos for transfer. So instead of 'promising' parents a healthy child, PGD in these cases can only aim at reducing reproductive risk. From an ethical point of view, this raises challenging questions about parental and medical responsibilities. The main argument in favour of PGD is that it offers couples at risk the opportunity of reducing their chances of having a severely affected child. Potential objections are manifold, but we conclude that none of them supplies convincing moral arguments to regard risk-reducing PGD as unacceptable. Nevertheless, introducing this new application of PGD in clinical practice will raise further complex issues of determining conditions for its responsible use.

Preimplantation genetic diagnosis as a strategy to prevent having a child born with an heritable eye disease.

PubMed

Yahalom, Claudia; Macarov, Michal; Lazer-Derbeko, Galit; Altarescu, Gheona; Imbar, Tal; Hyman, Jordana H; Eldar-Geva, Talia; Blumenfeld, Anat

2018-05-21

In developed countries, genetically inherited eye diseases are responsible for a high percentage of childhood visual impairment. We aim to report our experience using preimplantation genetic diagnostics (PGD) in order to avoid transmitting a genetic form of eye disease associated with childhood visual impairment and ocular cancer. Retrospective case series of women who underwent in vitro fertilization (IVF) and PGD due to a familial history of inherited eye disease and/or ocular cancer, in order to avoid having a child affected with the known familial disease. Each family underwent genetic testing in order to identify the underlying disease-causing mutation. IVF and PGD treatment were performed; unaffected embryos were implanted in their respective mothers. Thirty-five unrelated mothers underwent PGD, and the following hereditary conditions were identified in their families: albinism (10 families); retinitis pigmentosa (7 families); retinoblastoma (4 families); blue cone monochromatism, achromatopsia, and aniridia (2 families each); and Hermansky-Pudlak syndrome, Leber congenital amaurosis, Norrie disease, papillorenal syndrome, primary congenital cataract, congenital glaucoma, Usher syndrome type 1F, and microphthalmia with coloboma (1 family each). Following a total of 88 PGD cycles, 18 healthy (i.e., unaffected) children were born. Our findings underscore the importance an ophthalmologist plays in informing patients regarding the options now available for using prenatal and preimplantation genetic diagnosis to avoid having a child with a potentially devastating genetic form of eye disease or ocular cancer. This strategy is highly relevant, particularly given the limited options currently available for treating these conditions.

Awareness and attitude regarding reproductive options of persons carrying a BRCA mutation and their partners.

PubMed

Gietel-Habets, J J G; de Die-Smulders, C E M; Derks-Smeets, I A P; Tibben, A; Tjan-Heijnen, V C G; van Golde, R; Gomez-Garcia, E; Kets, C M; van Osch, L A D M

2017-03-01

To what extent are BRCA mutation carriers and their partners in the Netherlands aware about preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND) as reproductive options and what is their attitude towards these options? Awareness of PGD (66%) and PND (61%) among BRCA mutation carriers and their partners is relatively high and 80% and 26%, respectively, of BRCA carriers and their partners find offering PGD and PND for hereditary breast and ovarian cancer (HBOC) acceptable. Internationally, awareness of PGD among persons with a genetic cancer predisposition appears to be relatively low (35%) and although acceptability is generally high (71%), only a small proportion of mutation carriers would consider using PGD (36%). However, for HBOC, there are no studies available that investigated the perspective of individuals with a confirmed BRCA1/2 mutation and their partners about PGD and PND including demographic and medical correlates of awareness and acceptability. A cross-sectional survey was completed by 191 participants between July 2012 and June 2013. Participants were recruited through patient organizations (88%) and the databases of two Clinical Genetics departments in the Netherlands (12%). Male and female BRCA carriers and their partners completed an online survey, which assessed demographic and medical characteristics, and awareness, knowledge, acceptability and consideration of PGD and PND as main outcomes. Correlations between demographic and medical characteristics and the main outcomes were investigated. The majority of respondents were female (87%), of reproductive age (86%) and about half reported a desire for a child in the future. About two-thirds (66%) were aware of PGD and 61% of PND for HBOC. PGD knowledge was moderate (5.5 on a 9-point scale) and acceptability of PGD and PND for HBOC was 80% and 26%, respectively. A minority would personally consider using PGD (39%) or PND (20%). Individuals with a higher educational level were more likely to be aware of PGD (P < 0.001) and PND (P < 0.001) and persons with a more immediate child wish were more often aware of PGD (P = 0.044) and had more knowledge about PGD (P = 0.001). PGD acceptability was positively associated with knowledge about PGD (P = 0.047), and PND acceptability was higher among partners in comparison to carriers (P = 0.001). Participants with a history of cancer and with a higher perceived seriousness of breast and ovarian cancer were more likely to consider using PGD (P = 0.003 and P < 0.001 respectively) or PND (P = 0.021 and P = 0.017 respectively). The response rate (23%) of participants invited by the clinical genetics departments was low, probably related to a simultaneous study that used a similar recruitment strategy within the same target group, which may have resulted in selection bias. Moreover, PGD knowledge was measured with an instrument that is not yet validated since to date such an instrument is not available in the literature. Finally, the cross-sectional design of this study limits us from drawing any causal conclusions. Improvement of information provision remains needed, in order to timely inform all couples with HBOC about the available reproductive options and enable them to make a balanced reproductive decision. This may limit the risk of negative psychological impact due to decisional conflict and possible regret. The Dutch breast cancer foundation Stichting Pink Ribbon (grant number 2010.PS11.C74). None of the authors have competing interests to declare. Not applicable. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Prostaglandin D2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia

PubMed Central

Garza, Luis A.; Liu, Yaping; Yang, Zaixin; Alagesan, Brinda; Lawson, John A.; Norberg, Scott M.; Loy, Dorothy E.; Zhao, Tailun; Blatt, Hanz B.; Stanton, David C.; Carrasco, Lee; Ahluwalia, Gurpreet; Fischer, Susan M.; FitzGerald, Garret A.; Cotsarelis, George

2012-01-01

Testosterone is necessary for the development of male pattern baldness, known as androgenetic alopecia (AGA); yet, the mechanisms for decreased hair growth in this disorder are unclear. We show that prostaglandin D2 synthase (PTGDS) is elevated at the mRNA and protein levels in bald scalp compared to haired scalp of men with AGA. The product of PTGDS enzyme activity, prostaglandin D2 (PGD2), is similarly elevated in bald scalp. During normal follicle cycling in mice, Ptgds and PGD2 levels increase immediately preceding the regression phase, suggesting an inhibitory effect on hair growth. We show that PGD2 inhibits hair growth in explanted human hair follicles and when applied topically to mice. Hair growth inhibition requires the PGD2 receptor G protein (heterotrimeric guanine nucleotide)–coupled receptor 44 (GPR44), but not the PGD2 receptor 1 (PTGDR). Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets prostaglandin-endoperoxide synthase 2 expression to the skin, demonstrates elevated levels of PGD2 in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD2 as an inhibitor of hair growth in AGA and suggest the PGD2-GPR44 pathway as a potential target for treatment. PMID:22440736

Preimplantation genetic diagnosis for BRCA1/2--a novel clinical experience.

PubMed

Sagi, M; Weinberg, N; Eilat, A; Aizenman, E; Werner, M; Girsh, E; Siminovsky, Y; Abeliovich, D; Peretz, T; Simon, A; Laufer, N

2009-05-01

To describe our 2-year experience with preimplantation genetic diagnosis (PGD) for carriers of mutations in the genes BRCA1 and BRCA2, the dilemmas incurred and the lessons learned. We collected data on those carriers of BRCA1/2 mutations who applied for PGD counseling and who decided to proceed. We describe the PGD procedures that were conducted and their outcome. Ten carriers of BRCA1/2 mutations applied for PGD counseling, seven were healthy, and three were BC survivors. Eight women needed in vitro fertilization (IVF) because of coexisting infertility. After counseling, six opted for the procedure and five of them underwent PGD for the BRCA mutation. In one of these PGD, fluorescence in situ hybridization (FISH) analysis for chromosomes 21, X and Y was also performed. Three women conceived, each in the first treatment attempt. One of them gave birth to twins, the second to a singleton and the third is currently pregnant. During the pregnancies, dilemmas concerning PGD confirmation were discussed. PGD is an acceptable reproductive option for BRCA mutation carriers, especially for those who require IVF due to fertility problems. Discussion of this option should be carried out with sensitivity, taking into account the age of the woman, her health, fertility status and emotional state. Confirmatory prenatal diagnosis may not always be encouraged. (c) 2009 John Wiley & Sons, Ltd.

The role of TGF-β in the association between primary graft dysfunction and bronchiolitis obliterans syndrome

PubMed Central

DerHovanessian, Ariss; Weigt, S. Samuel; Palchevskiy, Vyacheslav; Shino, Michael Y.; Sayah, David M.; Gregson, Aric L.; Noble, Paul W.; Palmer, Scott M.; Fishbein, Michael C.; Kubak, Bernard M.; Ardehali, Abbas; Ross, David J.; Saggar, Rajan; Lynch, Joseph P.; Elashoff, Robert M.; Belperio, John A.

2016-01-01

Primary graft dysfunction (PGD) is a possible risk factor for bronchiolitis obliterans syndrome (BOS) following lung transplantation; however, the mechanism for any such association is poorly understood. Based on TGF-β's association with acute and chronic inflammatory disorders, we hypothesized that it may play a role in the continuum between PGD and BOS. Thus, the association between PGD and BOS was assessed in a single-center cohort of lung transplant recipients. Bronchoalveolar lavage fluid concentrations of TGF-β and procollagen collected within 24 hours of transplantation were compared across the spectrum of PGD, and incorporated into Cox models of BOS. Immunohistochemistry localized expression of TGF-β and its receptor in early lung biopsies post-transplant. We found an association between PGD and BOS in both bilateral and single lung recipients with a hazard ratio of 3.07 (95% CI 1.76-5.38) for the most severe form of PGD. TGF-β and procollagen concentrations were elevated during PGD (p<0.01), and associated with increased rates of BOS. Expression of TGF-β and its receptor localized to allograft infiltrating mononuclear and stromal cells, and the airway epithelium. These findings validate the association between PGD and the subsequent development of BOS, and suggest that this association may be mediated by receptor/TGF-β biology. PMID:26461171

The clinical utility of PGD with HLA matching: a collaborative multi-centre ESHRE study.

PubMed

Kakourou, G; Kahraman, S; Ekmekci, G C; Tac, H A; Kourlaba, G; Kourkouni, E; Sanz, A Cervero; Martin, J; Malmgren, H; Giménez, C; Gold, V; Carvalho, F; Billi, C; Chow, J F C; Vendrell, X; Kokkali, G; Liss, J; Steffann, J; Traeger-Synodinos, J

2018-02-08

Has PGD-HLA been successful relative to diagnostic and clinical efficacy? The diagnostic efficacy of PGD-HLA protocols was found lower in this study in comparison to published PGD-HLA protocols and to that reported for general PGD by ESHRE (78.5 vs 94.1% and vs 92.6%, respectively), while the clinical efficacy has proven very difficult to assess due to inadequate follow-up of both the ART/PGD and HSCT procedure outcomes. The first clinical cases for PGD-HLA were reported in 2001. It is now a well-established procedure, with an increasing number of cycles performed every year. However, PGD-HLA is still offered by relatively few PGD centres, the currently available data is fragmented and most reports on PGD-HLA applications are limited in number and scope. Published systematic details on methodology, diagnostic results, overall ART success and haematopoietic stem cell transplantation (HSCT) outcomes are limited, precluding an evaluation of the true clinical utility of PGD-HLA cycles. This retrospective multi-centre cohort study aimed to investigate the diagnostic and clinical efficacy of the PGD-HLA procedure and the aspects of PGD-HLA cycles influencing positive outcomes: birth of genetically suitable donor-baby (or babies) and HSCT. In April 2014, 32 PGD centres (Consortium members and non-members) with published/known PGD-HLA activity were invited to participate. Between February and September 2015, 14 centres submitted their data, through a custom-designed secure database, with unique login access for each centre. Data parameters covered all aspects of PGD-HLA cycles (ART, embryology and genetic diagnosis), donor-babies born and HSCT. From 716 cycles submitted by 14 centres (performed between August 2001 and September 2015), the quality evaluation excluded 12 cycles, leaving 704, from 364 couples. The online database, based on REDCap, a free, secure, web-based data-capture application, was customized by Centre for Clinical Epidemiology and Outcomes Research (CLEO), Athens. Continuous variables are presented using mean, standard deviation, median and interquartile range, and categorical variables are presented as absolute and relative frequencies. The data included 704 HLA-PGD cycles. Mean maternal age was 33.5 years. Most couples (81.3%) requested HLA-typing with concurrent exclusion of a single monogenic disease (58.6% for beta-thalassaemia). In 92.5% couples, both partners were fertile, with an average 1.93 HLA-PGD cycles/couple. Overall, 9751 oocytes were retrieved (13.9/cycle) and 5532 embryos were analysed (7.9/cycle). Most cycles involved fresh oocytes (94.9%) and Day 3 embryo biopsy (85.3%). In 97.5% of cycles, the genotyping method involved PCR only. Of 4343 embryos diagnosed (78.5% of analysed embryos), 677 were genetically suitable (15.4% of those analysed for HLA alone, 11.6% of those analysed for HLA with exclusion of monogenic disease). Of the 364 couples, 56.6% achieved an embryo transfer (ET) and 598 embryos were transferred in 382 cycles, leading to 164 HCG-positive pregnancies (pregnancy rate/ET 41.3%, pregnancy rate/initiated cycle 23.3%) and 136 babies born (live birth rate/ET 34.3%, live birth rate/initiated cycle 19.3%) to 113 couples. Data analysis identified the following limitations to the overall success of the HLA-PGD procedure: the age of the mother undergoing the treatment cycle, the number of oocytes collected per cycle and genetic chance. HSCT was reported for 57 cases, of which 64.9% involved combined umbilical cord-blood and bone marrow transplantation from the HLA-identical sibling donor; 77.3% of transplants reported no complications. The findings of the study may be limited as not all PGD centres with PGD-HLA experience participated. Reporting bias on completion of the online database may be another potential limitation. Furthermore, the study is based on retrospective data collection from centres with variable practices and strategies for ART, embryology and genetic diagnosis. This is the first multi-centre study evaluating the clinical utility of PGD-HLA, indicating variations in practice and outcomes throughout 15 years and between centres. The study highlights parameters important for positive outcomes and provides important information for both scientists and couples interested in initiating a cycle. Above all, the study underlines the need for better collaboration between all specialists involved in the ART-PGD/HLA procedure, as well as the need for comprehensive and prospective long-term data collection, and encourages all specialists to aim to properly evaluate and follow-up all procedures, with the ultimate aim to promote best practice and encourage patient informed decision making. The study wishes to acknowledge ESHRE for funding the customization of the REDCap database. There are no competing interests. N/A. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Women's experience of pre-implantation genetic diagnosis: a qualitative study.

PubMed

Karatas, J C; Barlow-Stewart, K; Strong, K A; Meiser, B; McMahon, C; Roberts, C

2010-08-01

To provide an in-depth account of the experience of pre-implantation genetic diagnosis (PGD). Exploratory qualitative interview study. Participants were recruited from one major in vitro fertilization (IVF) clinic in Sydney, Australia. Data were collected through 14 in-depth interviews with women at different stages of PGD, utilized a thematic approach and facilitated by NVivo software. Women reported using PGD as empowering and led them to feel in control of their reproductive futures. Health professionals who did not tell women about PGD were seen as a barrier to accessing treatment. The ability to select embryos free from the genetic condition (for which it was at risk) alleviated stress. Despite this, stress experienced with PGD was significant for women, and often related to past experiences of reproductive trauma and grief. The outcome of embryos was also the cause of stress for women. Women undergoing PGD have a diverse range of reproductive and genetic histories, psychosocial circumstances and world views that all interact and impact their experience of PGD. Successful support and care of these women should address all of these factors and tailor the support provided for women using this physically and emotionally complex form of reproductive technology. (c) 2010 John Wiley & Sons, Ltd.

Conceptualizing Couples’ Decision Making in PGD: Emerging Cognitive, Emotional, and Moral Dimensions

PubMed Central

Hershberger, Patricia E.; Pierce, Penny F.

2009-01-01

Objective To illuminate and synthesize what is known about the underlying decision making processes surrounding couples’ preimplantation genetic diagnosis (PGD) use or disuse and to formulate an initial conceptual framework that can guide future research and practice. Methods This systematic review targeted empirical studies published in English from 1990 to 2008 that examined the decision making process of couples or individual partners that had used, were eligible for, or had contemplated PGD. Sixteen studies met the eligibility requirements. To provide a more comprehensive review, empirical studies that examined healthcare professionals’ perceptions of couples’ decision making surrounding PGD use and key publications from a variety of disciplines supplemented the analysis. Results The conceptual framework formulated from the review demonstrates that couples’ PGD decision making is composed of three iterative and dynamic dimensions: cognitive appraisals, emotional responses, and moral judgments. Conclusion Couples think critically about uncertain and probabilistic information, grapple with conflicting emotions and incorporate moral perspectives into their decision making about whether or not to use PGD. Practice Implications The quality of care and decisional support for couples who are contemplating PGD use can be improved by incorporating focused questions and discussion from each of the dimensions into counseling sessions. PMID:20060677

Receptors involved in the modulation of guinea pig urinary bladder motility by prostaglandin D2

PubMed Central

Guan, Na N; Svennersten, Karl; de Verdier, Petra J; Wiklund, N Peter; Gustafsson, Lars E

2015-01-01

Background and Purpose We have described a urothelium-dependent release of PGD2-like activity which had inhibitory effects on the motility of guinea pig urinary bladder. Here, we have pharmacologically characterized the receptors involved and localized the sites of PGD2 formation and of its receptors. Experimental Approach In the presence of selective DP and TP receptor antagonists alone or combined, PGD2 was applied to urothelium-denuded diclofenac-treated urinary bladder strips mounted in organ baths. Antibodies against PGD2 synthase and DP1 receptors were used with Western blots and for histochemistry. Key Results PGD2 inhibited nerve stimulation -induced contractions in strips of guinea pig urinary bladder with estimated pIC50 of 7.55 ± 0.15 (n = 13), an effect blocked by the DP1 receptor antagonist BW-A868C. After blockade of DP1 receptors, PGD2 enhanced the contractions, an effect abolished by the TP receptor antagonist SQ-29548. Histochemistry revealed strong immunoreactivity for PGD synthase in the urothelium/suburothelium with strongest reaction in the suburothelium. Immunoreactive DP1 receptors were found in the smooth muscle of the bladder wall with a dominant localization to smooth muscle membranes. Conclusions and Implications In guinea pig urinary bladder, the main effect of PGD2 is an inhibitory action via DP1 receptors localized to the smooth muscle, but an excitatory effect via TP receptors can also be evoked. The urothelium with its suburothelium might signal to the smooth muscle which is rich in PGD2 receptors of the DP1 type. The results are important for our understanding of regulation of bladder motility. PMID:25917171

Integrating patient voices into health information for self-care and patient-clinician partnerships: Veterans Affairs design recommendations for patient-generated data applications.

PubMed

Woods, Susan S; Evans, Neil C; Frisbee, Kathleen L

2016-05-01

Electronic health record content is created by clinicians and is driven largely by intermittent and brief encounters with patients. Collecting data directly from patients in the form of patient-generated data (PGD) provides an unprecedented opportunity to capture personal, contextual patient information that can supplement clinical data and enhance patients' self-care. The US Department of Veterans Affairs (VA) is striving to implement the enterprise-wide capability to collect and use PGD in order to partner with patients in their care, improve the patient healthcare experience, and promote shared decision making. Through knowledge gained from Veterans' and healthcare teams' perspectives, VA created a taxonomy and an evolving framework on which to design and develop applications that capture and help physicians utilize PGD. Ten recommendations for effectively collecting and integrating PGD into patient care are discussed, addressing health system culture, data value, architecture, policy, data standards, clinical workflow, data visualization, and analytics and population reach. Published by Oxford University Press on behalf of the American Medical Informatics Association 2016. This work is written by US Government employees and is in the public domain in the US.

6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling.

PubMed

Lin, Ruiting; Elf, Shannon; Shan, Changliang; Kang, Hee-Bum; Ji, Quanjiang; Zhou, Lu; Hitosugi, Taro; Zhang, Liang; Zhang, Shuai; Seo, Jae Ho; Xie, Jianxin; Tucker, Meghan; Gu, Ting-Lei; Sudderth, Jessica; Jiang, Lei; Mitsche, Matthew; DeBerardinis, Ralph J; Wu, Shaoxiong; Li, Yuancheng; Mao, Hui; Chen, Peng R; Wang, Dongsheng; Chen, Georgia Zhuo; Hurwitz, Selwyn J; Lonial, Sagar; Arellano, Martha L; Khoury, Hanna J; Khuri, Fadlo R; Lee, Benjamin H; Lei, Qunying; Brat, Daniel J; Ye, Keqiang; Boggon, Titus J; He, Chuan; Kang, Sumin; Fan, Jun; Chen, Jing

2015-11-01

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

[Value of preoperative pulmonary artery diastolic pressure on predicting primary graft dysfunction after bilateral lung transplantation for patients with idiopathic pulmonary fibrosis].

PubMed

Zhang, Feng; Xu, Hongyang; Jiang, Shuyun; Li, Jiaqiong; Lu, Shunmei; Wang, Dapeng; Zang, Zhidong; Pan, Hong; Chen, Jingyu

2017-05-01

To analyze the value of the potential risk factors on predicting primary graft dysfunction (PGD) after bilateral lung transplantation for the patients with idiopathic pulmonary fibrosis (IPF). A retrospective study was conducted. Fifty-eight patients with IPF who underwent the bilateral lung transplantation admitted to Wuxi People's Hospital Affiliated to Nanjing Medical University from June 2014 to March 2017 were enrolled. The grade 3 PGD happened within 72 hours after transplantation was taken as the outcome event, and these patients were divided into PGD and non-PGD groups. The age, gender, body mass index (BMI), underlying disease, and N-terminal-probrain natriuretic peptide (NT-proBNP) before operation, pulmonary artery systolic pressure (PASP), pulmonary artery diastolic pressure (PADP), and mean pulmonary artery pressure (mPAP) before and after operation, duration of operation, the volume of blood transfusion during operation and postoperation, the use of extracorporeal membrane oxygenation (ECMO) during the operation, blood purification treatment after operation, and shock within 3 days after operation were recorded. The differences of parameters mentioned above between the two groups were compared. The predictive factors of PGD were searched by binary logistic regression analysis, and the receiver operating characteristic curve (ROC) was plotted to analyze the predictive value of preoperative PADP for grade 3 PGD after transplantation. Among 58 patients who underwent the bilateral lung transplantation, 52 patients were enrolled. The rest patients were excluded because of incomplete clinical data. There were 17 patients in the PGD group, with a mortality rate of 47.06%. The non-PGD group included 35 patients with a mortality rate of 8.57%. PADP and mPAP ahead of operation, the dosage of red cells suspension after the operation, and the total amount of blood transfusion during and after the operation in PGD group were significantly higher than those in non-PGD group [PADP ahead of operation (mmHg, 1 mmHg = 0.133 kPa): 33.7±10.5 vs. 25.3±10.1, mPAP ahead of operation (mmHg): 40.4±14.1 vs. 32.8±11.1, the dosage of red cells suspension after the operation (mL): 700 (300, 1 500) vs. 300 (300, 500), the total amount of blood transfusion during and after the operation (mL): 2 250 (1 850, 4 275) vs. 1 800 (1 550, 2 800)], with statistically significant differences (all P < 0.05). There were no significant differences in age, gender, BMI, underlying disease, NT-proBNP before operation, PASP before and after operation, PADP and mPAP after operation, duration of operation, amount of plasma and red cells suspension as well as total amount of blood transfusion during operation, plasma amount and total amount of blood transfusion after operation, amount of plasma and red cells suspension during and after operation, use of ECMO during operation, blood purification treatment after operation, and shock after operation between the two groups (all P > 0.05). It was shown by binary logistic regression analysis that the preoperative PADP was the independent risk factor of grade 3 PGD after lung transplantation [odds ratio (OR) = 1.084, 95% confidence interval (95%CI) = 1.016-1.156, P = 0.015]. It was shown by ROC curve that the area under the ROC curve (AUC) of the PADP before operation for predicting the grade 3 PGD after lung transplantation was 0.728. When the cut-off value was 36 mmHg, the sensitivity was 47.1%, and the specificity was 91.4%. Compared with the non-PGD group, the patients with higher preoperative PADP were more common in the PGD group, and the patients in the PGD group were more likely to be characterized by grade 3 PGD after lung transplantation. The preoperative PADP was an effective predictor of grade 3 PGD after lung transplantation.

Pathophysiology and classification of primary graft dysfunction after lung transplantation

PubMed Central

Morrison, Morvern Isabel; Pither, Thomas Leonard

2017-01-01

The term primary graft dysfunction (PGD) incorporates a continuum of disease severity from moderate to severe acute lung injury (ALI) within 72 h of lung transplantation. It represents the most significant obstacle to achieving good early post-transplant outcomes, but is also associated with increased incidence of bronchiolitis obliterans syndrome (BOS) subsequently. PGD is characterised histologically by diffuse alveolar damage, but is graded on clinical grounds with a combination of PaO2/FiO2 (P/F) and the presence of radiographic infiltrates, with 0 being absence of disease and 3 being severe PGD. The aetiology is multifactorial but commonly results from severe ischaemia-reperfusion injury (IRI), with tissue-resident macrophages largely responsible for stimulating a secondary ‘wave’ of neutrophils and lymphocytes that produce severe and widespread tissue damage. Donor history, recipient health and operative factors may all potentially contribute to the likelihood of PGD development. Work that aims to minimise the incidence of PGD in ongoing, with techniques such as ex vivo perfusion of donor lungs showing promise both in research and in clinical studies. This review will summarise the current clinical status of PGD before going on to discuss its pathophysiology, current therapies available and future directions for clinical management of PGD. PMID:29268419

[Dual role for prostaglandin D2 in intestinal epithelial homeostasis].

PubMed

Le Loupp, Anne-Gaelle; Bach-Ngohou, Kalyane; Bettan, Armel; Denis, Marc; Masson, Damien

2015-01-01

Prostaglandin D2 (PGD2) and derivatives are lipid mediators involved in the control of the intestinal epithelial barrier homeostasis. Their involvement in the pathophysiology of chronic inflammatory bowel disease (IBD) is still debated. Several results highlight the duality of PGD2 as an anti- or pro-inflammatory mediator. This duality seems to be related to a differential expression of its receptors by intestinal epithelial cells and the surrounding immunocompetent cells. The enteric glial cells from the enteric nervous system (ENS) express the lipocalin-type-prostaglandin D synthase and secrete PGD2 and 15d-PGJ2. The protective role of the ENS in the homeostatic control of the epithelial intestinal barrier and its involvement in the pathogenesis of IBD have already been demonstrated. Thus, these lipid mediators seem to be new actors of the neuro-glio-epithelial unit and could play a crucial role maintaining gut barrier integrity. © 2015 médecine/sciences – Inserm.

Prognostic Value of High-Sensitivity Troponin-T to Identify Patients at Risk of Left Ventricular Graft Dysfunction After Heart Transplantation.

PubMed

Méndez, A B; Ordonez-Llanos, J; Mirabet, S; Galan, J; Maestre, M L; Brossa, V; Rivilla, M T; López, L; Koller, T; Sionis, A; Roig, E

2016-11-01

Primary graft dysfunction after heart transplantation (HTx) has a very high mortality rate, especially if the left ventricle (PGD-LV) is involved. Early diagnosis is important to select the appropriate therapy to improve prognosis. The value of high-sensitivity troponin T (HS-TNT) measurement obtained at patient arrival at the intensive care unit was analyzed in 71 HTx patients. Mild or moderate PGD-LV was defined by hemodynamic compromise with one of the following criteria: left ventricular ejection fraction <40%, hemodynamic compromise with right atrial pressure >15 mm Hg, pulmonary capillary wedge pressure >20 mm Hg, cardiac index <2.0 L/min/m 2 , hypotension (mean arterial pressure <70 mm Hg), and need for high-dose inotropes (inotrope score >10) or newly placed intra-aortic balloon pump. The mean recipient age was 54 ± 12 years (73% men), and donor age was 47 ± 11 years. Ischemic time was 200 ± 51 minutes, and coronary bypass time was 122 ± 31 minutes. Nine (13%) HTx patients were diagnosed with PGD-LV post-HTx, 8 with biventricular dysfunction. Four patients died, 2 with PGD-LV (22%) and 2 without PGD (4%). Mean HS-TNT before HTx was 158 ± 565 ng/L, and post-HT was 1621 ± 1269 ng/L. The area under the curve (receiver-operator characteristic) of HS-TNT to detect patients at risk of PGD-LV was 0.860 (P < .003). A cutoff value of HS-TNT >2000 ng/L had a sensitivity of 75% and specificity of 87% to identify patients at risk of PGD-LV. Multivariate analysis identified HS-TNT >2000 ng/L (P < .02) and coronary bypass-time (P < .01) as independent predictors of PGD-LV. HS-TNT >2000 ng/L at intensive care admission after HT and prolonged coronary bypass time were the most powerful predictors of PGD-LV. HS-TNT may be helpful for early detection of HTx patients at risk of PGD-LV. Copyright © 2016 Elsevier Inc. All rights reserved.

Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans

PubMed Central

Song, Wen-Liang; Stubbe, Jane; Ricciotti, Emanuela; Alamuddin, Naji; Ibrahim, Salam; Crichton, Irene; Prempeh, Maxwell; Lawson, John A.; Wilensky, Robert L.; Rasmussen, Lars Melholt; Puré, Ellen; FitzGerald, Garret A.

2012-01-01

The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1–dependent formation of PGD2 and PGE2 followed by COX-2–dependent production of PGE2. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD2 receptor DP1. NSAID-mediated suppression of COX-2–derived PGI2 has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD2. Here, we show that PGD2 biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1–derived PGD2 biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD2 was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD2, like PGI2, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy. PMID:22406532

Gender eugenics? The ethics of PGD for intersex conditions.

PubMed

Sparrow, Robert

2013-01-01

This article discusses the ethics of the use of preimplantation genetic diagnosis (PGD) to prevent the birth of children with intersex conditions/disorders of sex development (DSDs), such as congenital adrenal hyperplasia (CAH) and androgen insensitivity syndrome (AIS). While pediatric surgeries performed on children with ambiguous genitalia have been the topic of intense bioethical controversy, there has been almost no discussion to date of the ethics of the use of PGD to reduce the prevalence of these conditions. I suggest that PGD for those conditions that involve serious medical risks for those born with them is morally permissible and that PGD for other "cosmetic" variations in sexual anatomy is more defensible than might first appear. However, importantly, the arguments that establish the latter claim have radical and disturbing implications for our attitude toward diversity more generally.

Assisted reproductive technology (ART) cumulative live birth rates following preimplantation genetic diagnosis for aneuploidy (PGD-A) or morphological assessment of embryos: A cohort analysis.

PubMed

Lee, Evelyn; Chambers, Georgina Mary; Hale, Lyndon; Illingworth, Peter; Wilton, Leeanda

2017-12-27

Preimplantation genetic diagnosis for aneuploidy (PGD-A) for all 24 chromosomes improves implantation and clinical pregnancy rates per single assisted reproductive technology (ART) cycle. However, there is limited data on the live-birth rate of PGD-A over repeated cycles. To assess the cumulative live-birth rates (CLBR) of PGD-A compared with morphological assessment of embryos of up to three 'complete ART cycles' (fresh plus frozen/thaw cycles) in women aged 37 years or older. A retrospective cohort study of ART treatments undertaken by ART-naïve women at a large Australian fertility clinic between 2011 and 2014. Cohorts were assigned based on the embryo selection method used in their first fresh cycle [PGD-A, n = 110 women (PGD-A group); morphological assessment of embryos, n = 1983 women (control group)]. CLBR, time to clinical pregnancy and cycles needed to achieve a live birth were measured over multiple cycles. Compared to the control group, the PGD-A group achieved a higher per cycle live-birth rate (14.47% vs 9.12%, P < 0.01), took a shorter mean time to reach a clinical pregnancy leading to a live-birth (104.8 days vs 140.6 days, P < 0.05) and required fewer cycles to achieve a live-birth (6.91 cycles vs 10.96 cycles, P < 0.01). However, after three 'complete ART cycles', the CLBR was comparable for the two groups (30.90% vs 26.77%, P = 0.34). This is the first study to assess the effectiveness of PGD-A over multiple ART cycles. These real-world findings suggest that PGD-A leads to better outcomes than using morphological assessment alone in women of advanced maternal age. © 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review.

PubMed

Lee, Evelyn; Illingworth, Peter; Wilton, Leeanda; Chambers, Georgina Mary

2015-02-01

Is preimplantation genetic diagnosis for aneuploidy (PGD-A) with analysis of all chromosomes during assisted reproductive technology (ART) clinically and cost effective? The majority of published studies comparing a strategy of PGD-A with morphologically assessed embryos have reported a higher implantation rate per embryo using PGD-A, but insufficient data has been presented to evaluate the clinical and cost-effectiveness of PGD-A in the clinical setting. Aneuploidy is a leading cause of implantation failure, miscarriage and congenital abnormalities in humans, and a significant cause of ART failure. Preclinical evidence of PGD-A indicates that the selection and transfer of euploid embryos during ART should improve clinical outcomes. A systematic review of the literature was performed for full text English language articles using MEDLINE, EMBASE, SCOPUS, Cochrane Library databases, NHS Economic Evaluation Database and EconLit. The Downs and Black scoring checklist was used to assess the quality of studies. Clinical effectiveness was measured in terms of pregnancy, live birth and miscarriage rates. Nineteen articles meeting the inclusion criteria, comprising three RCTs in young and good prognosis patients and 16 observation studies were identified. Five of the observational studies included a control group of patients where embryos were selected based on morphological criteria (matched cohort studies). Of the five studies that included a control group and reported implantation rates, four studies (including two RCTs) demonstrated improved implantation rates in the PGD-A group. Of the eight studies that included a control group, six studies (including two RCTs) reported significantly higher pregnancy rates in the PGD-A group, and in the remaining two studies, equivalent pregnancies rates were reported despite fewer embryos being transferred in the PGD-A group. The three RCTs demonstrated benefit in young and good prognosis patients in terms of clinical pregnancy rates and the use of single embryo transfer. However, studies relating to patients of advanced maternal age, recurrent miscarriage and implantation failure were restricted to matched cohort studies, limiting the ability to draw meaningful conclusions. Relevant studies may have been missed and findings from RCTs currently being undertaken could not be included. Given the uncertain role of PGD-A techniques, high-quality experimental studies using intention-to-treat analysis and cumulative live birth rates including the comparative outcomes from remaining cryopreserved embryos are needed to evaluate the overall role of PGD-A in the clinical setting. It is only in this way that the true contribution of PGD-A to ART can be understood. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Learning about Sickle Cell Disease

MedlinePlus

... used in conjunction with in vitro fertilization, called pre-implantation genetic diagnosis (PGD), enables parents who carry the sickle cell trait to test embryos for the defective gene before implantation, and ...

An interaction between L-prostaglandin D synthase and arrestin increases PGD2 production.

PubMed

Mathurin, Karine; Gallant, Maxime A; Germain, Pascale; Allard-Chamard, Hugues; Brisson, Jessy; Iorio-Morin, Christian; de Brum Fernandes, Artur; Caron, Marc G; Laporte, Stéphane A; Parent, Jean-Luc

2011-01-28

L-type prostaglandin synthase (L-PGDS) produces PGD(2), a lipid mediator involved in neuromodulation and inflammation. Here, we show that L-PGDS and arrestin-3 (Arr3) interact directly and can be co-immunoprecipitated endogenously from MG-63 osteoblasts. Perinuclear L-PGDS/Arr3 co-localization is observed in PGD(2)-producing MG-63 cells and is induced by the addition of the L-PGDS substrate or co-expression of COX-2 in HEK293 cells. Inhibition of L-PGDS activity in MG-63 cells triggers redistribution of Arr3 and L-PGDS to the cytoplasm. Perinuclear localization of L-PGDS is detected in wild-type mouse embryonic fibroblasts (MEFs) but is more diffused in MEFs-arr-2(-/-)-arr-3(-/-). Arrestin-3 promotes PGD(2) production by L-PGDS in vitro. IL-1β-induced PGD(2) production is significantly lower in MEFs-arr-2(-/-)-arr-3(-/-) than in wild-type MEFs but can be rescued by expressing Arr2 or Arr3. A peptide corresponding to amino acids 86-100 of arrestin-3 derived from its L-PGDS binding domain stimulates L-PGDS-mediated PGD(2) production in vitro and in MG-63 cells. We report the first characterization of an interactor/modulator of a PGD(2) synthase and the identification of a new function for arrestin, which may open new opportunities for improving therapies for the treatment of inflammatory diseases.

PGD for all cystic fibrosis carrier couples: novel strategy for preventive medicine and cost analysis.

PubMed

Tur-Kaspa, I; Aljadeff, G; Rechitsky, S; Grotjan, H E; Verlinsky, Y

2010-08-01

Over 1000 children affected with cystic fibrosis (CF) are born annually in the USA. Since IVF with preimplantation genetic diagnosis (PGD) is an alternative to raising a sick child or to aborting an affected fetus, a cost-benefit analysis was performed for a national IVF-PGD program for preventing CF. The amount spent to deliver healthy children for all CF carrier-couples by IVF-PGD was compared with the average annual and lifetime direct medical costs per CF patient avoided. Treating annually about 4000 CF carrier-couples with IVF-PGD would result in 3715 deliveries of non-affected children at a cost of $57,467 per baby. Because the average annual direct medical cost per CF patient was $63,127 and life expectancy is 37 years, savings would be $2.3 million per patient and $2.2 billion for all new CF patients annually in lifetime treatment costs. Cumulated net saving of an IVF-PGD program for all carrier-couples for 37 years would be $33.3 billion. A total of 618,714 cumulative years of patients suffering because of CF and thousands of abortions could be prevented. A national IVF-PGD program is a highly cost-effective novel modality of preventive medicine and would avoid most births of individuals affected with debilitating genetic disease. 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

The stability and predictors of peer group deviance in university students.

PubMed

Kendler, Kenneth S; Myers, John; Dick, Danielle

2015-09-01

Peer group deviance (PGD) is strongly associated with current and future externalizing behaviors. Debate remains about the degree to which this association arises from social selection. The first year of university constitutes a social experiment in which most individuals leave their home environment and recreate for themselves a new peer group. PGD was measured in newly arrived university students and then 6 and 18 months later. Other personality and family traits were also assessed. PGD reported for high school friends at the start of university and university friends 6 months later were substantially correlated (+0.60). This correlation was only slightly diminished if restricted to students whose home was greater than 50 miles from the university. PGD was strongly predicted across three cohorts by male sex (+), extraversion (+), conscientiousness (-), a family history of alcohol use disorders (+) and depression (+), and religiosity (-).These predictors of PGD had a relatively stable impact over 18 months and, aside from sex, differed only modestly in males and females. As individuals change social groups from high school to university, the level of PGD remains relatively stable, suggesting that individuals play a strong role in selecting peer groups with consistent characteristics. PGD is also predicted cross-sectionally and longitudinally by personality, family background and religiosity. Our results suggest that the association between personal and peer deviance is due at least in part to the effects of social selection.

Testing the embryo, testing the fetus.

PubMed

Ehrich, K; Farsides, B; Williams, C; Scott, Rosamund

2007-12-01

This paper stems from an ethnographic, multidisciplinary study that explored the views and experiences of practitioners and scientists on social, ethical and clinical dilemmas encountered when working in the area of PGD for serious genetic disorders. We focus here on staff perceptions and experiences of working with embryos and helping women/couples to make choices that will result in selecting embryos for transfer and disposal of 'affected' embryos, compared to the termination of affected pregnancies following PND. Analysis and discussion of our data led us to consider the possible advantages of PGD and whether a gradualist account of the embryo's and fetus's moral status can account for all of these, particularly since a gradualist account concentrates on the significance of time (developmental stage) and makes no comment as to the significance of place (in-vitro, in-utero).

Elevated Rates of Prolonged Grief Disorder in African Americans

ERIC Educational Resources Information Center

Goldsmith, B.; Morrison, R. S.; Vanderwerker, L. C.; Prigerson, H. G.

2008-01-01

The prevalence of Prolonged Grief Disorder (PGD) in non-Whites is currently unknown. This study was performed to explore the prevalence of PGD in African Americans (AAs). Multivariable analysis of two studies of recently bereaved individuals found AAs to have significantly higher rates of PGD than Whites (21% [14 of 66] vs. 12% [55 of 471],…

Anticipating issues related to increasing preimplantation genetic diagnosis use: a research agenda.

PubMed

Klitzman, Robert; Appelbaum, Paul S; Chung, Wendy; Sauer, Mark

2008-01-01

Increasing use of preimplantation genetic diagnosis (PGD) poses numerous clinical, social, psychological, ethical, legal and policy dilemmas, many of which have received little attention. Patients and providers are now considering and using PGD for a widening array of genetic disorders, and patients may increasingly seek 'designer babies.' In the USA, although governmental oversight policies have been discussed, few specific guidelines exist. Hence, increasingly, patients and providers will face challenging ethical and policy questions of when and for whom to use PGD, and how it should be financed. These issues should be better clarified and addressed through collection of data concerning the current use of PGD in the USA, including factors involved in decision making about PGD use, as well as the education of the various communities that are, and should be, involved in its implementation. Improved understanding of these issues will ultimately enhance the development and implementation of future clinical guidelines and policies.

Selecting "saviour siblings": reconsidering the regulation in Australia of pre-implantation genetic diagnosis in conjunction with tissue typing.

PubMed

Taylor-Sands, Michelle

2007-05-01

In recent years, pre-implantation genetic diagnosis (PGD) has been developed to enable the selection of a tissue type matched "saviour sibling" for a sick child. This article examines the current regulatory framework governing PGD in Australia. The availability of PGD in Australia to create a saviour sibling depends on the regulation of ART services by each State and Territory. The limitations on the use of PGD vary throughout Australia, according to the level of regulation of ART in each jurisdiction. This article considers the limitations on the use of PGD for tissue typing in Australia and argues that some of these should be removed for a more consistent national approach. In particular, the focus in ART legislation on the "paramount interests" of the child to be born is inappropriate for the application of tissue typing, which necessarily involves the interests of other family members.

Methods in preimplantation genetic diagnosis.

PubMed

Lizcano Gil, Luis Arturo; Lucena, Carolina; Lucena, Elkin

2001-01-01

Preimplantation genetic diagnosis (PGD) is a new strategy, orientated toward primary prevention of congenital anomalies in couples with reproductive risk, such as advanced maternal age, carriers of chromosomal abnormalities, and carriers of monogenic conditions. For these patients, PGD is an acceptable alternative to prenatal diagnosis, mainly in those countries where pregnancy interruption is forbidden by law. PGD effectively avoids the implications linked to traditional prenatal diagnosis. Centres that provide medical servicies on reproductive biomedicine are responsible for the development and improvement of this new prevention strategy. Thanks to advances in micromanipulation techniques, associated with recent progress in molecular genetics, PGD may be employed for any genetic condition in the future.

An open trial of 'grief-help': a cognitive-behavioural treatment for prolonged grief in children and adolescents.

PubMed

Spuij, Mariken; Dekovic, Maja; Boelen, Paul A

2015-01-01

In the past years, there is growing recognition of a syndrome of disturbed grief referred to as prolonged grief disorder (PGD). Although mostly studied in adults, clinically significant PGD symptoms have also been observed in children and adolescents. To date, no effective treatment for childhood PGD yet exists. We recently developed a nine-session cognitive-behavioural treatment for childhood PGD combined with five sessions of parental counselling. In the current article, we present outcomes of treatment of 10 consecutive children and adolescents turning to our university clinic with elevated PGD symptoms as their primary problem and main reason to seek therapy. Patients were significantly improved at post-treatment, with large improvements in self-rated PGD and post-traumatic stress (effect sizes > 0.8) and small to moderate improvement in depression and parent-rated internalizing and externalizing problems (0.2 < effect sizes < 0.8). Additional predictor analysis of outcomes suggested that, among other things, this treatment approach is less efficacious for children and adolescents further removed from loss and those confronted with suicidal loss. That said, the treatment appears promising, and controlled evaluation is clearly indicated. Copyright © 2013 John Wiley & Sons, Ltd.

Antibiotic treatment of urinary tract infection by community pharmacists: a cross-sectional study.

PubMed

Booth, Jill L; Mullen, Alexander B; Thomson, David A M; Johnstone, Christopher; Galbraith, Susan J; Bryson, Scott M; McGovern, Elizabeth M

2013-04-01

Urinary tract infections (UTIs) are one of the most common conditions seen in female patients within primary care. Community pharmacists are familiar with symptomatic UTI management and supplying trimethoprim under patient group direction (PGD) for moderate-to-severe uncomplicated UTIs could improve patient access to treatment. To compare the care pathway of patients with UTI symptoms attending GP services with those receiving management, including trimethoprim supply under PGD, via community pharmacies. Prospective, cross-sectional, mixed methods approach in 10 community pharmacies within NHS Greater Glasgow and Clyde. Pharmacies invited a purposive sample of female patients to participate. Pharmacists had the option of supplying trimethoprim under PGD to patients with moderate-to-severe infection meeting the PGD inclusion criteria. Data from patient (questionnaires and semi-structured telephone interviews) and pharmacist (questionnaires and semi-structured, face-to-face interviews) were quantitatively and qualitatively analysed. Data were recorded on 153 patients, 97 presenting with GP prescriptions and 56 presenting directly in the pharmacy with symptoms suggestive of UTI, of whom 41 received trimethoprim via PGD and 15 received symptomatic management. Both GP adherence to local infection management guidelines and pharmacist application of PGD inclusion/exclusion criteria required improvement. There was demand and support, from patients and pharmacists, for access to antibiotic treatments for UTIs, without prescription, through community pharmacies. Operating within PGD controls, antibiotic treatments for UTIs could be provided via community pharmacy to improve patient access to treatment which may also maintain antibiotic stewardship and reduce GP workload.

The stability and predictors of peer group deviance in university students

PubMed Central

Myers, John; Dick, Danielle

2015-01-01

Background Peer group deviance (PGD) is strongly associated with current and future externalizing behaviors. Debate remains about the degree to which this association arises from social selection. The first year of university constitutes a social experiment in which most individuals leave their home environment and recreate for themselves a new peer group. Methods PGD was measured in newly arrived university students and then 6 and 18 months later. Other personality and family traits were also assessed. Results PGD reported for high school friends at the start of university and university friends 6 months later were substantially correlated (+0.60). This correlation was only slightly diminished if restricted to students whose home was greater than 50 miles from the university. PGD was strongly predicted across three cohorts by male sex (+), extraversion (+), conscientiousness (−), a family history of alcohol use disorders (+) and depression (+), and religiosity (−). These predictors of PGD had a relatively stable impact over 18 months and, aside from sex, differed only modestly in males and females. Conclusions As individuals change social groups from high school to university, the level of PGD remains relatively stable, suggesting that individuals play a strong role in selecting peer groups with consistent characteristics. PGD is also predicted cross-sectionally and longitudinally by personality, family background and religiosity. Our results suggest that the association between personal and peer deviance is due at least in part to the effects of social selection. PMID:25702166

Prostaglandin D2 regulates human colonic ion transport via the DP1 receptor.

PubMed

Medani, M; Collins, D; Mohan, H M; Walsh, E; Winter, D C; Baird, A W

2015-02-01

Prostaglandin D2 is released by mast cells and is important in allergies. Its role in gastrointestinal function is not clearly defined. This study aimed to determine the effect of exogenous PGD2 on ion transport in ex vivo normal human colonic mucosa. Mucosal sheets were mounted in Ussing chambers and voltage clamped to zero electric potential. Ion transport was quantified as changes in short-circuit current. In separate experiments epithelial monolayers or colonic crypts, isolated by calcium chelation, were treated with PGD2 and cAMP levels determined by ELISA or calcium levels were determined by fluorimetry. PGD2 caused a sustained, concentration-dependent rise in short-circuit current by increasing chloride secretion (EC50=376nM). This effect of PGD2 is mediated by the DP1 receptor, as the selective DP1 receptor antagonist BW A686C inhibited PGD2-induced but not PGE2-induced rise in short-circuit current. PGD2 also increased intracellular cAMP in isolated colonic crypts with no measurable influence on cytosolic calcium. PGD2 induces chloride secretion in isolated human colonic mucosa in a concentration-dependent manner with concomitant elevation of cytoplasmic cAMP in epithelial cells. The involvement of DP2 receptor subtypes has not previously been considered in regulation of ion transport in human intestine. Since inflammatory stimuli may induce production of eicosanoids, selective regulation of these pathways may be pivotal in determining therapeutic strategies and in understanding disease. Copyright © 2014. Published by Elsevier Inc.

Testing the embryo, testing the fetus

PubMed Central

Ehrich, K; Farsides, B; Williams, C; Scott, Rosamund

2008-01-01

This paper stems from an ethnographic, multidisciplinary study that explored the views and experiences of practitioners and scientists on social, ethical and clinical dilemmas encountered when working in the area of PGD for serious genetic disorders. We focus here on staff perceptions and experiences of working with embryos and helping women/couples to make choices that will result in selecting embryos for transfer and disposal of ‘affected’ embryos, compared to the termination of affected pregnancies following PND. Analysis and discussion of our data led us to consider the possible advantages of PGD and whether a gradualist account of the embryo’s and fetus’s moral status can account for all of these, particularly since a gradualist account concentrates on the significance of time (developmental stage) and makes no comment as to the significance of place (in-vitro, in-utero). PMID:18516224

Niacin Promotes Cardiac Healing after Myocardial Infarction through Activation of the Myeloid Prostaglandin D2 Receptor Subtype 1

PubMed Central

Kong, Deping; Li, Juanjuan; Shen, Yujun; Liu, Guizhu; Zuo, Shengkai; Tao, Bo; Ji, Yong; Lu, Ankang; Lazarus, Michael; Breyer, Richard M.

2017-01-01

Niacin is a well established drug used to lower cholesterol and prevent cardiovascular disease events. However, niacin also causes cutaneous flushing side effects due to release of the proresolution mediator prostaglandin D2 (PGD2). Recent randomized clinical trials have demonstrated that addition of niacin with laropiprant [a PGD2 receptor subtype 1 (DP1) blocker] to statin-based therapies does not significantly decrease the risk of cardiovascular disease events, but increases the risk of serious adverse events. Here, we tested whether, and how, niacin beneficial effects on myocardial ischemia require the activation of the PGD2/DP1 axis. Myocardial infarction (MI) was reproduced by ligation of the left anterior descending branch of the coronary artery in mice. We found that niacin increased PGD2 release in macrophages and shifted macrophages to M2 polarization both in vitro and in vivo by activation of DP1 and accelerated inflammation resolution in zymosan-induced peritonitis in mice. Moreover, niacin treatment facilitated wound healing and improved cardiac function after MI through DP1-mediated M2 bias and timely resolution of inflammation in infarcted hearts. In addition, we found that niacin intake also stimulated M2 polarization of peripheral monocytes in humans. Collectively, niacin promoted cardiac functional recovery after ischemic myocardial infarction through DP1-mediated M2 polarization and timely resolution of inflammation in hearts. These results indicated that DP1 inhibition may attenuate the cardiovascular benefits of niacin. PMID:28057839

Efficacy of metacognitive therapy for prolonged grief disorder: protocol for a randomised controlled trial

PubMed Central

Wenn, Jenine; O'Connor, Moira; Breen, Lauren J; Kane, Robert T; Rees, Clare S

2015-01-01

Introduction Studies of effective psychotherapy for individuals suffering from the effects of prolonged grief disorder (PGD) are scarce. This paper describes the protocol for an evaluation of a metacognitive therapy programme designed specifically for PGD, to reduce the psychological distress and loss of functioning resulting from bereavement. Methods and analysis The proposed trial comprises three phases. Phase 1 consists of a review of the literature and semistructured interviews with key members of the target population to inform the development of a metacognitive therapy programme for Prolonged Grief. Phase 2 involves a randomised controlled trial to implement and evaluate the programme. Male and female adults (N=34) will be randomly assigned to either a wait list or an intervention group. Measures of PGD, anxiety, depression, rumination, metacognitions and quality of life will be taken pretreatment and posttreatment and at the 3-month and 6-month follow-up. The generalised linear mixed model will be used to assess treatment efficacy. Phase 3 will test the social validity of the programme. Discussion This study is the first empirical investigation of the efficacy of a targeted metacognitive treatment programme for PGD. A focus on identifying and changing the metacognitive mechanisms underpinning the development and maintenance of prolonged grief is likely to be beneficial to theory and practice. Ethics Ethics approval was obtained from Curtin University Human Research Ethics Committee (Approval number HR 41/2013.) Trial registration number ACTRN12613001270707. PMID:26646828

Associations between prolonged grief disorder, depression, posttraumatic stress disorder, and anxiety in Rwandan genocide survivors.

PubMed

Schaal, Susanne; Dusingizemungu, Jean-Pierre; Jacob, Nadja; Neuner, Frank; Elbert, Thomas

2012-02-01

A number of studies have demonstrated that symptoms of prolonged grief disorder (PGD) represent a symptom cluster distinct from bereavement-related depression, anxiety, and posttraumatic stress disorder (PTSD). The aim of the present study was to confirm and extend these findings using the most recent criteria defining PGD. The authors interviewed a total of 400 orphaned or widowed survivors of the Rwandan genocide. The syndromes were strongly linked to each other with a high comorbidity. Principal axis factoring resulted in the emergence of 4 different factors. The symptoms of depression, along with the cognitive, emotional, and behavioral symptoms of PGD, loaded on the first factor, symptoms of anxiety on the second factor, symptoms of PTSD on the third factor, and the separation distress symptoms of PGD on the fourth factor. This indicates that the concept of PGD includes symptoms that are conceptually related to depression. However, the symptom cluster of separation distress presents a grief-specific dimension that may surface unrelated to depressive symptoms.

Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview

PubMed Central

Fernández, Raquel M.; Peciña, Ana; Sánchez, Beatriz; Lozano-Arana, Maria Dolores; García-Lozano, Juan Carlos; Pérez-Garrido, Rosario; Núñez, Ramiro; Antiñolo, Guillermo

2015-01-01

Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD). Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B). Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%), constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders. PMID:26258137

Prolonged Grief Disorder: Psychometric Validation of Criteria Proposed for DSM-V and ICD-11

PubMed Central

Prigerson, Holly G.; Horowitz, Mardi J.; Jacobs, Selby C.; Parkes, Colin M.; Aslan, Mihaela; Goodkin, Karl; Raphael, Beverley; Marwit, Samuel J.; Wortman, Camille; Neimeyer, Robert A.; Bonanno, George; Block, Susan D.; Kissane, David; Boelen, Paul; Maercker, Andreas; Litz, Brett T.; Johnson, Jeffrey G.; First, Michael B.; Maciejewski, Paul K.

2009-01-01

Background Bereavement is a universal experience, and its association with excess morbidity and mortality is well established. Nevertheless, grief becomes a serious health concern for a relative few. For such individuals, intense grief persists, is distressing and disabling, and may meet criteria as a distinct mental disorder. At present, grief is not recognized as a mental disorder in the DSM-IV or ICD-10. The goal of this study was to determine the psychometric validity of criteria for prolonged grief disorder (PGD) to enhance the detection and potential treatment of bereaved individuals at heightened risk of persistent distress and dysfunction. Methods and Findings A total of 291 bereaved respondents were interviewed three times, grouped as 0–6, 6–12, and 12–24 mo post-loss. Item response theory (IRT) analyses derived the most informative, unbiased PGD symptoms. Combinatoric analyses identified the most sensitive and specific PGD algorithm that was then tested to evaluate its psychometric validity. Criteria require reactions to a significant loss that involve the experience of yearning (e.g., physical or emotional suffering as a result of the desired, but unfulfilled, reunion with the deceased) and at least five of the following nine symptoms experienced at least daily or to a disabling degree: feeling emotionally numb, stunned, or that life is meaningless; experiencing mistrust; bitterness over the loss; difficulty accepting the loss; identity confusion; avoidance of the reality of the loss; or difficulty moving on with life. Symptoms must be present at sufficiently high levels at least six mo from the death and be associated with functional impairment. Conclusions The criteria set for PGD appear able to identify bereaved persons at heightened risk for enduring distress and dysfunction. The results support the psychometric validity of the criteria for PGD that we propose for inclusion in DSM-V and ICD-11. Please see later in the article for Editors' Summary PMID:19652695

Antibiotic treatment of urinary tract infection by community pharmacists: a cross-sectional study

PubMed Central

Booth, Jill L; Mullen, Alexander B; Thomson, David AM; Johnstone, Christopher; Galbraith, Susan J; Bryson, Scott M; McGovern, Elizabeth M

2013-01-01

Background Urinary tract infections (UTIs) are one of the most common conditions seen in female patients within primary care. Community pharmacists are familiar with symptomatic UTI management and supplying trimethoprim under patient group direction (PGD) for moderate-to-severe uncomplicated UTIs could improve patient access to treatment. Aim To compare the care pathway of patients with UTI symptoms attending GP services with those receiving management, including trimethoprim supply under PGD, via community pharmacies. Design and setting Prospective, cross-sectional, mixed methods approach in 10 community pharmacies within NHS Greater Glasgow and Clyde. Method Pharmacies invited a purposive sample of female patients to participate. Pharmacists had the option of supplying trimethoprim under PGD to patients with moderate-to-severe infection meeting the PGD inclusion criteria. Data from patient (questionnaires and semi-structured telephone interviews) and pharmacist (questionnaires and semi-structured, face-to-face interviews) were quantitatively and qualitatively analysed. Results Data were recorded on 153 patients, 97 presenting with GP prescriptions and 56 presenting directly in the pharmacy with symptoms suggestive of UTI, of whom 41 received trimethoprim via PGD and 15 received symptomatic management. Both GP adherence to local infection management guidelines and pharmacist application of PGD inclusion/exclusion criteria required improvement. There was demand and support, from patients and pharmacists, for access to antibiotic treatments for UTIs, without prescription, through community pharmacies. Conclusion Operating within PGD controls, antibiotic treatments for UTIs could be provided via community pharmacy to improve patient access to treatment which may also maintain antibiotic stewardship and reduce GP workload. PMID:23540480

Twenty-eight-year review of childhood renal diseases from renal biopsy data: A single centre in China.

PubMed

Jiang, Mengjie; Xiao, Zizheng; Rong, Liping; Xu, Yuanyuan; Chen, Lizhi; Mo, Ying; Sun, Liangzhong; Sun, Wei; Jiang, Xiaoyun

2016-12-01

The aim of the present study was to investigate the clinicopathologic characteristics of biopsy-proven childhood renal diseases and to compare the trends and changes during two different time intervals between 1984 and 2011 at the First Affiliated Hospital of Sun Yat-sen University in China. We retrospectively analyzed kidney biopsy data from children with renal diseases and compared the data during two time intervals, namely 1984-1997 and 1998-2011. A total of 1313 children were enrolled in the present study. There were 921 children with primary glomerular disease (PGD) and 312 children with secondary glomerular disease (SGD), accounting for 70.1% and 23.8% of participants, respectively. The major clinical manifestation of PGD was nephrotic syndrome (NS), which accounted for 31.2% of cases, while the main aetiology of SGD was lupus nephritis (40.7%). The main biopsy patterns of PGD were IgA nephritis (27.6%), minimal change disease (24.0%), and mesangial proliferative glomerulonephritis (16.9%). PGD was the major class of disease in both time intervals, but the ratio of PGD decreased over time, while the ratio of SGD and other glomerular diseases increased. PGD was also the major class of disease in each age group; however, the incidence of PGD decreased with increasing age. The incidence patterns of paediatric renal diseases changed over the 28-year period of this study. Our results show that different renal diseases characterize different age intervals. Furthermore, there are several associations between clinical presentation and biopsy features in childhood renal disease. © 2015 Asian Pacific Society of Nephrology.

Primary Graft Dysfunction and Mortality Following Lung Transplantation: A Role for Proadrenomedullin Plasma Levels.

PubMed

Riera, J; Senna, A; Cubero, M; Roman, A; Rello, J

2016-02-01

Primary graft dysfunction (PGD) after lung transplantation (LT) is a heterogeneous syndrome that comprises clinical presentations with diverse grades of severity. Proadrenomedullin (proADM) levels may be associated with PGD and may enhance its relationship with outcomes. We prospectively included 100 LT recipients. Plasma levels of proADM were measured at 24, 48 and 72 h after admission to the intensive care unit (ICU). We assessed their relationship with PGD grade and ICU mortality. Fifty patients (50%) presented grade 3 PGD at ICU admission. Twenty-two patients (22%) developed grade 3 PGD at 72 h, the only grade associated with higher mortality (odds ratio 6.84, 95% confidence interval [CI] 1.47-38.44). ProADM levels measured at 24 h (3.25 vs. 1.61 nmol/L; p = 0.016) and 72 h (2.17 vs. 1.35 nmol/L; p = 0.011) were higher in these patients than the rest of the population. When we added the individual predictive utility of grade 3 PGD at 72 h for ICU mortality (area under the curve [AUC] 0.72, 95% CI 0.53-0.90) to that of ProADM at 72 h, the predictive value of the model improved (AUC 0.81, 95% CI 0.65-0.97). Higher levels of proADM measured following LT are associated with grade 3 PGD at 72 h. ProADM enhances the association of this entity with mortality. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Indomethacin inhibits eosinophil migration to prostaglandin D2 : therapeutic potential of CRTH2 desensitization for eosinophilic pustular folliculitis.

PubMed

Kataoka, Naoko; Satoh, Takahiro; Hirai, Aiko; Saeki, Kazumi; Yokozeki, Hiroo

2013-09-01

Indomethacin is a cyclo-oxygenase inhibitor, and shows therapeutic potential for various eosinophilic skin diseases, particularly eosinophilic pustular folliculitis. One of the unique characteristics of indomethacin is that, unlike other non-steroidal anti-inflammatory drugs, it is a potent agonist of chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a receptor for prostaglandin D2 (PGD2 ). This study investigated the pharmacological actions of indomethacin on eosinophil migration to clarify the actual mechanisms underlying the therapeutic effects of indomethacin on eosinophilic pustular folliculitis. Eosinophils exhibited chemokinetic and chemotactic responses to both PGD2 and indomethacin through CRTH2 receptors. Pre-treatment of eosinophils with indomethacin greatly inhibited eosinophil migration to PGD2 and, to a much lesser extent, to eotaxin (CCL11); these effects could be mediated by homologous and heterologous desensitization of eosinophil CRTH2 and CCR3, respectively, by agonistic effects of indomethacin on CRTH2. Indomethacin also cancelled a priming effect of Δ(12) -PGJ2 , a plasma metabolite of PGD2 , on eosinophil chemotaxis to eotaxin. Indomethacin down-modulated cell surface expression of both CRTH2 and CCR3. Hair follicle epithelium and epidermal keratinocytes around eosinophilic pustules together with the eccrine apparatus of palmoplantar lesions of eosinophilic pustular folliculitis were immunohistochemically positive for lipocalin-type PGD synthase. Indomethacin may exert therapeutic effects against eosinophilic skin diseases in which PGD2 -CRTH2 signals play major roles by reducing eosinophil responses to PGD2 . © 2013 John Wiley & Sons Ltd.

Indomethacin inhibits eosinophil migration to prostaglandin D2: therapeutic potential of CRTH2 desensitization for eosinophilic pustular folliculitis

PubMed Central

Kataoka, Naoko; Satoh, Takahiro; Hirai, Aiko; Saeki, Kazumi; Yokozeki, Hiroo

2013-01-01

Summary Indomethacin is a cyclo-oxygenase inhibitor, and shows therapeutic potential for various eosinophilic skin diseases, particularly eosinophilic pustular folliculitis. One of the unique characteristics of indomethacin is that, unlike other non-steroidal anti-inflammatory drugs, it is a potent agonist of chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a receptor for prostaglandin D2 (PGD2). This study investigated the pharmacological actions of indomethacin on eosinophil migration to clarify the actual mechanisms underlying the therapeutic effects of indomethacin on eosinophilic pustular folliculitis. Eosinophils exhibited chemokinetic and chemotactic responses to both PGD2 and indomethacin through CRTH2 receptors. Pre-treatment of eosinophils with indomethacin greatly inhibited eosinophil migration to PGD2 and, to a much lesser extent, to eotaxin (CCL11); these effects could be mediated by homologous and heterologous desensitization of eosinophil CRTH2 and CCR3, respectively, by agonistic effects of indomethacin on CRTH2. Indomethacin also cancelled a priming effect of Δ12-PGJ2, a plasma metabolite of PGD2, on eosinophil chemotaxis to eotaxin. Indomethacin down-modulated cell surface expression of both CRTH2 and CCR3. Hair follicle epithelium and epidermal keratinocytes around eosinophilic pustules together with the eccrine apparatus of palmoplantar lesions of eosinophilic pustular folliculitis were immunohistochemically positive for lipocalin-type PGD synthase. Indomethacin may exert therapeutic effects against eosinophilic skin diseases in which PGD2-CRTH2 signals play major roles by reducing eosinophil responses to PGD2. PMID:23582181

Religious Scholars' Attitudes and Views on Ethical Issues Pertaining to Pre-Implantation Genetic Diagnosis (PGD) in Malaysia.

PubMed

Olesen, A; Nor, S N; Amin, L

2016-09-01

Pre-Implantation Genetic Diagnosis (PGD) represents the first fusion of genomics and assisted reproduction and the first reproductive technology that allows prospective parents to screen and select the genetic characteristics of their potential offspring. However, for some, the idea that we can intervene in the mechanisms of human existence at such a fundamental level can be, at a minimum, worrying and, at most, repugnant. Religious doctrines particularly are likely to collide with the rapidly advancing capability for science to make such interventions. This paper focuses on opinions and arguments of selected religious scholars regarding ethical issues pertaining to PGD. In-depth interviews were conducted with religious scholars from three different religious organizations in the Klang Valley, Malaysia. Findings showed that Christian scholars are very sceptical of the long-term use of PGD because of its possible effect on the value of humanity and the parent-children relationship. This differs from Islamic scholars, who view PGD as God-given knowledge in medical science to further help humans understand medical genetics. For Buddhist scholars, PGD is considered to be new medical technology that can be used to save lives, avoid suffering, and bring happiness to those who need it. Our results suggest that it is important to include the opinions and views of religious scholars when it comes to new medical technologies such as PGD, as their opinions will have a significant impact on people from various faiths, particularly in a multi-religious country like Malaysia where society places high value on marital relationships and on the traditional concepts of family.

Inhibition of prostaglandin D2 clearance in rat hepatocytes by the thromboxane receptor antagonists daltroban and ifetroban and the thromboxane synthase inhibitor furegrelate.

PubMed

Pestel, Sabine; Nath, Annegret; Jungermann, Kurt; Schieferdecker, Henrike L

2003-08-15

Prostanoids, i.e. prostaglandins and thromboxane, regulate liver-specific functions both in homeostasis and during defense reactions. For example, prostanoids are released from Kupffer cells, the resident liver macrophages, in response to the inflammatory mediator anaphylatoxin C5a, and mediate an enhanced glucose output from hepatocytes as energy supply. In perfused rat livers, the thromboxane receptor antagonist daltroban enhanced C5a-induced prostanoid overflow and reduced glucose output. It was the aim of this study to elucidate whether daltroban interfered with prostanoid release from Kupffer cells or prostanoid clearance by hepatocytes, and/or whether it directly influenced prostanoid-dependent glucose metabolism in these cells. In perfused rat livers, daltroban enhanced prostaglandin (PG)D(2) overflow not only after infusion of C5a (15-fold), but also after PGD(2) (10-fold). Neither daltroban nor another receptor antagonist, ifetroban, or the thromboxane synthase inhibitor furegrelate enhanced prostanoid release from Kupffer cells. In contrast, all inhibitors reduced clearance, i.e. uptake and degradation, of PGD(2) by hepatocytes: within 5 min uptake of 1 nmol/L PGD(2) was reduced from 43+/-5 fmol (controls) to 22+/-6 fmol (daltroban), 24+/-6 fmol (ifetroban) and 21+/-6 fmol (furegrelate). PGD(2) in the medium was reduced to 39+/-7% in the controls, but remained at 93+/-9%, 93+/-11% and 60+/-3% in the presence of the inhibitors. PGD(2)-dependent glucose output in the perfused liver or activation of glycogen phosphorylase in isolated hepatocytes remained unaffected by daltroban. These data clearly demonstrate that the thromboxane-inhibitors reduced PGD(2) clearance by hepatocytes, presumably by inhibition of prostanoid transport into the cells. In contrast, they did not interfere with PGD(2)-dependent glucose metabolism, suggesting an independent mechanism for the inhibition of glucose output from the liver.

Normothermic ex-vivo preservation with the portable Organ Care System Lung device for bilateral lung transplantation (INSPIRE): a randomised, open-label, non-inferiority, phase 3 study.

PubMed

Warnecke, Gregor; Van Raemdonck, Dirk; Smith, Michael A; Massard, Gilbert; Kukreja, Jasleen; Rea, Federico; Loor, Gabriel; De Robertis, Fabio; Nagendran, Jayan; Dhital, Kumud K; Moradiellos Díez, Francisco Javier; Knosalla, Christoph; Bermudez, Christian A; Tsui, Steven; McCurry, Kenneth; Wang, I-Wen; Deuse, Tobias; Lesèche, Guy; Thomas, Pascal; Tudorache, Igor; Kühn, Christian; Avsar, Murat; Wiegmann, Bettina; Sommer, Wiebke; Neyrinck, Arne; Schiavon, Marco; Calebrese, Fiorella; Santelmo, Nichola; Olland, Anne; Falcoz, Pierre-Emanuel; Simon, Andre R; Varela, Andres; Madsen, Joren C; Hertz, Marshall; Haverich, Axel; Ardehali, Abbas

2018-05-01

Severe primary graft dysfunction (PGD) of grade 3 (PGD3) is a common serious complication following lung transplantation. We aimed to assess physiological donor lung preservation using the Organ Care System (OCS) Lung device compared with cold static storage. In this non-inferiority, randomised, controlled, open-label, phase 3 trial (INSPIRE) recipients were aged 18 years or older and were registered as standard criteria primary double lung transplant candidates. Eligible donors were younger than 65 years old with a ratio of partial pressure of oxygen in arterial blood to the fraction of inspired oxygen of more than 300 mm Hg. Transplant recipients were randomly assigned (1:1) with permuted blocks, stratified by centre, to receive standard criteria donor lungs preserved in the OCS Lung device (OCS arm) or cold storage at 4°C (control arm). The composite primary effectiveness endpoint was absence of PGD3 within the first 72 h after transplant and 30-day survival in the per-protocol population, with a stringent 4% non-inferiority margin. Superiority was tested upon meeting non-inferiority. The primary safety endpoint was the mean number of lung graft-related serious adverse events within 30 days of transplant. We did analyses in the per-protocol and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, number NCT01630434. Between Nov 17, 2011, and Nov 24, 2014, we randomly assigned 370 patients, and 320 (86%) underwent transplantation (n=151 OCS and n=169 control); follow-up was completed in Nov 24, 2016. The primary endpoint was met in 112 (79·4%) of 141 patients (95% CI 71·8 to 85·8) in the OCS group compared with 116 (70·3%) of 165 patients (62·7 to 77·2) in the control group (non-inferiority point estimate -9·1%; 95% CI -∞ to -1·0; p=0·0038; and superiority test p=0·068). Patient survival at day 30 post-transplant was 135 (95·7%) of 141 patients (95% CI 91·0-98·4) in the OCS group and 165 patients (100%; 97·8-100·0) in the control group (p=0·0090) and at 12 months was 126 (89·4%) of 141 patients (83·1-93·9) for the OCS group compared with 146 (88·1%) of 165 patients (81·8-92·8) for the control group. Incidence of PGD3 within 72 h was reported in 25 (17·7%) of 141 patients in the OCS group (95% CI 11·8 to 25·1) and 49 (29·7%) of 165 patients in the control group (22·8 to 37·3; superiority test p=0·015). The primary safety endpoint was met (0·23 lung graft-related serious adverse events in the OCS group compared with 0·28 events in the control group [point estimate -0·045%; 95% CI -∞ to 0·047; non-inferiority test p=0·020]). In the intention-to-treat population, causes of death at 30 days and in hospital were lung graft failure or lung infection (n=2 for OCS vs n=7 for control), cardiac causes (n=4 vs n=1), vascular or stroke (n=3 vs n=0), metabolic coma (n=0 vs n=2), and generalised sepsis (n=0 vs n=1). The INSPIRE trial met its primary effectiveness and safety endpoints. Although no short-term survival benefit was reported, further research is needed to see whether the reduced incidence of PGD3 within 72 h of a transplant might translate into earlier recovery and improved long-term outcomes after lung transplantation. TransMedics Inc. Copyright © 2018 Elsevier Ltd. All rights reserved.

A Survey of the Island Province.

ERIC Educational Resources Information Center

McDowell, Stirling

1985-01-01

Briefly reviews some of the findings of the 1984 survey of public attitudes toward the provincial education system conducted by Prince Edward Island's School System Review Commission and discusses some of the commission's resulting 94 recommendations for improvement. (PGD)

Activated prostaglandin D2 receptors on macrophages enhance neutrophil recruitment into the lung

PubMed Central

Jandl, Katharina; Stacher, Elvira; Bálint, Zoltán; Sturm, Eva Maria; Maric, Jovana; Peinhaupt, Miriam; Luschnig, Petra; Aringer, Ida; Fauland, Alexander; Konya, Viktoria; Dahlen, Sven-Erik; Wheelock, Craig E.; Kratky, Dagmar; Olschewski, Andrea; Marsche, Gunther; Schuligoi, Rufina; Heinemann, Akos

2016-01-01

Background Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor–homologous molecule expressed on TH2 cells) in regulating macrophages have not been elucidated to date. Objective We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo. Methods In vitro studies, including migration, Ca2+ flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice. Results Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca2+ flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD2 receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD2-enhanced inflammatory response. Activation of PGD2 receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD2 synthesis. Conclusion For the first time, our results show that PGD2 markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation. PMID:26792210

Activated prostaglandin D2 receptors on macrophages enhance neutrophil recruitment into the lung.

PubMed

Jandl, Katharina; Stacher, Elvira; Bálint, Zoltán; Sturm, Eva Maria; Maric, Jovana; Peinhaupt, Miriam; Luschnig, Petra; Aringer, Ida; Fauland, Alexander; Konya, Viktoria; Dahlen, Sven-Erik; Wheelock, Craig E; Kratky, Dagmar; Olschewski, Andrea; Marsche, Gunther; Schuligoi, Rufina; Heinemann, Akos

2016-03-01

Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor-homologous molecule expressed on T(H)2 cells) in regulating macrophages have not been elucidated to date. We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo. In vitro studies, including migration, Ca(2+) flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice. Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca(2+) flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD2 receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD2-enhanced inflammatory response. Activation of PGD2 receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD2 synthesis. For the first time, our results show that PGD2 markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Prostaglandin D2 effects and DP1 /DP2 receptor distribution in guinea pig urinary bladder out-flow region.

PubMed

Guan, Na N; Svennersten, Karl; de Verdier, Petra J; Wiklund, N Peter; Gustafsson, Lars E

2017-02-01

The proximal urethra and urinary bladder trigone play important roles in continence. We have previously shown that PGD 2 is released from guinea pig bladder urothelium/suburothelium and can inhibit detrusor contractile responses. We presently wished to investigate PGD 2 actions in guinea pig out-flow region and the distribution of DP 1 /DP 2 receptors. The effects of PGD 2 on urothelium-intact trigone and proximal urethra contractility were studied in organ bath experiments. Expression of DP 1 /DP 2 receptor proteins was analysed by western blot. Immunohistochemistry was used to identify distribution of DP 1 /DP 2 receptors. PGD 2 in a dose-dependent manner inhibited trigone contractions induced by electrical field stimulation (EFS) and inhibited spontaneous contractions of the proximal urethra. PGD 2 was equally (trigone) or slightly less potent (urethra) compared with PGE 2 . Expression of DP 1 and DP 2 receptors was found in male guinea pig bladder trigone, neck and proximal urethra. In the trigone and proximal urethra, DP 1 receptors were found on the membrane of smooth muscle cells and weak immunoreactivty was observed in the urothelium. DP 2 receptors were distributed more widespread, weakly and evenly in the urothelium and smooth muscles. Inhibitory effects by PGD 2 on motor activity of guinea pig trigone and proximal urethra are consistent with finding DP 1 and DP 2 receptors located in the urothelium and smooth muscle cells of the trigone and proximal urethra, and PGD 2 may therefore be a modulator of the bladder out-flow region, possibly having a function in regulation of micturition and a role in overactive bladder syndrome. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Experiencing new forms of genetic choice: findings from an ethnographic study of preimplantation genetic diagnosis.

PubMed

Roberts, Celia; Franklin, Sarah

2004-12-01

Contemporary scientific and clinical knowledges and practices continue to make available new forms of genetic information, and to create new forms of reproductive choice. For example, couples at high risk of passing on a serious genetic condition to their offspring in Britain today have the opportunity to use Preimplantation Genetic Diagnosis (PGD) to select embryos that are unaffected by serious genetic disease. This information assists these couples in making reproductive choices. This article presents an analysis of patients' experiences of making the decision to undertake PGD treatment and of making reproductive choices based on genetic information. We present qualitative interview data from an ethnographic study of PGD based in two British clinics which indicate how these new forms of genetic choice are experienced by patients. Our data suggest that PGD patients make decisions about treatment in a complex way, taking multiple variables into account, and maintaining ongoing assessments of the multiple costs of engaging with PGD. Patients are aware of broader implications of their decisions, at personal, familial, and societal levels, as well as clinical ones. Based on these findings we argue that the ethical and social aspects of PGD are often as innovative as the scientific and medical aspects of this technique, and that in this sense, science cannot be described as "racing ahead" of society.

Lessons from the 2004 Asian tsunami: Nature, prevalence and determinants of prolonged grief disorder among tsunami survivors in South Indian coastal villages.

PubMed

Rajkumar, Anto P; Mohan, Titus Sp; Tharyan, Prathap

2015-11-01

Prolonged grief disorder (PGD), previously called complicated grief, is associated with significant distress and long-term disability, and it may complicate assessments for post-traumatic stress disorder (PTSD) after traumatic events. In order to distinguish PGD from PTSD, we conducted a cross-sectional survey among tsunami survivors in five tsunami-affected coastal villages in India, 9 months after the Asian tsunami. Prevalence of PGD among 643 tsunami survivors was 14.2% (95% confidence interval (CI): 11.5%-16.9%) and among the 351 bereaved survivors was 25.9% (95% CI: 21.3%-30.5%). Spousal bereavement, extensive damage to homes, fewer years of education, and absence of tsunami-related physical injury differentiated those with PGD, after adjusting for potential confounders (p < .05). These factors were distinct from the factors associated with post-traumatic stress symptoms (PTSS) among these survivors. Scores on the avoidance, hyper-arousal and intrusion subscales of the Impact of Events Scale-Revised were significantly lower in those with PGD alone than in those with PTSS or with both disorders. Our findings support the validity of PGD in a non-Western post-disaster community and its distinctness from PTSD. They have important public health implications in planning responses to natural disasters and for future revisions of diagnostic classifications. © The Author(s) 2015.

FMR1 CGG repeat expansion mutation detection and linked haplotype analysis for reliable and accurate preimplantation genetic diagnosis of fragile X syndrome.

PubMed

Rajan-Babu, Indhu-Shree; Lian, Mulias; Cheah, Felicia S H; Chen, Min; Tan, Arnold S C; Prasath, Ethiraj B; Loh, Seong Feei; Chong, Samuel S

2017-07-19

Fragile X mental retardation 1 (FMR1) full-mutation expansion causes fragile X syndrome. Trans-generational fragile X syndrome transmission can be avoided by preimplantation genetic diagnosis (PGD). We describe a robust PGD strategy that can be applied to virtually any couple at risk of transmitting fragile X syndrome. This novel strategy utilises whole-genome amplification, followed by triplet-primed polymerase chain reaction (TP-PCR) for robust detection of expanded FMR1 alleles, in parallel with linked multi-marker haplotype analysis of 13 highly polymorphic microsatellite markers located within 1 Mb of the FMR1 CGG repeat, and the AMELX/Y dimorphism for gender identification. The assay was optimised and validated on single lymphoblasts isolated from fragile X reference cell lines, and applied to a simulated PGD case and a clinical in vitro fertilisation (IVF)-PGD case. In the simulated PGD case, definitive diagnosis of the expected results was achieved for all 'embryos'. In the clinical IVF-PGD case, delivery of a healthy baby girl was achieved after transfer of an expansion-negative blastocyst. FMR1 TP-PCR reliably detects presence of expansion mutations and obviates reliance on informative normal alleles for determining expansion status in female embryos. Together with multi-marker haplotyping and gender determination, misdiagnosis and diagnostic ambiguity due to allele dropout is minimised, and couple-specific assay customisation can be avoided.

Practices and ethical concerns regarding preimplantation diagnosis. Who regulates preimplantation genetic diagnosis in Brazil?

PubMed Central

Damian, B.B.; Bonetti, T.C.S.; Horovitz, D.D.G.

2014-01-01

Preimplantation genetic diagnosis (PGD) was originally developed to diagnose embryo-related genetic abnormalities for couples who present a high risk of a specific inherited disorder. Because this technology involves embryo selection, the medical, bioethical, and legal implications of the technique have been debated, particularly when it is used to select features that are not related to serious diseases. Although several initiatives have attempted to achieve regulatory harmonization, the diversity of healthcare services available and the presence of cultural differences have hampered attempts to achieve this goal. Thus, in different countries, the provision of PGD and regulatory frameworks reflect the perceptions of scientific groups, legislators, and society regarding this technology. In Brazil, several texts have been analyzed by the National Congress to regulate the use of assisted reproduction technologies. Legislative debates, however, are not conclusive, and limited information has been published on how PGD is specifically regulated. The country requires the development of new regulatory standards to ensure adequate access to this technology and to guarantee its safe practice. This study examined official documents published on PGD regulation in Brazil and demonstrated how little direct oversight of PGD currently exists. It provides relevant information to encourage reflection on a particular regulation model in a Brazilian context, and should serve as part of the basis to enable further reform of the clinical practice of PGD in the country. PMID:25493379

Reprogenetics: Preimplantational genetics diagnosis

PubMed Central

Coco, Roberto

2014-01-01

Preimplantational Genetics Diagnosis (PGD) is requested by geneticists and reproductive specialists. Usually geneticists ask for PGD because one or both members of the couple have an increased genetic risk for having an affected offspring. On the other hand, reproductive specialists ask for embryo aneuploidy screening (PGS) to assures an euploid embryo transfer, with the purpose to achieve an ongoing pregnancy, although the couple have normal karyotypes. As embryonic aneuploidies are responsible for pre and post implantation abortions, it is logical to considerer that the screening of the embryonic aneuploidies prior to embryo transfer could improve the efficiency of the in vitro fertilization procedures. Nevertheless, it is still premature to affirm this until well-designed clinical trials were done, especially in women of advanced age where the rate of embryos with aneuploidies is much greater. Although the indications of PGD are similar to conventional prenatal diagnosis (PND), PGD has less ethical objections than the PND. As with the PGD/PGS results only unaffected embryos are transferred, both methods can avoid the decision to interrupt the pregnancy due to a genetic problem; this makes an important difference when compared to conventional prenatal diagnosis. PMID:24764761

Evidence for biochemical and physiological differences between enzyme genotypes in Drosophila melanogaster.

PubMed Central

Cavener, D R; Clegg, M T

1981-01-01

The in vivo flux of carbon through the pentose shunt is investigated as a function of different 6-phosphogluconate dehydrogenase (6Pgd) and glucose-6-phosphate dehydrogenase (G6pd) genotypes by using differential radioactive labeling of the C-1 and C-6 positions of glucose. Alternative 6Pgd-G6pd genotypes are shown to differ in relative in vivo carbon flux through the pentose shunt. The relative in vitro specific activity differences between the 6PgdSS and 6PgdFF genotypes appear to be primarily responsible for these differences. In addition, the pentose-shunt activity is correlated with the rate of lipid synthesis. This correlation is consistent with the major metabolic function of the pathway, which is to produce NADPH for lipid synthesis. Taken together, the results of these experiments show that different genotypes of 6Pgd are associated with measurable biochemical and physiological differences. Higher order phenotypic differences of this kind must be demonstrated to support the hypothesis that natural selection can discriminate among allozymes of a given genetic locus. PMID:6794031

Ethical issues in new uses of preimplantation genetic diagnosis: should parents be allowed to use preimplantation genetic diagnosis to choose the sexual orientation of their children?

PubMed

Dahl, Edgar

2003-07-01

Extending the application of preimplantation genetic diagnosis (PGD) to screen embryos for non-medical traits such as gender, height and intelligence, raises serious moral, legal, and social issues. In this paper I consider the possibility of using PGD to select the sexual orientation of offspring. After considering five potential objections, I conclude that parents should be permitted to use PGD to choose the sexual orientation of their children.

Single-tube tetradecaplex panel of highly polymorphic microsatellite markers < 1 Mb from F8 for simplified preimplantation genetic diagnosis of hemophilia A.

PubMed

Zhao, M; Chen, M; Tan, A S C; Cheah, F S H; Mathew, J; Wong, P C; Chong, S S

2017-07-01

Essentials Preimplantation genetic diagnosis (PGD) of severe hemophilia A relies on linkage analysis. Simultaneous multi-marker screening can simplify selection of informative markers in a couple. We developed a single-tube tetradecaplex panel of polymorphic markers for hemophilia A PGD use. Informative markers can be used for linkage analysis alone or combined with mutation detection. Background It is currently not possible to perform single-cell preimplantation genetic diagnosis (PGD) to directly detect the common inversion mutations of the factor VIII (F8) gene responsible for severe hemophilia A (HEMA). As such, PGD for such inversion carriers relies on indirect analysis of linked polymorphic markers. Objectives To simplify linkage-based PGD of HEMA, we aimed to develop a panel of highly polymorphic microsatellite markers located near the F8 gene that could be simultaneously genotyped in a multiplex-PCR reaction. Methods We assessed the polymorphism of various microsatellite markers located ≤ 1 Mb from F8 in 177 female subjects. Highly polymorphic markers were selected for co-amplification with the AMELX/Y indel dimorphism in a single-tube reaction. Results Thirteen microsatellite markers located within 0.6 Mb of F8 were successfully co-amplified with AMELX/Y in a single-tube reaction. Observed heterozygosities of component markers ranged from 0.43 to 0.84, and ∼70-80% of individuals were heterozygous for ≥ 5 markers. The tetradecaplex panel successfully identified fully informative markers in a couple interested in PGD for HEMA because of an intragenic F8 point mutation, with haplotype phasing established through a carrier daughter. In-vitro fertilization (IVF)-PGD involved single-tube co-amplification of fully informative markers with AMELX/Y and the mutation-containing F8 amplicon, followed by microsatellite analysis and amplicon mutation-site minisequencing analysis. Conclusions The single-tube multiplex-PCR format of this highly polymorphic microsatellite marker panel simplifies identification and selection of informative markers for linkage-based PGD of HEMA. Informative markers can also be easily co-amplified with mutation-containing F8 amplicons for combined mutation detection and linkage analysis. © 2017 International Society on Thrombosis and Haemostasis.

Preimplantation genetic diagnosis for cystic fibrosis: the Montpellier center's 10-year experience.

PubMed

Girardet, A; Ishmukhametova, A; Willems, M; Coubes, C; Hamamah, S; Anahory, T; Des Georges, M; Claustres, M

2015-02-01

This study provides an overview of 10 years of experience of preimplantation genetic diagnosis (PGD) for cystic fibrosis (CF) in our center. Owing to the high allelic heterogeneity of CF transmembrane conductance regulator (CFTR) mutations in south of France, we have set up a powerful universal test based on haplotyping eight short tandem repeats (STR) markers together with the major mutation p.Phe508del. Of 142 couples requesting PGD for CF, 76 have been so far enrolled in the genetic work-up, and 53 had 114 PGD cycles performed. Twenty-nine cycles were canceled upon in vitro fertilization (IVF) treatment because of hyper- or hypostimulation. Of the remaining 85 cycles, a total of 493 embryos were biopsied and a genetic diagnosis was obtained in 463 (93.9%), of which 262 (without or with a single CF-causing mutation) were transferable. Twenty-eight clinical pregnancies were established, yielding a pregnancy rate per transfer of 30.8% in the group of seven couples with one member affected with CF, and 38.3% in the group of couples whose both members are carriers of a CF-causing mutation [including six couples with congenital bilateral absence of the vas deferens (CBAVD)]. So far, 25 children were born free of CF and no misdiagnosis was recorded. Our test is applicable to 98% of couples at risk of transmitting CF. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The clinical application of single-sperm-based SNP haplotyping for PGD of osteogenesis imperfecta.

PubMed

Chen, Linjun; Diao, Zhenyu; Xu, Zhipeng; Zhou, Jianjun; Yan, Guijun; Sun, Haixiang

2018-05-15

Osteogenesis imperfecta (OI) is a genetically heterogeneous disorder, presenting either autosomal dominant, autosomal recessive or X-linked inheritance patterns. The majority of OI cases are autosomal dominant and are caused by heterozygous mutations in either the COL1A1 or COL1A2 gene. In these dominant disorders, allele dropout (ADO) can lead to misdiagnosis in preimplantation genetic diagnosis (PGD). Polymorphic markers linked to the mutated genes have been used to establish haplotypes for identifying ADO and ensuring the accuracy of PGD. However, the haplotype of male patients cannot be determined without data from affected relatives. Here, we developed a method for single-sperm-based single-nucleotide polymorphism (SNP) haplotyping via next-generation sequencing (NGS) for the PGD of OI. After NGS, 10 informative polymorphic SNP markers located upstream and downstream of the COL1A1 gene and its pathogenic mutation site were linked to individual alleles in a single sperm from an affected male. After haplotyping, a normal blastocyst was transferred to the uterus for a subsequent frozen embryo transfer cycle. The accuracy of PGD was confirmed by amniocentesis at 19 weeks of gestation. A healthy infant weighing 4,250 g was born via vaginal delivery at the 40th week of gestation. Single-sperm-based SNP haplotyping can be applied for PGD of any monogenic disorders or de novo mutations in males in whom the haplotype of paternal mutations cannot be determined due to a lack of affected relatives. ADO: allele dropout; DI: dentinogenesis imperfect; ESHRE: European Society of Human Reproduction and Embryology; FET: frozen embryo transfer; gDNA: genomic DNA; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; MDA: multiple displacement amplification; NGS: next-generation sequencing; OI: osteogenesis imperfect; PBS: phosphate buffer saline; PCR: polymerase chain reaction; PGD: preimplantation genetic diagnosis; SNP: single-nucleotide polymorphism; STR: short tandem repeat; TE: trophectoderm; WGA: whole-genome amplification.

Queerin' the PGD clinic : human enhancement and the future of bodily diversity.

PubMed

Sparrow, Robert

2013-06-01

Disability activists influenced by queer theory and advocates of "human enhancement" have each disputed the idea that what is "normal" is normatively significant, which currently plays a key role in the regulation of pre-implantation genetic diagnosis (PGD). Previously, I have argued that the only way to avoid the implication that parents have strong reasons to select children of one sex (most plausibly, female) over the other is to affirm the moral significance of sexually dimorphic human biological norms. After outlining the logic that generates this conclusion, I investigate the extent to which it might also facilitate an alternative, progressive, opening up of the notion of the normal and of the criteria against which we should evaluate the relative merits of different forms of embodiment. This paper therefore investigates the implications of ideas derived from queer theory for the future of PGD and of PGD for the future of queerness.

War and bereavement: consequences for mental and physical distress.

PubMed

Morina, Nexhmedin; von Lersner, Ulrike; Prigerson, Holly G

2011-01-01

Little is known about the long-term impact of the killing of a parent in childhood or adolescence during war on distress and disability in young adulthood. This study assessed current prevalence rates of mental disorders and levels of dysfunction among young adults who had lost their father due to war-related violence in childhood or adolescence. 179 bereaved young adults and 175 non-bereaved young adults were interviewed a decade after experiencing the war in Kosovo. Prevalence rates of Major Depressive Episode (MDE), anxiety, and substance use disorders, and current suicide risk were assessed using the Mini-International Neuropsychiatric Interview. The syndrome of Prolonged Grief Disorder (PGD) was assessed with the Prolonged Grief Disorder Interview (PG-13). Somatic symptoms were measured with the Patient Health Questionnaire. General health distress was assessed with the General Health Questionnaire. Bereaved participants were significantly more likely to suffer from either MDE or any anxiety disorder than non-bereaved participants (58.7% vs. 40%). Among bereaved participants, 39.7% met criteria for Post-Traumatic Stress Disorder, 34.6% for PGD, and 22.3% for MDE. Bereaved participants with PGD were more likely to suffer from MDE, any anxiety disorder, or current suicide risk than bereaved participants without PGD. Furthermore, these participants reported significantly greater physical distress than bereaved participants without PGD. War-related loss during middle childhood and adolescence presents significant risk for adverse mental health and dysfunction in young adulthood in addition to exposure to other war-related traumatic events. Furthermore, the syndrome of PGD can help to identify those with the greatest degree of distress and dysfunction.

PGD2 induces eotaxin-3 via PPARγ from sebocytes: a possible pathogenesis of eosinophilic pustular folliculitis.

PubMed

Nakahigashi, Kyoko; Doi, Hiromi; Otsuka, Atsushi; Hirabayashi, Tetsuya; Murakami, Makoto; Urade, Yoshihiro; Zouboulis, Christos C; Tanizaki, Hideaki; Egawa, Gyohei; Miyachi, Yoshiki; Kabashima, Kenji

2012-02-01

Eosinophilic pustular folliculitis (EPF) is a chronic intractable pruritic dermatosis characterized by massive eosinophil infiltrates involving the pilosebaceous units. Recently, EPF has been regarded as an important clinical marker of HIV infection, and its prevalence is increasing in number. The precise mechanism by which eosinophils infiltrate into the pilosebaceous units remains largely unknown. Given that indomethacin, a COX inhibitor, can be successfully used to treat patients with EPF, we can assume that COX metabolites such as prostaglandins (PGs) are involved in the etiology of EPF. To determine the involvement of PGs in the pathogenesis of EPF. We performed immunostaining for PG synthases in EPF skin lesions. We examined the effect of PGD(2) on induction of eotaxin, a chemoattractant for eosinophils, in human keratinocytes, fibroblasts, and sebocytes and sought to identify its responsible receptor. Hematopoietic PGD synthase was detected mainly in infiltrating inflammatory cells in EPF lesions, implying that PGD(2) was produced in the lesions. In addition, PGD(2) and its immediate metabolite 15-deoxy-Δ 12,14-PGJ(2) (15d-PGJ(2)) induced sebocytes to produce eotaxin-3 via peroxisome proliferator-activated receptor gamma. Consistent with the above findings, eotaxin-3 expression was immunohistochemically intensified in sebaceous glands of the EPF lesions. The PGD(2)/PGJ(2)-peroxisome proliferator-activated receptor gamma pathway induces eotaxin production from sebocytes, which may explain the massive eosinophil infiltrates observed around pilosebaceous units in EPF. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Establishing a comprehensive genetic diagnosis strategy for hemophilia B and its application in Chinese population.

PubMed

Lin, X Y; Wang, J; Xiao, X; Xu, Y W; Yan, Q J; Jiang, W Y

2018-04-01

To reduce the incidence of hemophilia B (HB) which with no complete cure currently, prenatal diagnosis and preimplantation genetic diagnosis (PGD) are effective and feasible means. However, previous studies about genetic diagnosis in HB mostly just focused on the detection of patients and carriers. Here, we established a comprehensive genetic diagnosis strategy for HB and worked it out in Chinese population. The strategy includes the detection of patients and carriers, prenatal diagnosis, and PGD. Seven unrelated HB families from Chinese population involved in this study. Firstly, probands and available members were carried out coagulation laboratory assays, and the clinical information has been recorded. Secondly, we used DNA direct sequencing to screen the whole FIX gene of them. The pathogenicity of novel mutations was verified according to 2015 ACMG-AM guidelines. For prenatal diagnosis, a mix of DNA direct sequencing and STR linkage analysis was employed. To explore a better PGD protocol, Karyomapping was first applied in PGD of HB, comparing with conventional PCR-based methods. Six different pathogenic mutations including 1 novel duplication (c.660_661dup ATCA) were identified. The results of prenatal diagnosis were consistent with birth outcomes. In the PGD case, 4 of 11 embryos were confirmed to be normal and one of them was transferred and led to a healthy birth. The established genetic diagnosis strategy for HB in our study was comprehensive and well applied in clinic practice. Besides, we recommended that DNA direct sequencing combined with Karyomapping was a better PGD protocol. © 2017 John Wiley & Sons Ltd.

Is pre-implantation genetic diagnosis (PGD) more of a strain regarding satisfaction with marital quality for male or female partners? A three-year follow-up study.

PubMed

Järvholm, Stina; Thurin-Kjellberg, Ann; Broberg, Malin

2017-04-27

Men and women with a hereditary genetic disease are faced with different options when they plan to become parents. One is pre-implantation genetic diagnosis (PGD) which is a combination of in vitro fertilization (IVF) and genetic analysis of the embryo before implantation. The present study focuses on how men and women planning for PGD experience the quality of marital satisfaction when they apply for treatment and again, three years later. The study was a prospective cohort study where all couples (n = 22) applying for PGD during 2010 and 2011 were eligible. Nineteen women and 17 men (i.e. 17 couples and two women) participated. Participants answered several questionnaires (Dyadic Adjustment Scale, Hospital Anxiety and Depression Scale and Parental Stress Questionnaire) before PGD treatment, and again three years later. Women who underwent PGD rated the quality of their marital relationship similarly to that of first-time parents and IVF couples, whereas men rated the marital quality somewhat lower than the contrasts groups. Satisfaction with marital quality was stable over the three-year period although men were less satisfied than women on both occasions. At year three, there was a significant correlation between martial satisfaction and parental stress in men, and between martial satisfaction and anxiety and depression in women. Men are equally, or more, affected by their situation than their female partners, with consequences for satisfaction with marital quality. For this reason they should be included in any counselling offered.

Inhibition of the pentose phosphate shunt by 2,3-diphosphoglycerate in erythrocyte pyruvate kinase deficiency.

PubMed

Tomoda, A; Lachant, N A; Noble, N A; Tanaka, K R

1983-07-01

Pentose phosphate shunt activity was studied by the release of 14CO2 from 14C-1-glucose and 14C-2-glucose in the red cells of five patients with pyruvate kinase deficiency and found to be significantly decreased after new methylene blue stimulation when compared to high reticulocyte controls. Incubated Heinz body formation was increased and the ascorbate cyanide test was positive in blood from these patients. The activity of glucose-6-phosphate dehydrogenase (G6PD) as well as that of 6-phosphogluconate dehydrogenase (6PGD) was inhibited to 20% of baseline in normal red cell haemolysate by 4 mM 2,3-diphosphoglycerate at pH 7.1. 2,3-Diphosphoglycerate was a competitive inhibitor with 6-phosphogluconate (Ki=1.05 mM) and a noncompetitive inhibitor with NADP (Ki=3.3 mM) for 6PGD. Since the intracellular concentrations of glucose-6-phosphate, 6-phosphogluconate and NADP are below their Kms for G6PD and 6PGD, the kinetic data suggest that increased concentrations of 2,3-diphosphoglycerate in pyruvate kinase deficient red cells are sufficiently high to suppress pentose phosphate shunt activity. This suppression may be an additional factor contributing to the haemolytic anaemia of pyruvate kinase deficiency, particularly during periods of infection or metabolic stress.

Evaluation of 1100 couples with recurrent pregnancy loss using conventional cytogenetic, PGD, and PGS: hype or hope.

PubMed

Farahmand, Kamelia; Kalantari, Hamid; Fakhri, Mostafa; Fazeli, Abolhasan Shahzadeh; Moradi, Shabnam Zari; Almadani, Navid; Hashemi, Mehrdad; Gourabi, Hamid; Mohseni-Meybodi, Anahita

2016-06-01

Recurrent pregnancy loss (RPL) is an important clinical problem, mostly resulting from chromosomal or genetic defects, while in 30-60% of cases, it is idiopathic. The aim of this study is to evaluate the frequency and types of chromosomal abnormalities, also pre-implantation genetic diagnosis (PGD) and pre-implantation genetic screening (PGS) outcomes among Iranian couples with RPL. This retrospective study was conducted on 1100 Iranian couples (2200 individuals) with RPL referred to Royan Institute between 2008 and 2014. Karyotyping had been performed using standard cytogenetic techniques. PGD results of RPL patients with abnormal karyotypes and PGS results of RPL patients with normal karyotypes were also analyzed. The frequency of chromosomal abnormalities in these patients was 4.95%. Women demonstrated more abnormalities (6.82%) in comparison to men (3.09%). The successful rate of pregnancy after PGD and PGS was 52 and 18.64%, respectively. The observation of 4.95% chromosomal abnormalities among the patients with RPL could support this hypothesis that there is a direct relationship between chromosomal abnormalities and RPL. More than half of the patients who underwent PGD had successful pregnancy; therefore, this approach can improve the success rate of pregnancy in them. The results of PGS cycles showed that this technique could increase the live birth rate in RPL patients.

Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin.

PubMed

Elf, S; Lin, R; Xia, S; Pan, Y; Shan, C; Wu, S; Lonial, S; Gaddh, M; Arellano, M L; Khoury, H J; Khuri, F R; Lee, B H; Boggon, T J; Fan, J; Chen, J

2017-01-12

The oxidative pentose phosphate pathway (PPP) is crucial for cancer cell metabolism and tumor growth. We recently reported that targeting a key oxidative PPP enzyme, 6-phosphogluconate dehydrogenase (6PGD), using our novel small-molecule 6PGD inhibitors Physcion and its derivative S3, shows anticancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase, exhibit non-immune hemolytic anemia upon exposure to aspirin and various antimalarial drugs. Inspired by these clinical observations, we examined the anticancer potential of combined treatment with 6PGD inhibitors and antimalarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to antimalarial agent dihydroartemisinin (DHA). Combined treatment with DHA and Physcion activates AMP-activated protein kinase, leading to synergistic inhibition of human leukemia cell viability. Moreover, our combined therapy synergistically attenuates tumor growth in xenograft nude mice injected with human K562 leukemia cells and cell viability of primary leukemia cells from human patients, but shows minimal toxicity to normal hematopoietic cells in mice as well as red blood cells and mononucleocytes from healthy human donors. Our findings reveal the potential for combined therapy using optimized doses of Physcion and DHA as a novel antileukemia treatment without inducing hemolysis.

Media debates and 'ethical publicity' on social sex selection through preimplantation genetic diagnosis (PGD) technology in Australia.

PubMed

Whittaker, Andrea

2015-01-01

This paper offers a critical discourse analysis of media debate over social sex selection in the Australian media from 2008 to 2014. This period coincides with a review of the National Health and Medical Research Council's Ethical Guidelines on the Use of Assisted Reproductive Technology in Clinical Practice and Research (2007), which underlie the regulation of assisted reproductive clinics and practice in Australia. I examine the discussion of the ethics of pre-implatation genetic diagnosis (PGD) within the media as 'ethical publicity' to the lay public. Sex selection through PGD is both exemplary of and interconnected with a range of debates in Australia about the legitimacy of certain reproductive choices and the extent to which procreative liberties should be restricted. Major themes emerging from media reports on PGD sex selection in Australia are described. These include: the spectre of science out of control; ramifications for the contestation over the public funding of abortion in Australia; private choices versus public authorities regulating reproduction; and the ethics of travelling overseas for the technology. It is concluded that within Australia, the issue of PGD sex selection is framed in terms of questions of individual freedom against the principle of sex discrimination - a principle enshrined in legislation - and a commitment to publically-funded medical care.

The flavonoid luteolin inhibits niacin-induced flush

PubMed Central

Papaliodis, D; Boucher, W; Kempuraj, D; Theoharides, T C

2008-01-01

Background and purpose: Sustained release niacin effectively lowers serum cholesterol, LDL and triglycerides, while raising HDL. However, 75% of patients experience cutaneous warmth and itching known as flush, leading to discontinuation. Acetylsalicylic acid (aspirin) reduces this flush only by about 30%, presumably through decreasing prostaglandin D2 (PGD2). We investigated whether niacin-induced flush in a rat model involves PGD2 and 5-HT, and the effect of certain flavonoids. Experimental approach: Three skin temperature measurements from each ear were recorded with an infrared pyrometer for each time point immediately before i.p. injection with either niacin or a flavonoid. The temperature was then measured every 10 min for 60 min. Key results: Niacin (7.5 mg per rat, equivalent to a human dose of 1750 mg per 80 kg) maximally increased ear temperature to 1.9±0.2 oC at 45 min. Quercetin and luteolin (4.3 mg per rat; 1000 mg per human), administered i.p. 45 min prior to niacin, inhibited the niacin effect by 96 and 88%, respectively. Aspirin (1.22 mg per rat; 325 mg per human) inhibited the niacin effect by only 30%. Niacin almost doubled plasma PGD2 and 5-HT, but aspirin reduced only PGD2 by 86%. In contrast, luteolin inhibited both plasma PGD2 and 5-HT levels by 100 and 67%, respectively. Conclusions and implications. Niacin-induced skin temperature increase is associated with PGD2 and 5-HT elevations in rats; luteolin may be a better inhibitor of niacin-induced flush because it blocks the rise in both mediators. PMID:18223672

When hope and grief intersect: rates and risks of prolonged grief disorder among bereaved individuals and relatives of disappeared persons in Colombia.

PubMed

Heeke, Carina; Stammel, Nadine; Knaevelsrud, Christine

2015-03-01

Forced disappearance is a frequent phenomenon in violent conflicts and regimes, yet little is known about unresolved grief processes as a possible outcome of the disappearance of a loved one. This study investigates prolonged grief disorder (PGD) and its risk factors in a sample of persons who lost a significant other to disappearance as compared with a sample of bereaved individuals, both groups having experienced displacement due to the armed conflict in Colombia. In a cross-sectional study conducted in four Colombian provinces, 73 persons who lost a significant other to disappearance and 222 bereaved individuals completed measures of PGD (PG-13), depression (HSCL-25), and PTSD (PCL-C) via face-to-face interviews. Trauma- and loss-related variables, including the extent to which significant others of disappeared persons hoped that their loved one was still alive, were assessed. Results indicated that 23% of participants who lost a significant other to disappearance met criteria for PGD as compared to 31.5% in bereaved participants. No differences were found between the two groups in terms of symptom severity of PGD, depression, posttraumatic stress disorder, or traumatic exposure. Regression analysis indicated that, among relatives and friends of disappeared persons, the extent of hope predicted PGD above and beyond depression severity whereas among bereaved persons, PGD was predicted by time since the loss, the number of traumatic events and symptom severity of PTSD and depression. The instruments were not validated for use in Colombia; generalizability of findings is limited. Forced disappearance is related to prolonged grief reactions, particularly when those left behind maintain hope that the disappeared person is still alive. Copyright © 2014 Elsevier B.V. All rights reserved.

War and Bereavement: Consequences for Mental and Physical Distress

PubMed Central

Morina, Nexhmedin; von Lersner, Ulrike; Prigerson, Holly G.

2011-01-01

Background Little is known about the long-term impact of the killing of a parent in childhood or adolescence during war on distress and disability in young adulthood. This study assessed current prevalence rates of mental disorders and levels of dysfunction among young adults who had lost their father due to war-related violence in childhood or adolescence. Methods 179 bereaved young adults and 175 non-bereaved young adults were interviewed a decade after experiencing the war in Kosovo. Prevalence rates of Major Depressive Episode (MDE), anxiety, and substance use disorders, and current suicide risk were assessed using the Mini–International Neuropsychiatric Interview. The syndrome of Prolonged Grief Disorder (PGD) was assessed with the Prolonged Grief Disorder Interview (PG-13). Somatic symptoms were measured with the Patient Health Questionnaire. General health distress was assessed with the General Health Questionnaire. Findings Bereaved participants were significantly more likely to suffer from either MDE or any anxiety disorder than non-bereaved participants (58.7% vs. 40%). Among bereaved participants, 39.7% met criteria for Post-Traumatic Stress Disorder, 34.6% for PGD, and 22.3% for MDE. Bereaved participants with PGD were more likely to suffer from MDE, any anxiety disorder, or current suicide risk than bereaved participants without PGD. Furthermore, these participants reported significantly greater physical distress than bereaved participants without PGD. Conclusion War-related loss during middle childhood and adolescence presents significant risk for adverse mental health and dysfunction in young adulthood in addition to exposure to other war-related traumatic events. Furthermore, the syndrome of PGD can help to identify those with the greatest degree of distress and dysfunction. PMID:21765944

Critical Issues for Dentistry: PGD Program Directors Respond.

ERIC Educational Resources Information Center

Atchison, Kathryn A.; Cheffetz, Susan E.

2002-01-01

Surveyed directors of programs in postgraduate education in general dentistry (PGD) about critical issues facing their programs. Identified 12 themes: lack of postdoctoral applicants; student quality; professionalism and attitudes; number of postdoctoral positions; lack of funding; quality of facilities; special patient care; program curriculum;…

The effectiveness of Grief-Help, a cognitive behavioural treatment for prolonged grief in children: study protocol for a randomised controlled trial.

PubMed

Spuij, Mariken; Prinzie, Peter; Dekovic, Maja; van den Bout, Jan; Boelen, Paul A

2013-11-20

There is growing recognition of a syndrome of disturbed grief referred to as prolonged grief disorder (PGD). PGD is mostly studied in adults, but clinically significant PGD symptoms have also been observed in children and adolescents. Yet, to date no effective treatment for childhood PGD exists. The aims of this study are: (1) to investigate the effectiveness of Grief-Help, a nine-session cognitive-behavioural treatment for childhood PGD, combined with five sessions of parental counselling, immediately after the treatment and at three, six and twelve months follow-up; (2) to examine tentative mediators of the effects of Grief-Help, (i.e., maladaptive cognitions and behaviours and positive parenting), and (3) to determine whether demographic variables, child personality, as well as symptoms of PGD, anxiety, and depression in parents moderate the treatment effectiveness. We will conduct a Randomised Controlled Trial (RCT) in which 160 children and adolescents aged 8-18 years are randomly allocated to cognitive behavioural Grief-Help or to a supportive counselling intervention; both treatments are combined with five sessions of parental counselling. We will recruit participants from clinics for mental health in the Netherlands. The primary outcome measure will be the severity of Prolonged Grief Disorder symptoms according to the Inventory of Prolonged Grief for Children (IPG-C). Secondary outcomes will include PTSD, depression and parent-rated internalizing and externalizing problems. Mediators like positive parenting and maladaptive cognitions and behaviours will be identified. We will also examine possible moderators including demographic variables (e.g. time since loss, cause of death), psychopathology symptoms in parents (PGD, anxiety and depression) and child personality. Assessments will take place in both groups at baseline, after the treatment-phase and three, six and twelve months after the post-treatment assessment. We aim to contribute to the improvement of mental health care for children and adolescents suffering from loss. By comparing Grief-Help with supportive counselling, and by investigating mediators and moderators of its effectiveness we hope to provide new insights in the effects of interventions for bereaved children, and their mechanisms of change. Netherlands Trial Register NTR3854.

The changing spectrum of primary glomerular diseases within 15 years: a survey of 3331 patients in a single Chinese centre.

PubMed

Zhou, Fu-de; Zhao, Ming-hui; Zou, Wan-zhong; Liu, Gang; Wang, Haiyan

2009-03-01

Primary glomerular disease (PGD) is the leading cause of end-stage renal disease (ESRD) in China. With the development of socioeconomic status of Chinese people in the last two decades, PGD in ESRD is intent to decrease. However, whether this affects the spectrum of PGD is not clear. The aim of the current study is to investigate the changing spectrum of PGD in China. The records of 5398 consecutive native renal biopsies performed in adults (>or=14 years of age) in our centre between 1993 and 2007 were retrospectively analysed. The criteria for renal biopsy and pathologic diagnosis were kept unchanged. The patients were grouped according to a 5-year interval, 1993-97 (period 1), 1998-2002 (period 2) and 2003-07 (period 3). Then they were divided into four groups according to age for stratified analysis: 14-24 years, 25-44 years, 45-59 years and the elderly (>or=60 years). Three thousand, three hundred and thirty-one patients were diagnosed with PGD. PGD remained the most common renal disease, accounting for 65.9%, 57.7% and 63.2% in period 1, 2 and 3, respectively, without any significant difference. The proportion of elder patients increased significantly from 0% in 1993 to 9.1% in 2007 (P < 0.001). Within 1993-97, the leading PGD was IgA nephropathy (50.7%), followed by non-IgA MsPGN (19.9%), membranous nephropathy (MN) (13.3%) and minimal change disease (MCD) (6.3%), while within 2003-07, the most common PGD was still IgAN (58.2%), but followed by MN (14.3%), MCD (13.4%) and non-IgA MsPGN (7.0%). The age-adjusted frequency of IgAN and MCD increased significantly from period 1 to period 3 (P < 0.01 and P < 0.001, respectively), while that of non-IgA MsPGN, EnPGN and MPGN decreased significantly (P < 0.001, P < 0.01 and P < 0.05, respectively). There was no significant change in the age-adjusted frequency of FSGS, MN and CreGN during the study period. However, when patients were stratified by age, a sixfold increase in frequency of FSGS was identified in the 14- to 24-year group (P < 0.01). The spectrum of primary glomerulonephritis has changed within the last 15 years. The relative frequency of non-IgA MsPGN, EnPGN and MPGN decreased significantly, while that of MCD and IgA nephropathy increased significantly. The relative frequency of FSGS increased significantly in younger patients.

BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD.

PubMed

Derks-Smeets, I A P; van Tilborg, T C; van Montfoort, A; Smits, L; Torrance, H L; Meijer-Hoogeveen, M; Broekmans, F; Dreesen, J C F M; Paulussen, A D C; Tjan-Heijnen, V C G; Homminga, I; van den Berg, M M J; Ausems, M G E M; de Rycke, M; de Die-Smulders, C E M; Verpoest, W; van Golde, R

2017-11-01

The aim of this study was to determine whether BRCA1/2 mutation carriers produce fewer mature oocytes after ovarian stimulation for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), in comparison to a PGD control group. A retrospective, international, multicenter cohort study was performed on data of first PGD cycles performed between January 2006 and September 2015. Data were extracted from medical files. The study was performed in one PGD center and three affiliated IVF centers in the Netherlands and one PGD center in Belgium. Exposed couples underwent PGD because of a pathogenic BRCA1/2 mutation, controls for other monogenic conditions. Only couples treated in a long gonadotropin-releasing hormone (GnRH) agonist-suppressive protocol, stimulated with at least 150 IU follicle stimulating hormone (FSH), were included. Women suspected to have a diminished ovarian reserve status due to chemotherapy, auto-immune disorders, or genetic conditions (other than BRCA1/2 mutations) were excluded. A total of 106 BRCA1/2 mutation carriers underwent PGD in this period, of which 43 (20 BRCA1 and 23 BRCA2 mutation carriers) met the inclusion criteria. They were compared to 174 controls selected by frequency matching. Thirty-eight BRCA1/2 mutation carriers (18 BRCA1 and 20 BRCA2 mutation carriers) and 154 controls proceeded to oocyte pickup. The median number of mature oocytes was 7.0 (interquartile range (IQR) 4.0-9.0) in the BRCA group as a whole, 6.5 (IQR 4.0-8.0) in BRCA1 mutation carriers, 7.5 (IQR 5.5-9.0) in BRCA2 mutation carriers, and 8.0 (IQR 6.0-11.0) in controls. Multiple linear regression analysis with the number of mature oocytes as a dependent variable and adjustment for treatment center, female age, female body mass index (BMI), type of gonadotropin used, and the total dose of gonadotropins administered revealed a significantly lower yield of mature oocytes in the BRCA group as compared to controls (p = 0.04). This finding could be fully accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50). Ovarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserve.

Prolonged grief and post-traumatic stress among relatives of missing persons and homicidally bereaved individuals: A comparative study.

PubMed

Lenferink, Lonneke I M; van Denderen, Mariëtte Y; de Keijser, Jos; Wessel, Ineke; Boelen, Paul A

2017-02-01

Traumatic loss (e.g., homicide) is associated with elevated prolonged grief disorder (PGD) and posttraumatic stress disorder (PTSD). Several studies comparing relatives of missing persons with homicidally bereaved individuals showed inconsistent results about the difference in PGD- and PTSD-levels between the groups. These studies were conducted in the context of armed conflict, which may confound the results. The current study aims to compare PGD- and PTSD-levels between the groups outside the context of armed conflict. Relatives of long-term missing persons (n=134) and homicidally bereaved individuals (n=331) completed self-report measures of PGD and PTSD. Multilevel regression modelling was used to compare symptom scores between the groups. Homicidally bereaved individuals reported significantly higher levels of PGD (d=0.86) and PTSD (d=0.28) than relatives of missing persons, when taking relevant covariates (i.e., gender, time since loss, and kinship to the disappeared/deceased person) into account. A limitation of this study is the use of self-report measures instead of clinical interviews. Prior studies among relatives of missing persons and homicidally bereaved individuals in the context of armed conflict may not be generalizable to similar samples outside these contexts. Future research is needed to further explore differences in bereavement-related psychopathology between different groups and correlates and treatment of this psychopathology. Copyright © 2016 Elsevier B.V. All rights reserved.

Peroxisome proliferator-activated receptor-γ is expressed in eosinophils in nasal polyps.

PubMed

Asaka, Chikara; Honda, Kohei; Ito, Eiko; Fukui, Naoko; Chihara, Junichi; Ishikawa, Kazuo

2011-01-01

Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptors, which regulate fatty acid metabolites. One of the natural ligands for PPARγ is 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), a major metabolite of prostaglandin D(2) (PGD(2)). Recently, PPARγ has been shown to play an important role in anti-inflammatory reactions, including within-airway allergic diseases, in a mouse model. Our aim was to clarify the expression and localization of PPARγ and PGD(2) synthase, which produces ligands of PPARγ, in nasal polyps by immunohistochemical analysis. Nasal polyps of chronic rhinosinusitis patients (6 asthmatic patients and 6 nonasthmatic patients) were obtained during surgery. May-Grünwald-Giemsa staining was performed to evaluate the eosinophil infiltration of the polyps. To identify the cells expressing PPARγ protein and PGD(2) synthase, double immunostaining was performed using anti-PPARγ antibody, monoclonal antileukocyte antibodies, and PGD(2) synthase antibody. The number of eosinophils and the number of PPARγ-positive cells in the nasal polyps of the asthmatic patients were significantly higher than those in the nonasthmatic patients. PPARγ was expressed on eosinophils and T cells of the infiltrating cells in the nasal polyps. PGD(2) synthase was also expressed on PPARγ-positive cells. PPARγ is involved in nasal polyposis pathogenesis, acting on eosinophils and T cells. Copyright © 2011 S. Karger AG, Basel.

[BETWEEN USAGE AND POLEMIC, AN ARGUMENT IN FAVOUR OF CLARIFYING THE TERMINOLOGY FOR PREIMPLANTATION GENETIC DIAGNOSIS].

PubMed

Côté, Stéphanie; Ravitsky, Vardit; Hamet, Pavel; Bouffard, Chantal

2015-12-01

Over 30 years ago, preimplantation genetic diagnosis (PGD) was developed to help couples at risk of transmitting a serious genetic disease to their offspring. Today, the range of medical and non-medical uses of PGD has expanded considerably and some raise much controversy. This is the case, for example, with In-Vitro Fertilization to select embryos as 'saviour siblings' or to screen for susceptibility and predisposition to late onset diseases or conditions of variable penetrance. The situation is even more problematic in the case of sex selection or selection of traits that are culturally valued or discredited (such as deafness, behavioral traits, or height). The debate surrounding PGD has been employing terms to describe these particular uses that have contributed to a focus on the negative effects, thus preventing a distinction between the abuses and the benefits of this reproductive technology. In this context, this paper proposes a terminological clarification that would allow distinguishing medical and non-medical use and, therefore, the issues relevant to each. A more accurate and less generic nomenclature could prevent a conflation of different levels of ethical, clinical and social issues under the single term 'PGD'. For the vast majority of medical uses, we propose to keep: 'preimplantation genetic diagnosis (PGD)', which emphasizes that it is a genetic diagnosis. For non-medical uses, we suggest: 'preimplantation genetic trait selection (PGTS)'.

The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus.

PubMed

Girardet, Anne; Viart, Victoria; Plaza, Stéphanie; Daina, Gemma; De Rycke, Martine; Des Georges, Marie; Fiorentino, Francesco; Harton, Gary; Ishmukhametova, Aliya; Navarro, Joaquima; Raynal, Caroline; Renwick, Pamela; Saguet, Florielle; Schwarz, Martin; SenGupta, Sioban; Tzetis, Maria; Roux, Anne-Françoise; Claustres, Mireille

2016-04-01

Cystic fibrosis (CF) is one of the most common indications for preimplantation genetic diagnosis (PGD) for single gene disorders, giving couples the opportunity to conceive unaffected children without having to consider termination of pregnancy. However, there are no available standardized protocols, so that each center has to develop its own diagnostic strategies and procedures. Furthermore, reproductive decisions are complicated by the diversity of disease-causing variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene and the complexity of correlations between genotypes and associated phenotypes, so that attitudes and practices toward the risks for future offspring can vary greatly between countries. On behalf of the EuroGentest Network, eighteen experts in PGD and/or molecular diagnosis of CF from seven countries attended a workshop held in Montpellier, France, on 14 December 2011. Building on the best practice guidelines for amplification-based PGD established by ESHRE (European Society of Human Reproduction and Embryology), the goal of this meeting was to formulate specific guidelines for CF-PGD in order to contribute to a better harmonization of practices across Europe. Different topics were covered including variant nomenclature, inclusion criteria, genetic counseling, PGD strategy and reporting of results. The recommendations are summarized here, and updated information on the clinical significance of CFTR variants and associated phenotypes is presented.

Pre-term birth and low birth weight following preimplantation genetic diagnosis: analysis of 88 010 singleton live births following PGD and IVF cycles.

PubMed

Sunkara, Sesh Kamal; Antonisamy, Belavendra; Selliah, Hepsy Y; Kamath, Mohan S

2017-02-01

Is PGD associated with the risk of adverse perinatal outcomes such as pre-term birth (PTB) and low birth weight (LBW)? There was no increase in the risk of adverse perinatal outcomes of PTB, and LBW following PGD compared with autologous IVF. Pregnancies resulting from ART are associated with a higher risk of pregnancy complications compared with spontaneously conceived pregnancies. The possible reason of adverse obstetric outcomes following ART has been attributed to the underlying infertility itself and embryo specific epigenetic modifications due to the IVF techniques. It is of interest whether interventions such as embryo biopsy as performed in PGD affect perinatal outcomes. Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA), the statutory regulator of ART in the UK. The HFEA has collected data prospectively on all ART performed in the UK since 1991. Data from 1996 to 2011 involving a total of 88 010 singleton live births were analysed including 87 571 following autologous stimulated IVF ± ICSI and 439 following PGD cycles. Data on all women undergoing either a stimulated fresh IVF ± ICSI treatment cycle or a PGD cycle during the period from 1996 to 2011 were analysed to compare perinatal outcomes of PTB and LBW among singleton live births. Logistic regression analysis was performed adjusting for female age category, year of treatment, previous IVF cycles, infertility diagnosis, number of oocytes retrieved, whether IVF or ICSI was used and day of embryo transfer. There was no increase in the risk of PTB and LBW following PGD versus autologous stimulated IVF ± ICSI treatment, unadjusted odds of PTB (odds ratio (OR) 0.68, 95% CI: 0.46-0.99) and LBW (OR 0.56, 95% CI: 0.37-0.85). After adjusting for the potential confounders, there was again no increase in the risk of the adverse perinatal outcomes following PGD: PTB (adjusted odds ratio (aOR) 0.66, 95% CI: 0.45-0.98) and LBW (aOR 0.58, 95% CI: 0.38-0.88). Although the analysis was adjusted for a number of important confounders, the data set had no information on confounders such as smoking, body mass index and the medical history of women during pregnancy to allow adjustment. There was no information on the stage of embryo at biopsy, whether blastomere or trophectoderm biopsy. The demonstration that PGD is not associated with higher risk of PTB and LBW provides reassurance towards its current expanding application. No funding was obtained. There are no competing interests to declare. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Intensity of pentose phosphate metabolism of carbohydrates in various brain areas in normal and starved animals].

PubMed

Kerimov, B F

2002-01-01

The activities of key enzymes of pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G-6 PD) and 6-phosphogluconate dehydrogenase (6-PGD), were studied in cytoplasmatic fractions of brain cortical (limbic, orbital, sensorimotor cortex) and subcortical (myelencefalon, mesencefalon, hypothalamus) structures of rats subjected to starvation for 1, 2, 3, 5 and 7 days. Short-term starvation (1-3 days) caused activation of 6-GPD and 6-PGD both in cortical and subcortical structures. Long-term starvation for 5-7 days caused a decrease of activities of the pentose phosphate pathway enzymes in all studied structures. It is suggested that enzymes of pentose phosphate pathway in nervous tissues are functionally and metabolically related to glutathione system and during starvation they indirectly participate in the regulation lipid peroxidation processes.

Lack of maintenance of gait pattern as measured by instrumental methods suggests psychogenic gait.

PubMed

Merello, Marcelo; Ballesteros, Diego; Rossi, Malco; Arena, Julieta; Crespo, Marcos; Cervio, Andres; Cuello Oderiz, Carolina; Rivero, Alberto; Cerquetti, Daniel; Risk, Marcelo; Balej, Jorge

2012-01-01

Fluctuation is a common feature of all psychogenic gait disorder (PGD) patterns. Whether this fluctuation involves only the degree of impairment or whether it affects the gait pattern itself remains an interesting question. We hypothesize that, on repeated measurements, both normal and abnormal gait may present quantitative differences while maintaining their basic underlying pattern; conversely, in psychogenic gait, the basic pattern appears not to be preserved. Using an optoelectronic system, data acquired from 19 normal subjects and 66 patients were applied to train a neural network (NN) and subsequently classify gait patterns into four different groups (normal, ataxic, spastic-paraparetic and parkinsonian). Five patients who fulfilled clinical criteria for psychogenic gait and six controls were then prospectively evaluated on two separate occasions, three months apart. Normal controls and ataxic, parkinsonian or spastic patients were correctly identified by the NN, and categorized within the corresponding groups at baseline as well as at a three-month follow-up evaluation. NN analysis showed that after three months, no PGD patient preserved the gait pattern detected at baseline, even though this finding was not clinically apparent. Modification of gait pattern detected by repeated kinematic measurement and NN analysis could suggest the presence of PGD, particularly in difficult-to-diagnose cases.

Protocol for the administration of haemofiltration fluids and using patient group electrolytes direction.

PubMed

Kingston, Diana; Sykes, Siobhan; Raper, Sarah

2002-01-01

A patient group direction (PGD) is a specific written instruction for the supply or administration of named medicines in an identified clinical situation The introduction of a PGD must demonstrate a benefit for patients Haemofiltration is widely accepted as the treatment of choice when caring for critically ill patients in acute renal failure on an intensive care unit The haemofiltration PGD improves patient care by providing standardisation in administration of fluids and electrolytes and enabling nurses to respond rapidly to changes in biochemistry during haemofiltration This paper describes the development and implementation of a protocol to enable nurses to administer haemofiltration fluids and electrolytes under a patient group direction.

Modification of dyskinesias following the intrastriatal injection of prostaglandins in the rodent.

PubMed Central

Costall, B.; Holmes, S. W.; Kelly, M. E.; Naylor, R. J.

1985-01-01

The abilities of prostaglandin E1 (PGE1), PGE2, PGD2 and PGF2 alpha to antagonize striatal dopamine function were assessed following bilateral and unilateral injections into the striata of the rat and guinea-pig. Three tests were used to assess the effects of the bilateral injections, ability to antagonize dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin (0.025 mg kg-1 s.c.), ability to antagonize stereotyped behaviour induced by apomorphine (0.5 or 2 mg kg-1 s.c.) and ability to induce catalepsy. Asymmetry/circling behaviour revealed on challenge with apomorphine (0.25 mg kg-1 s.c.) was measured following unilateral injection into the striatum. In the rat, dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin was antagonized by PGE1 (0.001-1 micrograms) and PGE2 (0.00001-1 micrograms) but not by PGD2 or PGF2 alpha (1 microgram). Stereotyped behaviour induced by apomorphine was not antagonized by any of the prostaglandins. A weak catalepsy was induced by PGE1 (1 microgram only), PGE2 (0.001-1 micrograms) and PGD2 (0.001-1 micrograms) but not by PGF2 alpha. Asymmetry and circling behaviour was only observed following the unilateral injection into the striatum of PGE1 and PGD2 (0.01-1 microgram) and challenge with apomorphine. In the guinea-pig the actions of PGE1 and E2 were compared with those of PGF2 alpha. Dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin was antagonized by bilateral injections into the striatum of PGE2 (0.001-1 microgram), but not PGE1 (0.5 micrograms) and PGF2 alpha (1 microgram) but not PGE, (0.5 micrograms) and PGF2 alpha (1 microgram).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3862460

Quantitative analysis of adipose tissue on chest CT to predict primary graft dysfunction in lung transplant recipients: a novel optimal biomarker approach

NASA Astrophysics Data System (ADS)

Tong, Yubing; Udupa, Jayaram K.; Wang, Chuang; Wu, Caiyun; Pednekar, Gargi; Restivo, Michaela D.; Lederer, David J.; Christie, Jason D.; Torigian, Drew A.

2018-02-01

In this study, patients who underwent lung transplantation are categorized into two groups of successful (positive) or failed (negative) transplantations according to primary graft dysfunction (PGD), i.e., acute lung injury within 72 hours of lung transplantation. Obesity or being underweight is associated with an increased risk of PGD. Adipose quantification and characterization via computed tomography (CT) imaging is an evolving topic of interest. However, very little research of PGD prediction using adipose quantity or characteristics derived from medical images has been performed. The aim of this study is to explore image-based features of thoracic adipose tissue on pre-operative chest CT to distinguish between the above two groups of patients. 140 unenhanced chest CT images from three lung transplant centers (Columbia, Penn, and Duke) are included in this study. 124 patients are in the successful group and 16 in failure group. Chest CT slices at the T7 and T8 vertebral levels are captured to represent the thoracic fat burden by using a standardized anatomic space (SAS) approach. Fat (subcutaneous adipose tissue (SAT)/ visceral adipose tissue (VAT)) intensity and texture properties (1142 in total) for each patient are collected, and then an optimal feature set is selected to maximize feature independence and separation between the two groups. Leave-one-out and leave-ten-out crossvalidation strategies are adopted to test the prediction ability based on those selected features all of which came from VAT texture properties. Accuracy of prediction (ACC), sensitivity (SEN), specificity (SPE), and area under the curve (AUC) of 0.87/0.97, 0.87/0.97, 0.88/1.00, and 0.88/0.99, respectively are achieved by the method. The optimal feature set includes only 5 features (also all from VAT), which might suggest that thoracic VAT plays a more important role than SAT in predicting PGD in lung transplant recipients.

["Designer baby" changed to French for "double hope baby"].

PubMed

Fagniez, P-L; Loriau, J; Tayar, C

2005-10-01

Scientific advances during the last decades regarding potential intervention on embryos arouse many questions in society to prepare the ground concerning the limits that should be set for these practices. For the first time in 1994, a parliamentary proceeding allowed the definition of a French model of bioethics through laws of the same name. These laws, among others, authorized in a well and strictly defined setting the practice of preimplantation genetic diagnosis (PGD). Because of technical progress concerning PGD, new questions arose, especially concerning the accomplishment of designer babies. The French Chamber of Representatives came in with a new law that banishes the concept of designer babies and replaces it with another concept: double hope babies, in French "bébé du double espoir". A first hope of a pregnancy giving birth to a healthy child and the second being that this child conceived with the aid of PGD could help treat an elder brother. Because of the issuing of two specific laws in a ten years interval, France occupies a privileged place in a Europe where bioethical issues continue to be debated, particularly PGD.

[Changes of prostaglandin D2,carboxypeptidase A3 and platelet activating factor in guinea pig in anaphylactic shock].

PubMed

Yang, Kai; Guo, Xiang-jie; Yan, Xue-bin; Gao, Cai-rong

2012-06-01

To detect the changes of leukotriene E4(LTE4), prostaglandin D2(PGD2), carboxypeptidase A3(CPA3) and platelet activating factor (PAF) in guinea pigs died from anaphylactic shock. Guinea pigs were used for establishing anaphylactic shock models. The levels of LTE4, PGD2 and CPA3, and PAF were detected in urine, plasma, and brain tissues with ELISA kit, respectively. The significant biomarkers were selected comparing with control group. The changes of PGD2, CPA3 and PAF in the guinea pigs at time zero, 12 and 24 hours after death were observed and compared respectively. The effect of platelet activating factor acetylhydrolase (PAF-AH) to PAF in guinea pig brain was examined and compared. There were no statistically differences of LTE4 levels in urine observed between experimental group and control group. The levels of CPA3, PGD2 and PAF in the experimental group were significantly higher than that in the control group at 0 h. The levels of PAF at 12 and 24 hours after anaphylactic shock were significantly higher than that in the control group. The levels of PAF decreased significantly after pretreatment with PAF-AH. LTE4 in urine cannot be selected as a biomarker to determine the anaphylactic shock. PGD2 and CPA3 in plasma, and PAF in brain tissue may be used as biomarkers to determine the anaphylactic shock. PAF-AH may be potentially useful for clinical treatment of anaphylactic shock.

Prostaglandin H2 induces the migration of human eosinophils through the chemoattractant receptor homologous molecule of Th2 cells, CRTH2.

PubMed

Schuligoi, Rufina; Sedej, Miriam; Waldhoer, Maria; Vukoja, Anela; Sturm, Eva M; Lippe, Irmgard T; Peskar, Bernhard A; Heinemann, Akos

2009-01-01

The major mast cell product PGD2 is released during the allergic response and stimulates the chemotaxis of eosinophils, basophils, and Th2-type T lymphocytes. The chemoattractant receptor homologous molecule of Th2 cells (CRTH2) has been shown to mediate the chemotactic effect of PGD2. PGH2 is the common precursor of all PGs and is produced by several cells that express cyclooxygenases. In this study, we show that PGH2 selectively stimulates human peripheral blood eosinophils and basophils but not neutrophils, and this effect is prevented by the CRTH2 receptor antagonist (+)-3-[[(4-fluorophenyl)sulfonyl] methyl amino]-1,2,3,4-tetrahydro-9H-carbazole-9-acetic acid (Cay10471) but not by the hematopoietic PGD synthase inhibitor 4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine (HQL79). In chemotaxis assays, eosinophils showed a pronounced migratory response toward PGH2, but eosinophil degranulation was inhibited by PGH2. Moreover, collagen-induced platelet aggregation was inhibited by PGH2 in platelet-rich plasma, which was abrogated in the presence of the D-type prostanoid (DP) receptor antagonist 3-[(2-cyclohexyl-2-hydroxyethyl)amino]-2,5-dioxo-1-(phenylmethyl)-4-imidazolidine-heptanoic acid (BWA868c). Each of these effects of PGH2 was enhanced in the presence of plasma and/or albumin. In eosinophils, PGH2-induced calcium ion (Ca2+) flux was subject to homologous desensitization with PGD2. Human embryo kidney (HEK)293 cells transfected with human CRTH2 or DP likewise responded with Ca2+ flux, and untransfected HEK293 cells showed no response. These data indicate that PGH2 causes activation of the PGD2 receptors CRTH2 and DP via a dual mechanism: by interacting directly with the receptors and/or by giving rise to PGD2 after catalytic conversion by plasma proteins.

A birth in non-mosaic Klinefelter's syndrome after testicular fine needle aspiration, intracytoplasmic sperm injection and preimplantation genetic diagnosis.

PubMed

Reubinoff, B E; Abeliovich, D; Werner, M; Schenker, J G; Safran, A; Lewin, A

1998-07-01

Non-mosaic Klinefelter patients are generally azoospermic due to primary testicular failure. Nevertheless, in some cases, testicular spermatozoa may be recovered and utilized to fertilize oocytes via intracytoplasmic sperm injection (ICSI). As the risk for an increased number of gonosomes in these spermatozoa is unclear, preimplantation genetic diagnosis (PGD) may be attempted in the resulting embryos. In the present study, we report our experience with the combined approach of sperm retrieval by testicular fine needle aspiration (FNA), ICSI and PGD in seven consecutive non-mosaic Klinefelter individuals. In four patients, between one and five spermatozoa were retrieved in five out of nine consecutive attempts. In a fifth patient, only 10 round spermatids could be isolated. Mature spermatozoa were injected into a total of 16 metaphase-II oocytes, of which 11 (69%) remained intact. Two distinct pronuclei (2PN) were observed in four oocytes (36%) while a single pronucleus (1PN) was documented in two oocytes. Five cleavage stage embryos developed from the oocytes of two couples. Upon the request of one couple, their three embryos (two derived from 1PN oocytes) were transferred without PGD but pregnancy was not achieved. PGD by fluorescence in-situ hybridization (FISH) was performed in the two embryos of the other couple which were derived from normal fertilization. PGD results of one embryo were 18,18,X,X,Y, the embryo was not transferred and FISH analysis of the remaining blastomeres identified variable chromosome numbers in the nuclei. The second embryo was diagnosed as normal and was transferred, resulting in a successful pregnancy and birth. In conclusion, the results of this report indicate that a pregnancy and birth may be attained in azoospermic non-mosaic Klinefelter individuals by testicular FNA combined with ICSI. Due to the unknown risk of gonosomes aneuploidy in embryos from Klinefelter patients, PGD or prenatal diagnosis should be recommended.

Preimplantation diagnosis to create 'saviour siblings': a critical discussion of the current and future legal frameworks in South Africa.

PubMed

Strode, Ann; Soni, Sheetal

2011-12-14

Pre-implantation genetic diagnosis (PGD) is a technology used in conjunction with in vitro fertilisation to screen embryos for genetic conditions prior to transfer. It was initially developed to screen mutations for severe, irreversible, genetic conditions. Currently, PGD makes it possible to select against more than 100 different genetic conditions. It has been proposed as a method for creating a tissue-matched child who can in turn serve as a compatible stem cell donor to save a sick sibling in need of a stem cell transplant. The advantage of this method is that it provides genetic information before implantation of an embryo into the womb, making it possible to ensure that only tissue-matched embryos are transferred to the uterus. A couple can therefore avoid the difficult choice of either terminating the pregnancy at a later point if the fetus is not a match, or extending their family again in the hope that their next child will be tissue compatible. Many people have expressed disapproval of the use of PGD for this purpose, and it is associated with many conflicting interests including religion, ethics as well as legal regulation. In order to manage these issues some jurisdictions have created legal frameworks to regulate the use of this technology. Many of these are modelled on the UK's Human Fertilisation and Embryology Authority and its guardian legislation. This paper critiques the current and future South African legal framework to establish whether it is able to adequately regulate the use of PGD as well as guard against misuse of the technology. It concludes that changes are required to the future framework in order to ensure that it regulates the circumstances in which PGD may occur and that the Minister of Health should act expediently in finalising draft regulations which will regulate PGD in the future.

Omega-3 Fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment.

PubMed

Tull, Samantha P; Yates, Clara M; Maskrey, Benjamin H; O'Donnell, Valerie B; Madden, Jackie; Grimble, Robert F; Calder, Philip C; Nash, Gerard B; Rainger, G Ed

2009-08-01

Inflammation is a physiological response to tissue trauma or infection, but leukocytes, which are the effector cells of the inflammatory process, have powerful tissue remodelling capabilities. Thus, to ensure their precise localisation, passage of leukocytes from the blood into inflamed tissue is tightly regulated. Recruitment of blood borne neutrophils to the tissue stroma occurs during early inflammation. In this process, peptide agonists of the chemokine family are assumed to provide a chemotactic stimulus capable of supporting the migration of neutrophils across vascular endothelial cells, through the basement membrane of the vessel wall, and out into the tissue stroma. Here, we show that, although an initial chemokine stimulus is essential for the recruitment of flowing neutrophils by endothelial cells stimulated with the inflammatory cytokine tumour necrosis factor-alpha, transit of the endothelial monolayer is regulated by an additional and downstream stimulus. This signal is supplied by the metabolism of the omega-6-polyunsaturated fatty acid (n-6-PUFA), arachidonic acid, into the eicosanoid prostaglandin-D(2) (PGD(2)) by cyclooxygenase (COX) enzymes. This new step in the neutrophil recruitment process was revealed when the dietary n-3-PUFA, eicosapentaenoic acid (EPA), was utilised as an alternative substrate for COX enzymes, leading to the generation of PGD(3). This alternative series eicosanoid inhibited the migration of neutrophils across endothelial cells by antagonising the PGD(2) receptor. Here, we describe a new step in the neutrophil recruitment process that relies upon a lipid-mediated signal to regulate the migration of neutrophils across endothelial cells. PGD(2) signalling is subordinate to the chemokine-mediated activation of neutrophils, but without the sequential delivery of this signal, neutrophils fail to penetrate the endothelial cell monolayer. Importantly, the ability of the dietary n-3-PUFA, EPA, to inhibit this process not only revealed an unsuspected level of regulation in the migration of inflammatory leukocytes, it also contributes to our understanding of the interactions of this bioactive lipid with the inflammatory system. Moreover, it indicates the potential for novel therapeutics that target the inflammatory system with greater affinity and/or specificity than supplementing the diet with n-3-PUFAs.

The effectiveness of Grief-Help, a cognitive behavioural treatment for prolonged grief in children: study protocol for a randomised controlled trial

PubMed Central

2013-01-01

Background There is growing recognition of a syndrome of disturbed grief referred to as prolonged grief disorder (PGD). PGD is mostly studied in adults, but clinically significant PGD symptoms have also been observed in children and adolescents. Yet, to date no effective treatment for childhood PGD exists. The aims of this study are: (1) to investigate the effectiveness of Grief-Help, a nine-session cognitive-behavioural treatment for childhood PGD, combined with five sessions of parental counselling, immediately after the treatment and at three, six and twelve months follow-up; (2) to examine tentative mediators of the effects of Grief-Help, (i.e., maladaptive cognitions and behaviours and positive parenting), and (3) to determine whether demographic variables, child personality, as well as symptoms of PGD, anxiety, and depression in parents moderate the treatment effectiveness. Methods/Design We will conduct a Randomised Controlled Trial (RCT) in which 160 children and adolescents aged 8–18 years are randomly allocated to cognitive behavioural Grief-Help or to a supportive counselling intervention; both treatments are combined with five sessions of parental counselling. We will recruit participants from clinics for mental health in the Netherlands. The primary outcome measure will be the severity of Prolonged Grief Disorder symptoms according to the Inventory of Prolonged Grief for Children (IPG-C). Secondary outcomes will include PTSD, depression and parent-rated internalizing and externalizing problems. Mediators like positive parenting and maladaptive cognitions and behaviours will be identified. We will also examine possible moderators including demographic variables (e.g. time since loss, cause of death), psychopathology symptoms in parents (PGD, anxiety and depression) and child personality. Assessments will take place in both groups at baseline, after the treatment-phase and three, six and twelve months after the post-treatment assessment. Discussion We aim to contribute to the improvement of mental health care for children and adolescents suffering from loss. By comparing Grief-Help with supportive counselling, and by investigating mediators and moderators of its effectiveness we hope to provide new insights in the effects of interventions for bereaved children, and their mechanisms of change. Trial registration Netherlands Trial Register NTR3854 PMID:24252587

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.

PubMed

Harper, Joyce C; Geraedts, Joep; Borry, Pascal; Cornel, Martina C; Dondorp, Wybo; Gianaroli, Luca; Harton, Gary; Milachich, Tanya; Kääriäinen, Helena; Liebaers, Inge; Morris, Michael; Sequeiros, Jorge; Sermon, Karen; Shenfield, Françoise; Skirton, Heather; Soini, Sirpa; Spits, Claudia; Veiga, Anna; Vermeesch, Joris Robert; Viville, Stéphane; de Wert, Guido; Macek, Milan

2013-11-01

In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005.

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy

PubMed Central

Harper, Joyce C; Geraedts, Joep; Borry, Pascal; Cornel, Martina C; Dondorp, Wybo; Gianaroli, Luca; Harton, Gary; Milachich, Tanya; Kääriäinen, Helena; Liebaers, Inge; Morris, Michael; Sequeiros, Jorge; Sermon, Karen; Shenfield, Françoise; Skirton, Heather; Soini, Sirpa; Spits, Claudia; Veiga, Anna; Vermeesch, Joris Robert; Viville, Stéphane; de Wert, Guido; Macek, Milan

2013-01-01

In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation – ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005. PMID:24225486

Prostaglandins in the kidney: developments since Y2K.

PubMed

Nasrallah, Rania; Clark, Jordan; Hébert, Richard L

2007-10-01

There are five major PGs (prostaglandins/prostanoids) produced from arachidonic acid via the COX (cyclo-oxygenase) pathway: PGE(2), PGI(2) (prostacyclin), PGD(2), PGF(2alpha) and TXA(2) (thromboxane A(2)). They exert many biological effects through specific G-protein-coupled membrane receptors, namely EP (PGE(2) receptor), IP (PGI(2) receptor), DP (PGD(2) receptor), FP (PGF(2alpha) receptor) and TP (TXA(2) receptor) respectively. PGs are implicated in physiological and pathological processes in all major organ systems, including cardiovascular function, gastrointestinal responses, reproductive processes, renal effects etc. This review highlights recent insights into the role of each prostanoid in regulating various aspects of renal function, including haemodynamics, renin secretion, growth responses, tubular transport processes and cell fate. A thorough review of the literature since Y2K (year 2000) is provided, with a general overview of PGs and their synthesis enzymes, and then specific considerations of each PG/prostanoid receptor system in the kidney.

Associations between Prolonged Grief Disorder, Depression, Posttraumatic Stress Disorder, and Anxiety in Rwandan Genocide Survivors

ERIC Educational Resources Information Center

Schaal, Susanne; Dusingizemungu, Jean-Pierre; Jacob, Nadja; Neuner, Frank; Elbert, Thomas

2012-01-01

A number of studies have demonstrated that symptoms of prolonged grief disorder (PGD) represent a symptom cluster distinct from bereavement-related depression, anxiety, and posttraumatic stress disorder (PTSD). The aim of the present study was to confirm and extend these findings using the most recent criteria defining PGD. The authors interviewed…

Regulating preimplantation genetic diagnosis in Australia: Disability and parental choice.

PubMed

de Souza, Michelle

2015-06-01

Preimplantation genetic diagnosis (PGD) is the process by which an early in vitro embryo is screened for a genetic condition. As the name suggests, the procedure is undertaken prior to the embryo being implanted into a woman and therefore affected embryos can be discarded. This article argues that the objections previously put forward opposing the use of PGD to select against disability are flawed. It also argues that permitting parents to act in a procreatively beneficent manner and to preserve their child's right to an open future are good reasons for parents to have the freedom to select against disability. In light of this, are there any sound reasons to limit the use of PGD to selection against serious disabilities?

Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction.

PubMed

Diamond, Joshua M; Akimova, Tatiana; Kazi, Altaf; Shah, Rupal J; Cantu, Edward; Feng, Rui; Levine, Matthew H; Kawut, Steven M; Meyer, Nuala J; Lee, James C; Hancock, Wayne W; Aplenc, Richard; Ware, Lorraine B; Palmer, Scott M; Bhorade, Sangeeta; Lama, Vibha N; Weinacker, Ann; Orens, Jonathan; Wille, Keith; Crespo, Maria; Lederer, David J; Arcasoy, Selim; Demissie, Ejigayehu; Christie, Jason D

2014-03-01

Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses. We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach. Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1. After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 × 10(-5)) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5' promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10(-5)). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells. Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted.

Metabolites of arachidonic acid formed by human gastrointestinal tissues and their actions on the muscle layers.

PubMed Central

Bennett, A.; Hensby, C. N.; Sanger, G. J.; Stamford, I. F.

1981-01-01

1. Gas chromatography-mass spectrometry demonstrated the presence of arachidonic acid (AA), 6-keto-prostaglandin F1 alpha and thromboxane B2 (TxB2) in all extracts of homogenized muscle or mucosa from human stomach, terminal ileum or sigmoid colon. Prostaglandin D2 (PGD2), PGE2 or PGF2 alpha were usually found more often in the mucosal extracts. The 12-hydroxy-derivative of AA (12-HETE) was detected in all extracts of the colon but in only some of the other tissues. 2. Most prostanoids tested contracted the longitudinal muscle, the order of potency being U-46619 (an epoxymethano analogue of PGH2) greater than PGE2 greater than PGF2 alpha greater than PGD2; PGI2 usually caused relaxation, whereas its breakdown products or TxB2 had weak and variable effects. 3. U-46619 or, less potently, PGF2 alpha contracted the circular muscle, whereas PGI2 and usually PGE2 caused relaxation. PGD2, 6-keto-PGF1 alpha, 6,15-diketo-PGF1 alpha or TxB2 usually had little or no effect. 4. PGI2 antagonized contractions to some excitatory prostanoids, without greatly affecting contractions to acetylcholine. 5. For both muscle layers there was a gradient in sensitivity to prostanoids along the gastrointestinal tract. The sensitivities were stomach greater than distal ileum greater than sigmoid colon. 6. The results are discussed in relation to gastrointestinal physiology and pathophysiology. PMID:7317691

Can Characteristics of Reciprocal Translocations Predict the Chance of Transferable Embryos in PGD Cycles?

PubMed Central

Dul, Elsbeth; van Echten-Arends, Jannie; Groen, Henk; Kastrop, Peter; Amory-van Wissen, Lucie; Engelen, John; Land, Jolande; Coonen, Edith; van Ravenswaaij-Arts, Conny

2014-01-01

Translocation carriers have an increased risk of miscarriage or the birth of a child with congenital anomalies. Preimplantation genetic diagnosis (PGD) is performed in translocation carriers to select for balanced embryos and, thus, increase the chance of an ongoing pregnancy. However, a common experience is that reciprocal translocation carriers produce a high percentage of unbalanced embryos, which cannot be transferred. Therefore, the pregnancy rates in PGD in this patient group are low. In a cohort of 85 reciprocal translocation carriers undergoing PGD we have searched for cytogenetic characteristics of the translocations that can predict the percentage of balanced embryos. Using shape algorithms, the most likely segregation mode per translocation was determined. Shape algorithm, breakpoint location, and relative chromosome segment sizes proved not to be independent predictors of the percentage of balanced embryos. The ratio of the relative sizes of the translocated segments of both translocation chromosomes can give some insight into the chance of transferable embryos: Very asymmetrical translocations have a higher risk of unbalanced products (p = 0.048). Counseling of the couples on the pros and cons of all their reproductive options remains very important. PMID:26237378

Can Characteristics of Reciprocal Translocations Predict the Chance of Transferable Embryos in PGD Cycles?

PubMed

Dul, Elsbeth; van Echten-Arends, Jannie; Groen, Henk; Kastrop, Peter; Wissen, Lucie Amory-van; Engelen, John; Land, Jolande; Coonen, Edith; van Ravenswaaij-Arts, Conny

2014-04-02

Translocation carriers have an increased risk of miscarriage or the birth of a child with congenital anomalies. Preimplantation genetic diagnosis (PGD) is performed in translocation carriers to select for balanced embryos and, thus, increase the chance of an ongoing pregnancy. However, a common experience is that reciprocal translocation carriers produce a high percentage of unbalanced embryos, which cannot be transferred. Therefore, the pregnancy rates in PGD in this patient group are low. In a cohort of 85 reciprocal translocation carriers undergoing PGD we have searched for cytogenetic characteristics of the translocations that can predict the percentage of balanced embryos. Using shape algorithms, the most likely segregation mode per translocation was determined. Shape algorithm, breakpoint location, and relative chromosome segment sizes proved not to be independent predictors of the percentage of balanced embryos. The ratio of the relative sizes of the translocated segments of both translocation chromosomes can give some insight into the chance of transferable embryos: Very asymmetrical translocations have a higher risk of unbalanced products (p = 0.048). Counseling of the couples on the pros and cons of all their reproductive options remains very important.

Single lung transplantation and fatal fat embolism acquired from the donor: management and literature review.

PubMed

López-Sánchez, Marta; Alvarez-Antoñán, Carlos; Arce-Mateos, Félix P; Gómez-Román, José; Quesada-Suescun, Antonio; Zurbano-Goñi, Felipe

2010-01-01

Fat embolism (FE) is a consequence of skeletal trauma that occurs in more than 90% of cases of severe trauma. However, most of these emboli are clinically insignificant. We report the case of a 59-yr-old man with massive progressive fibrosis who died from widespread FE after a single-lung transplantation (SLT). The lung donor was a 22-yr-old woman who died from traumatic cerebral injury. She had sustained a closed fracture of the tibia, fibula and pelvis. The PaO(2)/FiO(2) before procurement was 452 mmHg. A left SLT using cardiopulmonary bypass was performed. In the immediate postoperative period, profound pulmonary edema in the transplanted lung developed, with overinflation of the native lung and systemic hypotension. Severe Primary Graft Dysfunction (PGD) was suspected and nitric oxide (NO) and independent lung ventilation (ILV) initiated. Over the next 24 h the patient's condition deteriorated and extracorporeal membrane oxygenation (ECMO) was initiated. The patient died 45 h after transplantation as cardiovascular and respiratory function continued to decline and massive thoracic bleeding secondary to coagulopathy appeared. Post-mortem examination revealed both massive FE in the non-transplanted donor lung and in the allograft lung. Only two previous cases of donor-acquired FE and PGD after lung transplantation (LT) have been reported. Occult pulmonary FE in a traumatized donor should be considered a cause of PGD.

Sequential induction of prostaglandin E and D synthases in inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schuligoi, Rufina; Grill, Magdalena; Heinemann, Akos

Enhanced biosynthesis of prostaglandin (PG)D{sub 2} and subsequent formation of 15-deoxy-{delta}{sup 12,14}-PGJ{sub 2} has been suggested to contribute to resolution of inflammation. The primary aim of the present study in mouse heart was, therefore, to determine at the transcriptional level if there is sequential induction of PGE and PGD synthases (S) during inflammation. Expression of interleukin (IL)-1{beta} in heart was enhanced 4 h after systemic inflammation and declined thereafter within 3-5 days to basal levels. In contrast to cyclooxygenase-2 and membrane-bound (m)-PGES-1, which both peaked 4 h after endotoxin administration, hematopoietic (H)-PGDS expression was enhanced only 48 h after endotoxin.more » The expression of lipocalin-type (L)-PGDS was not significantly influenced. mRNA encoding the putative target of 15-deoxy-{delta}{sup 12,14}-PGJ{sub 2}, peroxisome proliferator-activated receptor {gamma}, was enhanced between 4 and 24 h after induction of inflammation. Treatment of mice with acetylsalicylic acid or indomethacin at doses effective to cause near-complete inhibition of PGE{sub 2} and PGD{sub 2} biosynthesis in heart ex vivo resulted in enhanced expression of IL-1{beta} 24 h after endotoxin administration. These results provide additional support for the hypothesis of a shift towards PGD{sub 2} biosynthesis during resolution of inflammation.« less

Integration of PGD-virtual charts into an engineering design process

NASA Astrophysics Data System (ADS)

Courard, Amaury; Néron, David; Ladevèze, Pierre; Ballere, Ludovic

2016-04-01

This article deals with the efficient construction of approximations of fields and quantities of interest used in geometric optimisation of complex shapes that can be encountered in engineering structures. The strategy, which is developed herein, is based on the construction of virtual charts that allow, once computed offline, to optimise the structure for a negligible online CPU cost. These virtual charts can be used as a powerful numerical decision support tool during the design of industrial structures. They are built using the proper generalized decomposition (PGD) that offers a very convenient framework to solve parametrised problems. In this paper, particular attention has been paid to the integration of the procedure into a genuine engineering design process. In particular, a dedicated methodology is proposed to interface the PGD approach with commercial software.

Fast model updating coupling Bayesian inference and PGD model reduction

NASA Astrophysics Data System (ADS)

Rubio, Paul-Baptiste; Louf, François; Chamoin, Ludovic

2018-04-01

The paper focuses on a coupled Bayesian-Proper Generalized Decomposition (PGD) approach for the real-time identification and updating of numerical models. The purpose is to use the most general case of Bayesian inference theory in order to address inverse problems and to deal with different sources of uncertainties (measurement and model errors, stochastic parameters). In order to do so with a reasonable CPU cost, the idea is to replace the direct model called for Monte-Carlo sampling by a PGD reduced model, and in some cases directly compute the probability density functions from the obtained analytical formulation. This procedure is first applied to a welding control example with the updating of a deterministic parameter. In the second application, the identification of a stochastic parameter is studied through a glued assembly example.

Intracytoplasmic sperm injection (ICSI) in 2006: evidence and evolution.

PubMed

2007-01-01

The introduction of intracytoplasmic sperm injection (ICSI) in 1992 has dramatically changed the management of severe male infertility. In severe male infertility, live birth rates with ICSI are superior to those with other non-donor treatments. In non-male infertility, however, pregnancy rates are not better with ICSI than with in vitro fertilization (IVF). With obstructive or non-obstructive azoospermia, reasonable pregnancy rates are now possible with ICSI after recovery of sperm from the testes followed by ICSI. Genetic counselling is indicated for severe male infertility, whether or not ICSI is considered. ICSI is indicated in preimplantation genetic diagnosis (PGD) to avoid contamination by extraneous DNA in the case of PCR-based testing and to increase the number of embryos available for testing. In turn, PGD may be indicated in pregnancies that are at high risk of aneuploidy because of genetic factors associated with azoospermia. As with IVF, not all couples succeed, but 2% of couples with failed ICSI cycles will conceive without treatment. ICSI outcome studies indicate that there is a significant increase in prematurity, low birthweight, and perinatal mortality associated with single and multiple births, similar to the outcomes of conventional IVF. However, as evidenced in long-term follow-up studies, the higher rates of urogenital abnormalities and increased use of healthcare may be associated with paternal characteristics.

Factorial structure of complicated grief: associations with loss-related traumatic events and psychosocial impacts of mass conflict amongst West Papuan refugees.

PubMed

Tay, Alvin Kuowei; Rees, Susan; Chen, Jack; Kareth, Moses; Silove, Derrick

2016-03-01

Definitions of complicated grief vary across diagnostic systems, being represented as persistent complex bereavement (PCB) in DSM-5 and prolonged grief disorder (PGD) in the proposed revision of the ICD system. A past study in a high-income country has identified a six-factor structure for complicated grief, but there are no data testing this or any other model across cultures. The present study reports findings from a survey amongst West Papuan refugees (n = 230, response rate = 92 %) residing in Port Moresby, Papua New Guinea. We applied culturally adapted measures of conflict-related traumatic event (TEs) (drawing specifically on domains of conflict and loss), symptoms of complicated grief adapted and modified to the culture, and a multidimensional psychosocial index of the broader effects of conflict and displacement. Confirmatory factor analysis yielded a single higher order construct of complicated grief comprising six factors of yearning/preoccupation; shock/disbelief; anger/negative appraisal; behavioural change; estrangement from others/impairment; and a novel dimension of confusion/diminished identity. In contrast, our analysis failed to support DSM or ICD models of PCB or PGD. A Multiple Indicators Multiple Causes (MIMIC) model revealed that traumatic loss and the sense of injustice each were associated with the unitary construct of complicated grief and its subdomains of yearning/preoccupation; shock/disbelief; anger/negative appraisal (exclusive to injustice); and estrangement from others/social impairment (exclusive to TE domain of conflict and loss). Conflict and loss associated with feelings of injustice may be especially pathogenic in generating the anger/negative appraisal component of complicated grief amongst refugees.

This School System Ensures that Reading Stays Fundamental.

ERIC Educational Resources Information Center

Thompson, Margery

1985-01-01

Reading Is Fundamental (RIF), Incorporated, has distributed over 57 million books in its 18 years. RIF programs have raised children's interest in reading and their levels of reading achievement, and have increased library use and parent involvement. The national RIF organization offers several forms of support for local programs. (PGD)

Discipline--Still Number One on the Administrator's List of Problems.

ERIC Educational Resources Information Center

Bartosh, Fred, Jr.; Barilla, John

1985-01-01

Describes the components of a discipline record system that can improve understanding of where, when, and why problems occur and what methods prove successful for handling them. Also identifies a number of factors that affect the success of discipline conferences between administrators and the parents of misbehaving students. (PGD)

Effect of Single vs Bilateral Lung Transplantation on Plasma Surfactant Protein D Levels in Idiopathic Pulmonary Fibrosis

PubMed Central

Beers, Michael F.; Ahya, Vivek N.; Kawut, Steven M.; Sims, Karen D.; Lederer, David J.; Palmer, Scott M.; Wille, Keith; Lama, Vibha N.; Shah, Pali D.; Orens, Jonathan B.; Bhorade, Sangeeta; Crespo, Maria; Weinacker, Ann; Demissie, Ejigayehu; Bellamy, Scarlett; Christie, Jason D.; Ware, Lorraine B.

2011-01-01

Background: Serum levels of surfactant protein D (SP-D) have been suggested as reflecting epithelial damage in acute lung injury, COPD, and idiopathic pulmonary fibrosis (IPF). However, little is known about SP-D levels in the setting of lung transplantation. Methods: We examined plasma SP-D levels in 104 subjects from a prospective, multicenter cohort study of lung allograft recipients. Plasma SP-D was measured by enzyme-linked immunosorbent assay prior to transplant and daily for 3 days after transplant. Results: Subjects undergoing transplant for IPF had higher baseline SP-D levels (median, 325 ng/mL) compared with subjects with cystic fibrosis, COPD, and pulmonary hypertension (median, 100, 80, and 82 ng/mL, respectively; P = .0001). Among subjects with IPF undergoing bilateral transplant, SP-D levels declined rapidly postoperatively. In contrast, SP-D levels in subjects undergoing single lung transplant for IPF remained significantly higher than those of bilateral allograft recipients. Among subjects undergoing single lung transplant for IPF, the development of primary graft dysfunction (PGD) was associated with a subsequent rise in SP-D levels, whereas SP-D levels in IPF subjects undergoing bilateral transplant declined, even in the presence of grade 3 PGD. Importantly, single lung allograft recipients without PGD had higher postoperative SP-D levels than bilateral allograft recipients with PGD. Conclusions: Subjects undergoing lung transplant for IPF have significantly higher baseline plasma SP-D levels compared with those with other diagnoses. Plasma SP-D is likely a biomarker of the air-blood barrier integrity in the native IPF lung, but may be less useful as a biomarker of PGD after transplant. PMID:21349925

Modification of Helicobacter pylori peptidoglycan enhances NOD1 activation and promotes cancer of the stomach

DOE PAGES

Suarez, Giovanni; Romero-Gallo, Judith; Piazuelo, M. Blanca; ...

2015-03-02

Helicobacter pylori is the strongest known risk factor for gastric carcinogenesis. One cancer-linked locus is the cag pathogenicity island, which translocates components of peptidoglycan (PGN) into host cells. NOD1 is an intracellular immune receptor that senses PGN from Gram-negative bacteria and responds by inducing autophagy and activating NF-κB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering PGN structure. We previously demonstrated that the H. pylori cag+ strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. Using 2D-DIGE and mass spectrometry, we identified a novel mutation within the gene encoding the peptidoglycan deacetylase PgdA; therefore,more » we sought to define the role of H. pylori PgdA in NOD1-dependent activation of NF-κB, inflammation, and cancer. Co-culture of H. pylori strain 7.13 or its pgdA$-$ isogenic mutant with AGS gastric epithelial cells or HEK293 epithelial cells expressing a NF-κB reporter revealed that pgdA inactivation significantly decreased NOD1-dependent NF-κB activation and autophagy. Infection of Mongolian gerbils with an H. pylori pgdA$-$ mutant strain led to significantly decreased levels of inflammation and malignant lesions in the stomach; however, pre-activation of NOD1 prior to bacterial challenge reciprocally suppressed inflammation and cancer in response to wild-type H. pylori. Expression of NOD1 differs in human gastric cancer specimens compared to non-cancer samples harvested from the same patients. In conclusion, these results indicate that PGN deacetylation plays an important role in modulating host inflammatory responses to H. pylori, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche.« less

Complex chromosomal rearrangement-a lesson learned from PGS.

PubMed

Frumkin, Tsvia; Peleg, Sagit; Gold, Veronica; Reches, Adi; Asaf, Shiri; Azem, Foad; Ben-Yosef, Dalit; Malcov, Mira

2017-08-01

The aim of the study is to report a case of non-diagnosed complex chromosomal rearrangement (CCR) identified by preimplantation genetic screening (PGS) followed by preimplantation genetic diagnosis (PGD) which resulted in a pregnancy and delivery of healthy offspring. A 29-year-old woman and her spouse, both diagnosed previously with normal karyotypes, approached our IVF-PGD center following eight early spontaneous miscarriages. PGS using chromosomal microarray analysis (CMA) was performed on biopsied trophectoderm. Fluorescence in situ hybridization (FISH), as well as re-karyotype, were performed on metaphase derived from peripheral blood of the couple. Subsequently, in the following PGD cycle, a total of seven blastocysts underwent CMA. A gain or loss at three chromosomes (3, 7, 9) was identified in six out of seven embryos in the first PGS-CMA cycle. FISH analysis of parental peripheral blood samples demonstrated that the male is a carrier of a CCR involving those chromosomes; this was in spite of a former diagnosis of normal karyotypes for both parents. Re-karyotype verified the complex translocation of 46,XY,t (3;7;9)(q23;q22;q22). Subsequently, in the following cycle, a total of seven blastocysts underwent PGD-CMA for the identified complex translocation. Two embryos were diagnosed with balanced chromosomal constitution. A single balanced embryo was transferred and pregnancy was achieved, resulting in the birth of a healthy female baby. PGS employing CMA is an efficient method to detect unrevealed chromosomal abnormalities, including complicated cases of CCR. The combined application of array CGH and FISH technologies enables the identification of an increased number of CCR carriers for which PGD is particularly beneficial.

Genetic Variation in the Prostaglandin E2 Pathway Is Associated with Primary Graft Dysfunction

PubMed Central

Akimova, Tatiana; Kazi, Altaf; Shah, Rupal J.; Cantu, Edward; Feng, Rui; Levine, Matthew H.; Kawut, Steven M.; Meyer, Nuala J.; Lee, James C.; Hancock, Wayne W.; Aplenc, Richard; Ware, Lorraine B.; Palmer, Scott M.; Bhorade, Sangeeta; Lama, Vibha N.; Weinacker, Ann; Orens, Jonathan; Wille, Keith; Crespo, Maria; Lederer, David J.; Arcasoy, Selim; Demissie, Ejigayehu; Christie, Jason D.

2014-01-01

Rationale: Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses. Objectives: We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach. Methods: Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1. Measurements and Main Results: After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 × 10−5) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5′ promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10−5). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells. Conclusions: Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted. PMID:24467603

Electrophoretic study of enzymes from cereal aphid populations : 4. Detection of hidden genetic variation within populations of the grain aphid Sitobion avenae (F.) (Hemiptera: Aphididae).

PubMed

Loxdale, H D; Rhodes, J A; Fox, J S

1985-07-01

A study of variation in three peptidases (PEP-3 to -5) in a parthenogenetic S. avenae field population at Rothamsted using serial one-dimensional polyacrylamide gel electrophoresis (involving changes of gel concentration and electrophoretic run-time) increased the overall number of "allozymes" (mobility variants) detected from 10 under standard conditions (6% gels, 2 h run-time) to 22, as well as revealing putative heterozygous banding patterns under some test conditions. However, an examination of another enzyme, 6-phosphogluconate dehydrogenase (6-PGD) in a sample collected at Rothamsted the following year failed, using a combination of serial methods (changes of gel concentration) and isoelectric focusing, to increase the total number of 6-PGD bands separated (seven, none of which appeared to be allelic in origin). Nevertheless, some major bands were split into several bands, whilst other infrequent bands were either gained or lost. The findings are briefly discussed.

Blood pressure and psychological distress among North Africans in France: The role of perceived personal/group discrimination and gender.

PubMed

Loose, Florence; Tiboulet, Marie; Maisonneuve, Christelle; Taillandier-Schmitt, Anne; Dambrun, Michael

2017-09-10

The purpose of this study was to examine the associations between perceived ethnic discrimination and (physical and mental) health indicators among North African women and men living in France. This study included 82 North Africans, aged 18-64 years. Perceived discrimination was measured at both group level (PGD) and personal level (PPD). The physical health indicator was blood pressure. The mental health indicator was self-reported psychological distress. Multiple regression analyses showed that higher levels of PGD predicted higher blood pressure. PPD was not related to blood pressure. PPD was positively related to psychological distress among women, but not among men. PPD and PGD are associated with physical and mental health indicators in different ways among North African women and men in France. © 2017 Wiley Periodicals, Inc.

Preimplantation genetic diagnosis for aneuploidy testing in women older than 44 years: a multicenter experience.

PubMed

Ubaldi, Filippo Maria; Cimadomo, Danilo; Capalbo, Antonio; Vaiarelli, Alberto; Buffo, Laura; Trabucco, Elisabetta; Ferrero, Susanna; Albani, Elena; Rienzi, Laura; Levi Setti, Paolo E

2017-05-01

To report laboratory and clinical outcomes in preimplantation genetic diagnosis for aneuploidies (PGD-A) cycles for women 44 to 47 years old. Multicenter, longitudinal, observational study. In vitro fertilization (IVF) centers. One hundred and thirty-seven women aged 44.7 ± 0.7 years (range: 44.0-46.7) undergoing 150 PGD-A cycles during April 2013 to January 2016. Quantitative polymerase chain reaction-based PGD-A on trophectoderm biopsies and cryopreserved euploid single-embryo transfer (SET). Primary outcome measure: delivery rate per cycle; secondary outcome measures: miscarriage rate, and the rate and reasons for cycle cancelation with subanalyses for female age and number of metaphase 2 oocytes retrieved. In 102 (68.0%) of 150 cycles blastocyst development was obtained, but only 21 (14.0%) were euploid blastocysts. The overall euploidy rate was 11.8% (22 of 187). Twenty-one SET procedures were performed, resulting in 13 clinical pregnancies, of which 1 miscarried and 12 delivered. The delivery rate was 57.1% per transfer, 8.0% per cycle, and 8.8% per patient. The logistic regression analysis found that only female age (odds ratio 0.78) and number of metaphase 2 oocytes retrieved (odds ratio 1.25) statistically significantly correlated with the likelihood of delivery. The delivery rate per cycle was 10.6% (11 of 104) in patients aged 44.0 to 44.9 years and 2.6% in patients aged 45.0 to 45.9 years (n = 1 of 38). No euploid blastocysts were found for patients older than 45.0 years. Extensive counseling based on biological and clinical data should be provided to women older than 43 years who are requesting IVF because of their very low odds of success and high risk for embryonic aneuploidies. Nevertheless, the low miscarriage and good delivery rates reported in this study in women with good ovarian reserve aged 44 should encourage the use of PGD-A in this population. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Scintigraphy at 3 months after single lung transplantation and observations of primary graft dysfunction and lung function.

PubMed

Belmaati, Esther Okeke; Iversen, Martin; Kofoed, Klaus F; Nielsen, Michael B; Mortensen, Jann

2012-06-01

Scintigraphy has been used as a tool to detect dysfunction of the lung before and after transplantation. The aims of this study were to evaluate the development of the ventilation-perfusion relationships in single lung transplant recipients in the first year, at 3 months after transplantation, and to investigate whether scintigraphic findings at 3 months were predictive for the outcome at 12 months in relation to primary graft dysfunction (PGD) and lung function. A retrospective study was carried out on all patients who prospectively and consecutively were referred for a routine lung scintigraphy procedure 3 months after single lung transplantation (SLTX). A total of 41 patients were included in the study: 20 women and 21 men with the age span of patients at transplantation being 38-66 years (mean ± SD: 54.2 ± 6.0). Patient records also included lung function tests and chest X-ray images. We found no significant correlation between lung function distribution at 3 months and PGD at 72 h. There was also no significant correlation between PGD scores at 72 h and lung function at 6 and 12 months. The same applied to scintigraphic scores for heterogeneity at 3 months compared with lung function at 6 and 12 months. Fifty-five percent of all patients had decreased ventilation function measured in the period from 6 to 12 months. Forty-nine percent of the patients had normal perfusion evaluations, and 51% had abnormal perfusion evaluations at 3 months. For ventilation evaluations, 72% were normal and 28% were abnormal. There was a significant difference in the normal versus abnormal perfusion and ventilation scintigraphic images evaluated from the same patients. Ventilation was distributed more homogenously in the transplanted lung than perfusion in the same lung. The relative distribution of perfusion and ventilation to the transplanted lung of patients with and without a primary diagnosis of fibrosis did not differ significantly from each other. We conclude that PGD defined at 72 h does not lead to recognizable changes in ventilation-perfusion scintigrapy at 3 months, and scintigraphic findings do not correlate with development in lung function in the first 12 months.

Extracorporeal life support in preoperative and postoperative heart transplant management.

PubMed

Bermudez, Christian A; McMullan, D Michael

2017-10-01

Increased experience with extracorporeal life support (ECLS) as a mode of cardiac support has expanded its use to diverse patient populations including patients requiring a bridge to heart transplantation and patients requiring posttransplant support for primary graft dysfunction (PGD). The use of ECLS is associated with acceptable outcomes in well-selected patients. While outcomes with the use of extracorporeal membrane oxygenation (ECMO) as a bridge to heart transplant have been variable, several series have confirmed the safe use of ECLS to stabilize patients prior to left ventricular assist device (LVAD) implantation. These patients are then considered later, when in stable condition, for heart transplant. When ECLS is used prior to heart transplant, mortality is greatest during the first 6 months posttransplant. Patients who are alive 6 months after transplant appear to have similar survival rates as patients who were not supported with ECLS prior to transplant. ECLS support is a reliable therapeutic option for severe PGD and early graft failure after heart transplantation. In patients who require support for severe PGD, venoarterial-ECMO appears to result in better clinical outcomes than LVAD support. ECLS use for PGD after heart transplant continues to be the first line of support. Further studies are necessary to understand the optimal role of ECLS in heart transplantation.

Predictive value of sperm-FISH analysis on the outcome of preimplantation genetic diagnosis (PGD) for a pericentric inversion inv5(p15.3q11.2) carrier.

PubMed

Bernicot, I; Dechanet, C; Mace, A; Hedon, B; Hamamah, S; Pellestor, F; Anahory, T

2010-07-01

Pericentric inversions (PIs) are structural chromosomal abnormalities, potentially associated with infertility or multiple miscarriages. More rarely, at meiosis, odd numbers of genetic recombinations within the inversion loop produce recombinant gametes which may lead to aneusomy of recombination in the offspring. We report a FISH segregation analysis of an inv5(p15.3q11.2) carrier, both in sperm and blastomeres. In sperm, we directly evaluated the proportion of recombinant gametes and compared the results with chromosomal abnormalities found in blastomeres collected from embryos obtained following a preimplantation genetic diagnosis (PGD) procedure. A total of 7006 sperm nuclei were analyzed. The size of the inverted segment represented 27% of the total length of chromosome 5. The frequencies of balanced chromosomes (normal or inverted), recombinant chromosomes and unbalanced combinations were 97.1, 0.17 and 2.73%, respectively. Of six embryos, PGD FISH analysis revealed that one was a balanced embryo, whereas five were unbalanced and there were no recombinants. This study demonstrated the value of sperm-FISH analysis in providing reproductive genetic counseling for PI carriers. Our study also highlights the clinical relevance of performing PGD instead of prenatal diagnosis.

Choosing embryos: ethical complexity and relational autonomy in staff accounts of PGD

PubMed Central

Ehrich, Kathryn; Williams, Clare; Farsides, Bobbie; Sandall, Jane; Scott, Rosamund

2007-01-01

The technique of preimplantation genetic diagnosis (PGD) is commonly explained as a way of checking the genes of embryos produced by IVF for serious genetic diseases. However, complex accounts of this technique emerged during ethics discussion groups held for PGD staff. These form part of a study exploring the social processes, meanings and institutions that frame and produce ‘ethical problems’ for practitioners, scientists and others working in the specialty of PGD in the UK. Two ‘grey areas’ raised by staff are discussed in terms of how far staff are, or in the future may be, able to support autonomous choices of women/couples: accepting ‘carrier’ embryos within the goal of creating a ‘healthy’ child; and sex selection of embryos for social reasons. These grey areas challenged the staff's resolve to offer individual informed choice, in the face of their awareness of possible collective social effects that might ensue from individual choices. We therefore argue that these new forms of choice pose a challenge to conventional models of individual autonomy used in UK genetic and reproductive counselling, and that ‘relational autonomy’ may be a more suitable ethical model to describe the ethical principles being drawn on by staff working in this area. PMID:18092985

[Extending preimplantation genetic diagnosis to HLA typing: the French exception].

PubMed

Steffann, Julie; Frydman, Nelly; Burlet, Philippe; Gigarel, Nadine; Hesters, Laetitia; Kerbrat, Violaine; Lamazou, Frédéric; Munnich, Arnold; Frydman, René

2011-01-01

Umut-Talha, a "sibling savior", was born on 26 January 2011 at Beclère Hospital after embryo selection at the Paris preimplantation genetic diagnosis (PGD) center. His birth revived the controversy over "double PGD". This procedure, authorized in France since 2006, allows couples who already have a child with a serious, incurable genetic disease, to opt for PGD in order to select a healthy embryo that is HLA-matched to the affected sibling and who may thus serve as an ombilical cord blood donor. The procedure is particularly complex and the baby take-home rate is still very low. Double PGD is strictly regulated in France, and candidate couples must first receive individual authorization from the Biomedicine Agency. In our experience, these couples have a strong desire to have children, as reflected by the large number of prior spontaneous pregnancies (25% of couples). Likewise, most of these couples request embryo transfer even when there is no HLA-matched embryo, which accounts for more than half of embryo transfers. The controversy surrounding this practice has flared up again in recent weeks, over the concepts of "designer babies" and "double savior siblings" (the baby is selected to be free of the hereditary disease, and may also serve as a stem cell donor for the affected sibling).

Punctuated HT/UHT metamorphism during prolonged Archean orogenesis in the Pikwitonei Granulite Domain revealed by garnet petrochronology

NASA Astrophysics Data System (ADS)

Dragovic, Besim; Guevara, Victor; Caddick, Mark; Couëslan, Chris; Baxter, Ethan

2017-04-01

Fundamental to every modern continent's early (Archean) history is the generation of high temperature conditions required to produce the dense, strong, relatively anhydrous rocks that comprise most of Earth's stable cratonic crust. While the thermal gradients supported in Archean terranes are better understood, the timescales over which these conditions occur are more enigmatic. Garnet petrochronology allows for the interrogation of a semi-continuous record of these tectonometamorphic conditions, by linking pressure-temperature-fluid conditions (using phase equilibria modeling, trace element thermometry, stable isotope geochemistry) to a precise chronologic/chronometric record (e.g. high-precision Sm-Nd geochronology, geospeedometry of major and trace element diffusion profiles). Here, we utilize techniques from this burgeoning field of study to elucidate the rates and conditions of high temperature/ultra-high temperature (HT/UHT) metamorphism in the 2.7 Ga Pikwitonei Granulite Domain (PGD). The PGD represents over 150,000 km2 of dominantly granulite-facies metamorphic rocks situated at the NW edge of the Superior Province. Peak temperatures in the region range from 760°C in the southernmost part of the PGD, to 900-960˚C in the central/western PGD ( 40-60 km apart). Previous studies have suggested that metamorphism was long-lived in the region, occurring over 100 Ma, from 2.71-2.60 Ga [1, 2, 3]. High-precision garnet geochronology on microsampled garnets provides a detailed growth history of several lithologies across the region. Where necessary, bulk garnet analysis (i.e. dating based upon multiple whole garnet crystals rather than portions thereof) was also performed. While cooling from HT/UHT will result in some degree of intra-mineral age resetting, a detailed isotopic study of a range of large garnet porphyroblasts from the PGD (those which would be variably reset depending on peak T, grain size, and initial cooling rate) can retain information about both prograde, peak, and initial cooling history of the region. For example, fifteen Sm-Nd garnet ages were determined from a 7cm garnet from the southern PGD (peak T of 760˚C). The initiation of garnet growth was calculated to be 2666 ± 3 Ma, with the termination of garnet growth at 2610 ± 2 Ma, providing a growth duration of 56 ± 3 Ma. Across the larger, hotter, central and western parts of the PGD (peak T of 900-960˚C), major element zoning is preserved in garnets from throughout these localities, implying ultrahigh-temperature conditions over significantly shorter timescales. This suggests that while HT metamorphic conditions can be maintained region-wide for tens of Myr, punctuated UHT conditions that last for Myr to sub-Myr timescales occur locally. By integrating these petrochronological techniques to decipher P-T conditions and timescales, on samples from across the PGD, we seek to provide insight into the mechanisms for diachronous crustal heating and the formation of stable cratonic lithosphere. [1] Smit et al., 2013. EPSL, 381, 222-233. [2] Heaman et al., 2011. Can. J. Earth. Sci., 48, 205-245. [3] Guevara et al., 2016. AGU abstracts with programs

Single blastomere removal from murine embryos is associated with activation of matrix metalloproteinases and Janus kinase/signal transducers and activators of transcription pathways of placental inflammation

PubMed Central

Sato, Brittany L.M.; Sugawara, Atsushi; Ward, Monika A.; Collier, Abby C.

2014-01-01

Single blastomere removal from cleavage-stage embryos, a common procedure used in conjunction with preimplantation genetic diagnosis (PGD), may affect reproductive outcomes. We hypothesized that negative pregnancy outcomes associated with PGD may be due to impairment of placental signaling pathways. The goal of this study was to determine the molecular mechanisms through which placental signaling is deregulated by blastomere removal. Four-cell stage murine embryos produced by in vitro fertilization were subjected to removal of a single blastomere (biopsied) or to the same manipulations without the blastomere removal (controls). Placental tissues from term (18.5 day) pregnancies obtained after embryo transfer were tested for levels of nitrosative species, interleukin 6, signal transducers and activators of transcription (STAT) 1 and 3, suppressors of cytokine signaling (SOCS) 1, 2 and 3 and matrix metalloproteinases (MMP) 1, 2, 3 and 9. Significant increases in nitrosative stress (P < 0.05), phosphorylative activation of STAT1 (P < 0.05) but not STAT3, lower levels of the inhibitors SOCS2 (P < 0.01) and SOCS3 (P < 0.001) and activation of MMP9 (P < 0.001) were observed in placentas derived from biopsied embryos, compared with controls. Such effects could contribute to greater levels of premature membrane rupture, incorrect parturition, preterm birth and intrauterine growth restriction associated with PGD. This work has determined signaling mechanisms that may be responsible for blastomere removal effects on placental function, with the potential to become targets for improving obstetric and neonatal outcomes in assisted reproduction. PMID:25180268

Diagnostic and clinical considerations in prolonged grief disorder.

PubMed

Maercker, Andreas; Lalor, John

2012-06-01

This review focuses on the similarities and differences between prolonged grief disorder (PGD) and post-traumatic stress disorder (PTSD). It highlights how a PTSD-related understanding aids the investigation and clinical management of PGD. Grief has long been understood as a natural response to bereavement, as serious psychological and physiological stress has been regarded as a potential outcome of extreme or traumatic stress. PTSD was first included in DSM-III in 1980. In the mid-1980s, the first systematic investigation began into whether there is an extreme or pathological form of mourning. Meanwhile, there is much research literature on complicated, traumatic, or prolonged grief This literature is reviewed in this article, with the following questions: Is it possible to distinguish normal from non-normal grief? Which clinical presentation does PGD have-and how does this compare with PTSD? Finally, diagnostic, preventive, and therapeutic approaches and existing tools are presented.

Diagnostic and clinical considerations in prolonged grief disorder

PubMed Central

Maercker, Andreas; Lalor, John

2012-01-01

This review focuses on the similarities and differences between prolonged grief disorder (PGD) and post-traumatic stress disorder (PTSD). It highlights how a PTSD-related understanding aids the investigation and clinical management of PGD. Grief has long been understood as a natural response to bereavement, as serious psychological and physiological stress has been regarded as a potential outcome of extreme or traumatic stress. PTSD was first included in DSM-III in 1980. In the mid-1980s, the first systematic investigation began into whether there is an extreme or pathological form of mourning. Meanwhile, there is much research literature on complicated, traumatic, or prolonged grief This literature is reviewed in this article, with the following questions: Is it possible to distinguish normal from non-normal grief? Which clinical presentation does PGD have—and how does this compare with PTSD? Finally, diagnostic, preventive, and therapeutic approaches and existing tools are presented. PMID:22754289

Preimplantation genetic diagnosis and rational choice under risk or uncertainty.

PubMed

Zuradzki, Tomasz

2014-11-01

In this paper I present an argument in favour of a parental duty to use preimplantation genetic diagnosis (PGD). I argue that if embryos created in vitro were able to decide for themselves in a rational manner, they would sometimes choose PGD as a method of selection. Couples, therefore, should respect their hypothetical choices on a principle similar to that of patient autonomy. My thesis shows that no matter which moral doctrine couples subscribe to, they ought to conduct the PGD procedure in the situations when it is impossible to implant all of the created embryos and if there is a significant risk for giving birth to a child with a serious condition. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Prevalence and predictors of pathological gambling: results from the St. Louis personality, health and lifestyle (SLPHL) study

PubMed Central

Cunningham-Williams, Renee M.; Grucza, Richard A.; Cottler, Linda B.; Womack, Sharon B.; Books, Samantha J.; Przybeck, Thomas R.; Spitznagel, Edward L.; Cloninger, C. Robert

2006-01-01

Objectives We report the prevalence of and risk and protective factors for DSM-IV sub-threshold gambling (1–4 criteria) and pathological gambling disorder (PGD; 5–10 criteria) in a non-clinical household sample of St. Louis area gamblers. Methods Of the 7689 individuals contacted via Random Digit Dialing, 3292 were screened eligible. Of these, 1142 from households in 6 contiguous regions in Missouri and Illinois consented to participate and were mailed a St. Louis Area Personality, Health, and Lifestyle (SLPHL) Survey. Results Post-stratification weighted data (n = 913) indicate lifetime prevalence rates of 12.4% sub-threshold and 2.5% PGD (conditional prevalence = 21.5% and 4.3% respectively). Risk and protective factors for gambling severity varied in the sample. Conclusions Targeted prevention messages are warranted specifically for gamblers of varying risk for PGD. PMID:15804388

Depression, pregnancy-related anxiety and parental-antenatal attachment in couples using preimplantation genetic diagnosis.

PubMed

Winter, C; Van Acker, F; Bonduelle, M; Van Berkel, K; Belva, F; Liebaers, I; Nekkebroeck, J

2016-06-01

Do preimplantation genetic diagnosis (PGD) couples experience higher levels of stress during pregnancy and the perinatal period compared with couples who conceive spontaneously (SC) or with ICSI? PGD couples did not experience more psychological stress during pregnancy and beyond than ICSI or SC couples. Previous studies have shown that assisted reproduction technology (ART) couples are more prone to pregnancy-related anxieties than SC couples, but display depressed feelings to an equal or lesser extent. However, only one study has focused on a female PGD sample, which may be a more vulnerable group than other ART groups, due to the potentially complex hereditary background, adverse childhood experiences and losses. In that study, PGD women experienced a reduction in state anxiety, and maternal-antenatal attachment did not differ from normative data. Unfortunately, no data exist on pregnancy-related anxiety, depression and parental-antenatal attachment. Valuable information from both parents (e.g.: couples) is also lacking. For this longitudinal prospective study questionnaire, data from 185 women and 157 men (157 couples) were collected between February 2012 until April 2014. Data were analysed using multilevel analysis. The couples conceiving after PGD, ICSI or SC were followed from the first trimester of the pregnancy until the third month post-partum. A total of 60 PGD, 58 ICSI and 69 SC couples were initially recruited by various departments of Universitair Ziekenhuis Brussel (UZ Brussel). At each trimester (T1: 12-14 weeks, T2: 20-22 weeks, T3: 30-32 weeks) of pregnancy, depression (EPDS), pregnancy-related anxieties (PRAQ) and parental-antenatal attachment (M/PAAS) were recorded. At T4 (3 months post-partum), depression (EPDS) was assessed again. In the first trimester (T1) broad socio-demographic data and at T4 perinatal health data of both mother and child were recorded. Differences between conception groups over time were analysed using multilevel analyses, taking into account covariation between measurements and within couples. Several perinatal covariates as well as social desirability, coping and adult attachment style were controlled for. All three conception groups had similar scores for depression during pregnancy and beyond. Also, pregnancy-related anxiety scales did not differ among the three groups. All groups also followed a similar trajectory in time regarding their scores for anxiety, depression and parental-antenatal attachment. ART groups did not give more socially desirable answers than SC controls. The subsequent moderators: coping and adult attachment style did not add any relevant information. No interaction effects occurred between gender and conception groups. The participants were Caucasian, Dutch-speaking couples, with medium to high socio-economic status, from a single centre. Our data should be replicated by multicultural and multicentre studies. Furthermore, the inclusion of an additional control group of couples who did not opt for PGD but for prenatal diagnosis may point to the most beneficial strategy for the couple. PGD parents invest a similar amount of time and emotion in their future children compared with controls. This implies that successful PGD treatment makes an important psychological contribution towards the well-being of couples given their complex hereditary and family backgrounds. This research project was funded by grants from the internal research council of the Vrije Universiteit Brussel (OZR), the Flemish Fonds Wetenschappelijk Onderzoek (FWO) and the Wetenschappelijk Fonds Willy Gepts (WGFG). UZ Brussel and the Centre for Medical Genetics have received several educational grants for organizing the data collection, from IBSA, Ferring, Organon, Shering-Plough, Merck and Merck Belgium. M.B. has received consultancy and speaker's fees from Organon, Serono Symposia and Merck. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Insecurity of Tenure and Academic Freedom in Adult Education: An Historical Perspective.

ERIC Educational Resources Information Center

Fieldhouse, Roger

1987-01-01

This article examines the system under which lecturers were employed in British adult education before the Second World War, when the responsible agencies relied heavily on "full-time part-time tutors" who had no official status or employment security and were thus subject to pressures infringing on their academic freedom. (Author/PGD)

Adipose Gene Expression Profile Changes With Lung Allograft Reperfusion.

PubMed

Diamond, Joshua M; Arcasoy, Selim; McDonnough, Jamiela A; Sonett, Joshua R; Bacchetta, Matthew; D'Ovidio, Frank; Cantu, Edward; Bermudez, Christian A; McBurnie, Amika; Rushefski, Melanie; Kalman, Laurel H; Oyster, Michelle; D'Errico, Carly; Suzuki, Yoshikazu; Giles, Jon T; Ferrante, Anthony; Lippel, Matthew; Singh, Gopal; Lederer, David J; Christie, Jason D

2017-01-01

Obesity is a risk factor for primary graft dysfunction (PGD), a form of lung injury resulting from ischemia-reperfusion after lung transplantation, but the impact of ischemia-reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from six subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were downregulated in the postreperfusion time compared with baseline. Long pentraxin-3, a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5-fold increase, p = 0.04). Fibronectin leucine-rich transmembrane protein-3, a gene associated with cell adhesion and receptor signaling, was the most downregulated gene (4.3-fold decrease, p = 0.04). Ischemia-reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of nonobese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.

PubMed

Trabanelli, Sara; Chevalier, Mathieu F; Martinez-Usatorre, Amaia; Gomez-Cadena, Alejandra; Salomé, Bérengère; Lecciso, Mariangela; Salvestrini, Valentina; Verdeil, Grégory; Racle, Julien; Papayannidis, Cristina; Morita, Hideaki; Pizzitola, Irene; Grandclément, Camille; Bohner, Perrine; Bruni, Elena; Girotra, Mukul; Pallavi, Rani; Falvo, Paolo; Leibundgut, Elisabeth Oppliger; Baerlocher, Gabriela M; Carlo-Stella, Carmelo; Taurino, Daniela; Santoro, Armando; Spinelli, Orietta; Rambaldi, Alessandro; Giarin, Emanuela; Basso, Giuseppe; Tresoldi, Cristina; Ciceri, Fabio; Gfeller, David; Akdis, Cezmi A; Mazzarella, Luca; Minucci, Saverio; Pelicci, Pier Giuseppe; Marcenaro, Emanuela; McKenzie, Andrew N J; Vanhecke, Dominique; Coukos, George; Mavilio, Domenico; Curti, Antonio; Derré, Laurent; Jandus, Camilla

2017-09-19

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth.

Overlapping and Complementary Oxidative Stress Defense Mechanisms in Nontypeable Haemophilus influenzae

PubMed Central

Baker, Beth D.; Munson, Robert S.

2014-01-01

The Gram-negative commensal bacterium nontypeable Haemophilus influenzae (NTHI) can cause respiratory tract diseases that include otitis media, sinusitis, exacerbations of chronic obstructive pulmonary disease, and bronchitis. During colonization and infection, NTHI withstands oxidative stress generated by reactive oxygen species produced endogenously, by the host, and by other copathogens and flora. These reactive oxygen species include superoxide, hydrogen peroxide (H2O2), and hydroxyl radicals, whose killing is amplified by iron via the Fenton reaction. We previously identified genes that encode proteins with putative roles in protection of the NTHI isolate strain 86-028NP against oxidative stress. These include catalase (HktE), peroxiredoxin/glutaredoxin (PgdX), and a ferritin-like protein (Dps). Strains were generated with mutations in hktE, pgdX, and dps. The hktE mutant and a pgdX hktE double mutant were more sensitive than the parent to killing by H2O2. Conversely, the pgdX mutant was more resistant to H2O2 due to increased catalase activity. Supporting the role of killing via the Fenton reaction, binding of iron by Dps significantly mitigated the effect of H2O2-mediated killing. NTHI thus utilizes several effectors to resist oxidative stress, and regulation of free iron is critical to this protection. These mechanisms will be important for successful colonization and infection by this opportunistic human pathogen. PMID:25368297

From brute luck to option luck? On genetics, justice, and moral responsibility in reproduction.

PubMed

Denier, Yvonne

2010-04-01

The structure of our ethical experience depends, crucially, on a fundamental distinction between what we are responsible for doing or deciding and what is given to us. As such, the boundary between chance and choice is the spine of our conventional morality, and any serious shift in that boundary is thoroughly dislocating. Against this background, I analyze the way in which techniques of prenatal genetic diagnosis (PGD) pose such a fundamental challenge to our conventional ideas of justice and moral responsibility. After a short description of the situation, I first examine the influential luck egalitarian theory of justice, which is based on the distinction between choice and luck or, more specifically, between option luck and brute luck, and the way in which it would approach PGD (section II), followed by an analysis of the conceptual incoherencies (in section III) and moral problems (in section IV) that come with such an approach. Put shortly, the case of PGD shows that the luck egalitarian approach fails to express equal respect for the individual choices of people. The paradox of the matter is that by overemphasizing the fact of choice as such, without regard for the social framework in which they are being made, or for the fundamental and existential nature of particular choices-like choosing to have children and not to undergo PGD or not to abort a handicapped fetus-such choices actually become impossible.

Direct analysis of prostaglandin-E2 and -D2 produced in an inflammatory cell reaction and its application for activity screening and potency evaluation using turbulent flow chromatography liquid chromatography-high resolution mass spectrometry.

PubMed

Shin, Jeong-Sook; Peng, Lei; Kang, Kyungsu; Choi, Yongsoo

2016-09-09

Direct analysis of prostaglandin-E2 (PGE2) and -D2 (PGD2) produced from a RAW264.7 cell-based reaction was performed by liquid chromatography high-resolution mass spectrometry (LC-HRMS), which was online coupled with turbulent flow chromatography (TFC). The capability of this method to accurately measure PG levels in cell reaction medium containing cytokines or proteins as a reaction byproduct was cross-validated by two conventional methods. Two methods, including an LC-HRMS method after liquid-liquid extraction (LLE) of the sample and a commercial PGE2 enzyme-linked immunosorbent assay (ELISA), showed PGE2 and/or PGD2 levels almost similar to those obtained by TFC LC-HRMS over the reaction time after LPS stimulation. After the cross-validation, significant analytical throughputs, allowing simultaneous screening and potency evaluation of 80 natural products including 60 phytochemicals and 20 natural product extracts for the inhibition of the PGD2 produced in the cell-based inflammatory reaction, were achieved using the TFC LC-HRMS method developed. Among the 60 phytochemicals screened, licochalcone A and formononetin inhibited PGD2 production the most with IC50 values of 126 and 151nM, respectively. For a reference activity, indomethacin and diclofenac were used, measuring IC50 values of 0.64 and 0.21nM, respectively. This method also found a butanol extract of Akebia quinata Decne (AQ) stem as a promising natural product for PGD2 inhibition. Direct and accurate analysis of PGs in the inflammatory cell reaction using the TFC LC-HRMS method developed enables the high-throughput screening and potency evaluation of as many as 320 samples in less than 48h without changing a TFC column. Copyright © 2016 Elsevier B.V. All rights reserved.

Triiodothyronine-predominant Graves' disease in childhood: detection and therapeutic implications.

PubMed

Harvengt, Julie; Boizeau, Priscilla; Chevenne, Didier; Zenaty, Delphine; Paulsen, Anne; Simon, Dominique; Guilmin Crepon, Sophie; Alberti, Corinne; Carel, Jean-Claude; Léger, Juliane

2015-06-01

To assess in a pediatric population, the clinical characteristics and management of triiodothyronine-predominant Graves' disease (T3-P-GD), a rare condition well known in adults, but not previously described in children. We conducted a university hospital-based observational study. All patients with GD followed for more than 1 year between 2003 and 2013 (n=60) were included. T3-P-GD (group I) was defined as high free T3 (fT3) concentration (>8.0 pmol/l) associated with a normal free thyroxine (fT4) concentration and undetectable TSH more than 1 month after the initiation of antithyroid drug (ATD) treatment. Group II contained patients with classical GD without T3-P-GD. Eight (13%) of the patients were found to have T3-P-GD, a median of 6.3 (3.0-10.5) months after initial diagnosis (n=4) or 2.8 (2.0-11.9) months after the first relapse after treatment discontinuation (n=4). At GD diagnosis, group I patients were more likely to be younger (6.8 (4.3-11.0) vs 10.7 (7.2-13.7) years) and had more severe disease than group II patients, with higher serum TSH receptor autoantibodies (TRAb) levels: 40 (31-69) vs 17 (8-25) IU/l, P<0.04, and with slightly higher serum fT4 (92 (64-99) vs 63 (44-83) pmol/l) and fT3 (31 (30-46) vs 25 (17-31) pmol/l) concentrations. During the 3 years following T3-P-GD diagnosis, a double dose of ATD was required and median serum fT4:fT3 ratio remained lower in group I than in group II. Severe hyperthyroidism, with particularly high TRAb concentrations at diagnosis, may facilitate the identification of patients requiring regular serum fT3 determinations and potentially needing higher doses of ATD dosage during follow-up. © 2015 European Society of Endocrinology.

A recombinant plasmid containing CpG motifs as a novel vaccine adjuvant for immune protection against herpes simplex virus 2.

PubMed

He, Zhuojing; Xu, Juan; Tao, Wei; Fu, Ting; He, Fang; Hu, Ruxi; Jia, Lan; Hong, Yan

2016-08-01

The aim of the present study was to evaluate the efficacy of a herpes simplex virus type 2 (HSV-2) DNA vaccine co‑immunized with a plasmid adjuvant containing CpG motifs. A novel eukaryotic expression plasmid vector containing kanamycin resistance gene (pcDNA3Kan) was acquired from pET‑28a(+) and pcDNA3 plasmids. A gene encoding full length HSV‑2 glycoprotein D (gD) was amplified from the pcDNA3‑gD plasmid, which was cloned into pcDNA3Kan resulting in the construction of the recombinant plasmid pcDNA3Kan‑gD (pgD). A DNA segment containing 8 CpG motifs was synthesized, and cloned into pcDNA3Kan, resulting in the recombinant plasmid pcDNA3Kan‑CpG (pCpG). Mice were co‑inoculated with pgD (used as a DNA vaccine) and pCpG (used as an adjuvant) by bilateral intramuscular injection. Mice inoculated with pgD+pCpG showed higher titers of antibodies than those inoculated with the DNA vaccine alone (P<0.05). In addition, mice inoculated with pgD+pCpG showed the highest percentage of CD4+ T cells in the blood of all the groups (P﹤0.05). Thus, the present study demonstrated that pCpG could stimulate the HSV‑2 DNA vaccine to induce a stronger cell‑mediated immune response than the DNA vaccine alone. The aim of the present study was to evaluate the efficacy of a HSV‑2 DNA vaccine (pgD) co‑immunized with a plasmid adjuvant containing CpG motifs (pCpG). Whether the pCpG would be able to stimulate the pgD to induce a stronger immune response compared with pgD alone.

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Black, Adrienne T.; Gray, Joshua P.; Shakarjian, Michael P.

Prostaglandins belong to a class of cyclic lipid-derived mediators synthesized from arachidonic acid via COX-1, COX-2 and various prostaglandin synthases. Members of this family include prostaglandins such as PGE{sub 2}, PGF{sub 2{alpha}}, PGD{sub 2} and PGI{sub 2} (prostacyclin) as well as thromboxane. In the present studies we analyzed the effects of UVB on prostaglandin production and prostaglandin synthase expression in primary cultures of undifferentiated and calcium-differentiated mouse keratinocytes. Both cell types were found to constitutively synthesize PGE{sub 2}, PGD{sub 2} and the PGD{sub 2} metabolite PGJ{sub 2}. Twenty-four hours after treatment with UVB (25 mJ/cm{sup 2}), production of PGE{sub 2}more » and PGJ{sub 2} increased, while PGD{sub 2} production decreased. This was associated with increased expression of COX-2 mRNA and protein. UVB (2.5-25 mJ/cm{sup 2}) also caused marked increases in mRNA expression for the prostanoid synthases PGDS, mPGES-1, mPGES-2, PGFS and PGIS, as well as expression of receptors for PGE{sub 2} (EP1 and EP2), PGD{sub 2} (DP and CRTH2) and prostacyclin (IP). UVB was more effective in inducing COX-2 and DP in differentiated cells and EP1 and IP in undifferentiated cells. UVB readily activated keratinocyte PI-3-kinase (PI3K)/Akt, JNK and p38 MAP signaling pathways which are known to regulate COX-2 expression. While inhibition of PI3K suppressed UVB-induced mPGES-1 and CRTH2 expression, JNK inhibition suppressed mPGES-1, PGIS, EP2 and CRTH2, and p38 kinase inhibition only suppressed EP1 and EP2. These data indicate that UVB modulates expression of prostaglandin synthases and receptors by distinct mechanisms. Moreover, both the capacity of keratinocytes to generate prostaglandins and their ability to respond to these lipid mediators are stimulated by exposure to UVB.« less

Preimplantation genetic testing for aneuploidy: what technology should you use and what are the differences?

PubMed

Brezina, Paul R; Anchan, Raymond; Kearns, William G

2016-07-01

The purpose of the review was to define the various diagnostic platforms currently available to perform preimplantation genetic testing for aneuploidy and describe in a clear and balanced manner the various strengths and weaknesses of these technologies. A systematic literature review was conducted. We used the terms "preimplantation genetic testing," "preimplantation genetic diagnosis," "preimplantation genetic screening," "preimplantation genetic diagnosis for aneuploidy," "PGD," "PGS," and "PGD-A" to search through PubMed, ScienceDirect, and Google Scholar from the year 2000 to April 2016. Bibliographies of articles were also searched for relevant studies. When possible, larger randomized controlled trials were used. However, for some emerging data, only data from meeting abstracts were available. PGS is emerging as one of the most valuable tools to enhance pregnancy success with assisted reproductive technologies. While all of the current diagnostic platforms currently available have various advantages and disadvantages, some platforms, such as next-generation sequencing (NGS), are capable of evaluating far more data points than has been previously possible. The emerging complexity of different technologies, especially with the utilization of more sophisticated tools such as NGS, requires an understanding by clinicians in order to request the best test for their patients.. Ultimately, the choice of which diagnostic platform is utilized should be individualized to the needs of both the clinic and the patient. Such a decision must incorporate the risk tolerance of both the patient and provider, fiscal considerations, and other factors such as the ability to counsel patients on their testing results and how these may or may not impact clinical outcomes.

[Bereavement and complicated grief: towards a definition of Prolonged Grief Disorder for DSM-5].

PubMed

Lombardo, Luigi; Lai, Carlo; Luciani, Massimiliano; Morelli, Emanuela; Buttinelli, Elena; Aceto, Paola; Lai, Silvia; D'Onofrio, Marianna; Galli, Federico; Bellizzi, Fernando; Penco, Italo

2014-01-01

Mourning is a natural response to a loss and a condition which most people experience several times during their lives. Most individuals adjust adequately to the loss of a relative, neverthless, a small but noteworthy proportion of bereaved individuals experience a syndrome of prolonged psychological distress in relation to bereavement. Prolonged distress and disability in connection with bereavement has been termed Complicated Grief (CG) or Prolonged Grief Disorder (PGD). The purpose of this paper is to analyze the literature on loss and mourning making a review of the main studies published between 1993 and 2013, identified through a search conducted on Medline/PubMed, in order to describe the epidemiological and clinical aspects of "normal" grief and "complicated" grief, pointing out the path of the clinical definition of PGD and proposed diagnostic criteria for inclusion in the next edition of the Diagnostic and Statistic Manual of Mental Disorders, Fifth edition (DSM-5). The two main diagnostic systems proposed by Horowitz and Prigerson are also compared.

Medium-based noninvasive preimplantation genetic diagnosis for human α-thalassemias-SEA.

PubMed

Wu, Haitao; Ding, Chenhui; Shen, Xiaoting; Wang, Jing; Li, Rong; Cai, Bing; Xu, Yanwen; Zhong, Yiping; Zhou, Canquan

2015-03-01

To develop a noninvasive medium-based preimplantation genetic diagnosis (PGD) test for α-thalassemias-SEA. The embryos of α-thalassemia-SEA carriers undergoing in vitro fertilization (IVF) were cultured. Single cells were biopsied from blastomeres and subjected to fluorescent gap polymerase chain reaction (PCR) analysis; the spent culture media that contained embryo genomic DNA and corresponding blastocysts as verification were subjected to quantitative-PCR (Q-PCR) detection of α-thalassemia-SEA. The diagnosis efficiency and allele dropout (ADO) ratio were calculated, and the cell-free DNA concentration was quantitatively assessed in the culture medium. The diagnosis efficiency of medium-based α-thalassemias-SEA detection significantly increased compared with that of biopsy-based fluorescent gap PCR analysis (88.6% vs 82.1%, P < 0.05). There is no significant difference regarding ADO ratio between them. The optimal time for medium-based α-thalassemias-SEA detection is Day 5 (D5) following IVF. Medium-based α-thalassemias-SEA detection could represent a novel, quick, and noninvasive approach for carriers to undergo IVF and PGD.

Timing embryo biopsy for PGD - before or after cryopreservation?

PubMed

Shinar, S; Kornecki, N; Schwartz, T; Mey-Raz, N; Amir, H; Almog, B; Shavit, T; Hasson, J

2016-09-01

Pre-implantation genetic diagnosis (PGD) is required in order to screen and diagnose embryos of patients at risk of having a genetically affected offspring. A biopsy to diagnose the genetic profile of the embryo may be performed either before or after cryopreservation. The aim of this study was to determine which biopsy timing yields higher embryo survival rates. Retrospective cohort study of all PGD patients in a public IVF unit between 2010 and 2013. Inclusion criteria were patients with good-quality embryos available for cryopreservation by the slow freezing method. Embryos were divided into two groups: biopsy before and biopsy after cryopreservation. The primary outcome was embryo survival rates post thawing. Sixty-five patients met inclusion criteria. 145 embryos were biopsied before cryopreservation and 228 embryos were cryopreserved and biopsied after thawing. Embryo survival was significantly greater in the latter group (77% vs. 68%, p < 0.0001). Cryopreservation preceding biopsy results in better embryo survival compared to biopsy before cryopreservation.

Saviour embryos? Preimplantation genetic diagnosis as a therapeutic technology.

PubMed

Sparrow, Robert; Cram, David

2010-05-01

The creation of 'saviour siblings' is one of the most controversial uses of preimplantation genetic diagnosis (PGD). This paper outlines and invites ethical discussion of an extension of this technology, namely, the creation of 'saviour embryos' to serve as a source of stem cells to be used in potentially life-saving therapy for an existing child. A number of analogies between this hypothetical use of PGD and existing uses of IVF are offered and, in addition, between saviour embryos and proposed therapeutic applications of stem cell technology. The ethical significance of a number of disanalogies between these cases are explored and investigated. While the creation of saviour embryos would involve a significant shift in the rationale for IVF and PGD, it is suggested here that the urgent need of an existing individual should be prioritised over any obligations that might exist in relation to the creation or destruction of human embryos. Copyright (c) 2009 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Sulphur shuttling across a chaperone during molybdenum cofactor maturation.

PubMed

Arnoux, Pascal; Ruppelt, Christian; Oudouhou, Flore; Lavergne, Jérôme; Siponen, Marina I; Toci, René; Mendel, Ralf R; Bittner, Florian; Pignol, David; Magalon, Axel; Walburger, Anne

2015-02-04

Formate dehydrogenases (FDHs) are of interest as they are natural catalysts that sequester atmospheric CO2, generating reduced carbon compounds with possible uses as fuel. FDHs activity in Escherichia coli strictly requires the sulphurtransferase EcFdhD, which likely transfers sulphur from IscS to the molybdenum cofactor (Mo-bisPGD) of FDHs. Here we show that EcFdhD binds Mo-bisPGD in vivo and has submicromolar affinity for GDP-used as a surrogate of the molybdenum cofactor's nucleotide moieties. The crystal structure of EcFdhD in complex with GDP shows two symmetrical binding sites located on the same face of the dimer. These binding sites are connected via a tunnel-like cavity to the opposite face of the dimer where two dynamic loops, each harbouring two functionally important cysteine residues, are present. On the basis of structure-guided mutagenesis, we propose a model for the sulphuration mechanism of Mo-bisPGD where the sulphur atom shuttles across the chaperone dimer.

Saving or Subordinating Life? Popular Views in Israel and Germany of Donor Siblings Created through PGD.

PubMed

Raz, Aviad; Schües, Christina; Wilhelm, Nadja; Rehmann-Sutter, Christoph

2017-06-01

To explore how cultural beliefs are reflected in different popular views of pre-implantation genetic diagnosis for human leukocyte antigen match (popularly known as "savior siblings"), we compare the reception and interpretations, in Germany and Israel, of the novel/film My Sister's Keeper. Qualitative analysis of reviews, commentaries and posts is used to classify and compare normative assessments of PGD for HLA and how they reproduce, negotiate or oppose the national policy and its underlying cultural and ethical premises. Four major themes emanated from the comparison: loss of self-determination and autonomy; loss of dignity through instrumentalization; eugenics and euthanasia; and saving life. In both countries, most commentaries represented a dominant position, with a few negotiated positions. We also highlight the decoding of a relatively less explored bioethical aspect of My Sister's Keeper's narrative, namely the meaning of euthanasia. We conclude by discussing how the findings relate to attempts of providing cultural explanations for the regulation of HLA-PGD.

Sulphur shuttling across a chaperone during molybdenum cofactor maturation

NASA Astrophysics Data System (ADS)

Arnoux, Pascal; Ruppelt, Christian; Oudouhou, Flore; Lavergne, Jérôme; Siponen, Marina I.; Toci, René; Mendel, Ralf R.; Bittner, Florian; Pignol, David; Magalon, Axel; Walburger, Anne

2015-02-01

Formate dehydrogenases (FDHs) are of interest as they are natural catalysts that sequester atmospheric CO2, generating reduced carbon compounds with possible uses as fuel. FDHs activity in Escherichia coli strictly requires the sulphurtransferase EcFdhD, which likely transfers sulphur from IscS to the molybdenum cofactor (Mo-bisPGD) of FDHs. Here we show that EcFdhD binds Mo-bisPGD in vivo and has submicromolar affinity for GDP—used as a surrogate of the molybdenum cofactor’s nucleotide moieties. The crystal structure of EcFdhD in complex with GDP shows two symmetrical binding sites located on the same face of the dimer. These binding sites are connected via a tunnel-like cavity to the opposite face of the dimer where two dynamic loops, each harbouring two functionally important cysteine residues, are present. On the basis of structure-guided mutagenesis, we propose a model for the sulphuration mechanism of Mo-bisPGD where the sulphur atom shuttles across the chaperone dimer.

Novel Multiplex Fluorescent PCR-Based Method for HLA Typing and Preimplantational Genetic Diagnosis of β-Thalassemia.

PubMed

Khosravi, Sharifeh; Salehi, Mansour; Ramezanzadeh, Mahboobeh; Mirzaei, Hamed; Salehi, Rasoul

2016-05-01

Thalassemia is curable by bone marrow transplantation; however, finding suitable donors with defined HLA combination remains a major challenge. Cord blood stem cells with preselected HLA system through preimplantation genetic diagnosis (PGD) proved very useful for resolving scarce HLA-matched bone marrow donors. A thalassemia trait couple with an affected child was included in this study. We used informative STR markers at the HLA and beta globin loci to develop a single cell multiplex fluorescent PCR protocol. The protocol was extensively optimized on single lymphocytes isolated from the couple's peripheral blood. The optimized protocol was applied on single blastomeres biopsied from day 3 cleavage stage IVF embryos of the couple. Four IVF embryos biopsied on day 3 and a single blastomere of each were provided for genetic diagnosis of combined β-thalassemia mutations and HLA typing. Of these, one embryo was diagnosed as homozygous normal for the thalassemia mutation and HLA matched with the existing affected sibling. The optimized protocol worked well in PGD clinical cycle for selection of thalassemia-unaffected embryos with the desired HLA system. Copyright © 2016 IMSS. Published by Elsevier Inc. All rights reserved.

Genetic diversity of allozymes in turnip (Brassica rapa L. var. rapa) from the Nordic area.

PubMed

Persson, K; Fält, A S; von Bothmer, R

2001-01-01

Genetic diversity and relationships based on isozymes were studied in 31 accessions of turnip (Brassica rapa L. var. rapa). The material included varieties, elite stocks, landraces and older turnip of slash-and-burn type from the Nordic area. A total of 9 isozyme loci and 26 alleles were studied. The isozyme systems were ACO, DIA, GPI, GOT, PGM, PGD and SKD. The level of heterozygosity was reduced in the landraces, but it was high for the variety group 'Ostersundom'. Turnip has a higher genetic variation than other crops within B. rapa and than in other species with the same breeding system. The genetic diversity showed that 18.7% of the genetic variation was within the accessions, and the total H tau value was 0.358. Gpi-I and Pgd-I showed the lowest variation compared with the other loci. The cluster analysis revealed five clusters, with one main cluster including 25 of the 31 accessions. The dendrogram indicated that the variety group 'Ostersundom' clustered together whereas the variety group 'Bortfelder' was associated with country of origin. The landraces were spread in different clusters. The 'slash-and-burn' type of turnip belonged to two groups.

The Israeli National Committee for sex selection by pre-implantation genetic diagnosis: a novel approach (2005-2011).

PubMed

Pessach, Nirit; Glasser, Saralee; Soskolne, Varda; Barash, Amihai; Lerner-Geva, Liat

2014-01-01

Pre-implantation genetic diagnosis (PGD) for fetal sex selection raises complex dilemmas. In Israel, PGD is regulated by the Ministry of Health. It is basically prohibited, but exceptions can be made upon approval by the National Committee for Sex Selection by PGD for Non-Medical Reasons (the "Committee"). This report describes the Committee's work since its inception in May, 2005 through December, 2011. Files were abstracted onto a structured form. Discrete variables were analyzed by chi-square analysis, and continuous variables by T-Test. During the study period 411 applications were received. Two-thirds of the applicants (n = 276; 67.2%) were Jewish and 26.8% were Moslem Arab. Over two-thirds (n = 285; 69.3%) had no children of the requested sex and ≥4 children of the opposite sex. Three-quarters of the requests were for a male (n = 308; 74.9%): 100% of Arab and 63% of Jewish applicants. Many noted more than one reason for their request. The most frequent category (n = 201; 48.9%) was a strong emotional desire, followed by medically-related reasons (n = 83; 20.2%). For 216 applications a decision was arrived at, with 46 (21.3%) approved. Of the remaining 195 for 192 over a year had passed since last contact with the Committee. The likelihood of approval was higher if applicants met the criterion of ≥4 same-sex children than if they didn't (33.7% vs. 11.6%, P = 0.001). The largest number of approvals were those requested for 'emotional' reasons, while the highest approval rate was for religious reasons. This study reviewed the first seven years of Committee activity. Most requested males, and the primary reason was the parents' intense emotional desire. Only one-fifth of the decisions were approvals, possibly reflecting reluctance to encourage non-medically-indicated PGD, a viewpoint not unique to Israel. Limitations include the relatively small number of cases and lack of access to Committee deliberation protocols. It is recommended that longitudinal studies be conducted to gain insight into the consequences to individuals, couples and families--both those whose requests were approved and those denied-- of this major step in reproductive technologies and in society's effort to respond to them.

Three-dimensional radiation dosimetry using polymer gel and solid radiochromic polymer: From basics to clinical applications

PubMed Central

Watanabe, Yoichi; Warmington, Leighton; Gopishankar, N

2017-01-01

Accurate dose measurement tools are needed to evaluate the radiation dose delivered to patients by using modern and sophisticated radiation therapy techniques. However, the adequate tools which enable us to directly measure the dose distributions in three-dimensional (3D) space are not commonly available. One such 3D dose measurement device is the polymer-based dosimeter, which changes the material property in response to radiation. These are available in the gel form as polymer gel dosimeter (PGD) and ferrous gel dosimeter (FGD) and in the solid form as solid plastic dosimeter (SPD). Those are made of a continuous uniform medium which polymerizes upon irradiation. Hence, the intrinsic spatial resolution of those dosimeters is very high, and it is only limited by the method by which one converts the dose information recorded by the medium to the absorbed dose. The current standard methods of the dose quantification are magnetic resonance imaging, optical computed tomography, and X-ray computed tomography. In particular, magnetic resonance imaging is well established as a method for obtaining clinically relevant dosimetric data by PGD and FGD. Despite the likely possibility of doing 3D dosimetry by PGD, FGD or SPD, the tools are still lacking wider usages for clinical applications. In this review article, we summarize the current status of PGD, FGD, and SPD and discuss the issue faced by these for wider acceptance in radiation oncology clinic and propose some directions for future development. PMID:28396725

Live births after simultaneous avoidance of monogenic diseases and chromosome abnormality by next-generation sequencing with linkage analyses.

PubMed

Yan, Liying; Huang, Lei; Xu, Liya; Huang, Jin; Ma, Fei; Zhu, Xiaohui; Tang, Yaqiong; Liu, Mingshan; Lian, Ying; Liu, Ping; Li, Rong; Lu, Sijia; Tang, Fuchou; Qiao, Jie; Xie, X Sunney

2015-12-29

In vitro fertilization (IVF), preimplantation genetic diagnosis (PGD), and preimplantation genetic screening (PGS) help patients to select embryos free of monogenic diseases and aneuploidy (chromosome abnormality). Next-generation sequencing (NGS) methods, while experiencing a rapid cost reduction, have improved the precision of PGD/PGS. However, the precision of PGD has been limited by the false-positive and false-negative single-nucleotide variations (SNVs), which are not acceptable in IVF and can be circumvented by linkage analyses, such as short tandem repeats or karyomapping. It is noteworthy that existing methods of detecting SNV/copy number variation (CNV) and linkage analysis often require separate procedures for the same embryo. Here we report an NGS-based PGD/PGS procedure that can simultaneously detect a single-gene disorder and aneuploidy and is capable of linkage analysis in a cost-effective way. This method, called "mutated allele revealed by sequencing with aneuploidy and linkage analyses" (MARSALA), involves multiple annealing and looping-based amplification cycles (MALBAC) for single-cell whole-genome amplification. Aneuploidy is determined by CNVs, whereas SNVs associated with the monogenic diseases are detected by PCR amplification of the MALBAC product. The false-positive and -negative SNVs are avoided by an NGS-based linkage analysis. Two healthy babies, free of the monogenic diseases of their parents, were born after such embryo selection. The monogenic diseases originated from a single base mutation on the autosome and the X-chromosome of the disease-carrying father and mother, respectively.

Resistance to changing practice from pro re nata prescriptions to patient group directions in acute mental health settings.

PubMed

Price, O; Baker, J A

2013-09-01

Poor practice associated with pro re nata (PRN) prescriptions in mental health is known to be common and can increase the risk of serious and potentially fatal side effects. A contributing factor to poor practice is the lack of a clear chain of accountability between the decision to prescribe and administer PRN prescriptions. To address this problem, a patient group direction (PGD) for acute behavioural disturbance (lorazepam 0.5-2 mg) and staff training materials were developed. The intention was to replace PRN prescriptions with the PGD in two mental health trusts. One of the potential benefits of this would be the removal of the contribution of PRN to high and combined dose antipsychotic prescriptions. This proposal, however, was met with significant resistance in both trusts and did not replace PRN as a result. A series of interviews and focus groups were conducted with 16 RMNs working in the two trusts, to explore the reasons why the PGD was met with resistance. Senior nurses perceived resistance to be associated with anxieties over increased responsibility for decision making. Junior nurses reported concerns regarding the medicalization of the nursing role, the paperwork associated with the PGD and the training approach used. Future efforts to implement PGDs in mental health settings must carefully consider the methods for engaging effectively with participating organizations, in terms of managing change and completing the necessary groundwork for successful implementation. © 2012 John Wiley & Sons Ltd.

Preimplantation genetic diagnosis: development and regulation.

PubMed

Thomas, C

2006-06-01

Pre-implantation genetic diagnosis (PGD) is used to biopsy and analyse embryos created through in vitro fertilisation (IVF) to avoid implanting an embryo affected by a mutation or chromosomal abnormality associated with serious illness. It reduces the chance that the parents will be faced with a difficult decision of whether to terminate the pregnancy, if the disorder is detected during the course of gestation. PGD is widely accepted for this purpose although there have been suggestions that such procedures have the effect of de-valuing persons in the community with disabilities. PGD potentially has other more controversial purposes, including the selection of the sex of the baby for personal preferences such as balancing the family, rather than to avoid a sex-linked disorder. Recently PGD has become available to create a donor child who is Human Leukocyte Antigen (HLA) matched with a sibling in need of stem cell transplant. In most cases the intention is to utilise the cord blood. However, an HLA-matched child could potentially be required to be a donor of tissues and organs throughout life. This may arise should the initial cord blood donation fail for any one of several reasons, such as inadequate cord blood cell dose, graft failure after cord blood transplant, or the recipient child experiencing a recurrence of the original illness after transplant. However, such on-going demands could also arise if a HLA-matched child was fortuitously conceived by natural means. As such, the issue is not PGD, but rather whether to harvest bone marrow or a solid organ from a child. This raises the question of whether there should be limits and procedures to protect such children from exploitation until they achieve sufficient competence to be able to make mature and autonomous decisions about whether to donate, even if the consequence may in some cases be that it is too late to save the sibling. Additionally, the parents may not be able to make a dispassionate decision, when they have a conflict of interests between their children. As such, parents may not be the best proxy decision-makers in this area and the decision might be better made by an independent authority or court. This paper considers ethical and legal issues arising from PGD. It will compare the willingness of the HFEA in the United Kingdom to allow this process to be used even in cases where the condition suffered by the sibling is non-heritable, with the more restrictive guidelines in New Zealand and questions the constitutional basis on which ethics committees develop policy in the absence of a legislative framework.

PPARα, PPARγ and SREBP-1 pathways mediated waterborne iron (Fe)-induced reduction in hepatic lipid deposition of javelin goby Synechogobius hasta.

PubMed

Chen, Guang-Hui; Luo, Zhi; Chen, Feng; Shi, Xi; Song, Yu-Feng; You, Wen-Jing; Liu, Xu

2017-07-01

The 42-day experiment was conducted to investigate the effects and mechanism of waterborne Fe exposure influencing hepatic lipid deposition in Synechogobius hasta. For that purpose, S. hasta were exposed to four Fe concentrations (0 (control), 0.36, 0.72 and 1.07μM Fe) for 42days. On days 21 and 42, morphological parameters, hepatic lipid deposition and Fe contents, and activities and mRNA levels of enzymes and genes related to lipid metabolism, including lipogenic enzymes (6PGD, G6PD, ME, ICDH, FAS and ACC) and lipolytic enzymes (CPTI, HSL), were analyzed. With the increase of Fe concentration, hepatic Fe content tended to increase but HSI and lipid content tended to decrease. On day 21, Fe exposure down-regulated the lipogenic activities of 6PGD, G6PD, ICDH and FAS as well as the mRNA levels of G6PD, ACCa, FAS, SREBP-1 and PPARγ, but up-regulated CPT I, HSLa and PPARα mRNA levels. On day 42, Fe exposure down-regulated the lipogenic activities of 6PGD, G6PD, ICDH and FAS as well as the mRNA levels of 6PGD, ACCa, FAS and SREBP-1, but up-regulated CPT I, HSLa, PPARα and PPARγ mRNA levels. Using primary S. hasta hepatocytes, specific pathway inhibitors (GW6471 for PPARα and fatostatin for SREBP-1) and activator (troglitazone for PPARγ) were used to explore the signaling pathways of Fe reducing lipid deposition. The GW6471 attenuated the Fe-induced down-regulation of mRNA levels of 6PGD, G6PD, ME, FAS and ACCa, and attenuated the Fe-induced up-regulation of mRNA levels of CPT I, HSLa and PPARα. Compared with single Fe-incubated group, the mRNA levels of G6PD, ME, FAS, ACCa, ACCb and PPARγ were up-regulated while the CPT I mRNA levels were down-regulated after troglitazone pre-treatment; fatostatin pre-treatment down-regulated the mRNA levels of 6PGD, ME, FAS, ACCa, ACCb and SREBP-1, and increased the CPT I and HSLa mRNA levels. Based on these results above, our study indicated that Fe exposure reduced hepatic lipid deposition by down-regulating lipogenesis and up-regulating lipolysis, and PPARα, PPARγ and SREBP-1 pathways mediated the Fe-induced reduction of hepatic lipid deposition in S. hasta. Copyright © 2017 Elsevier Inc. All rights reserved.

Preliminary analysis of numerical chromosome abnormalities in reciprocal and Robertsonian translocation preimplantation genetic diagnosis cases with 24-chromosomal analysis with an aCGH/SNP microarray.

PubMed

Xie, Yanxin; Xu, Yanwen; Wang, Jing; Miao, Benyu; Zeng, Yanhong; Ding, Chenhui; Gao, Jun; Zhou, Canquan

2018-01-01

The aim of this study was to determine whether an interchromosomal effect (ICE) occurred in embryos obtained from reciprocal translocation (rcp) and Robertsonian translocation (RT) carriers who were following a preimplantation genetic diagnosis (PGD) with whole chromosome screening with an aCGH and SNP microarray. We also analyzed the chromosomal numerical abnormalities in embryos with aneuploidy in parental chromosomes that were not involved with a translocation and balanced in involved parental translocation chromosomes. This retrospective study included 832 embryos obtained from rcp carriers and 382 embryos from RT carriers that were biopsied in 139 PGD cycles. The control group involved embryos obtained from age-matched patient karyotypes who were undergoing preimplantation genetic screening (PGS) with non-translocation, and 579 embryos were analyzed in the control group. A single blastomere at the cleavage stage or trophectoderm from a blastocyst was biopsied, and 24-chromosomal analysis with an aCGH/SNP microarray was conducted using the PGD/PGS protocols. Statistical analyses were implemented on the incidences of cumulative aneuploidy rates between the translocation carriers and the control group. Reliable results were obtained from 138 couples, among whom only one patient was a balanced rcp or RT translocation carrier, undergoing PGD testing in our center from January 2012 to June 2014. For day 3 embryos, the aneuploidy rates were 50.7% for rcp carriers and 49.1% for RT carriers, compared with the control group, with 44.8% at a maternal age < 36 years. When the maternal age was ≥ 36 years, the aneuploidy rates were increased to 61.1% for rcp carriers, 56.7% for RT carriers, and 60.3% for the control group. There were no significant differences. In day 5 embryos, the aneuploidy rates were 24.5% for rcp carriers and 34.9% for RT carriers, compared with the control group with 53.6% at a maternal age < 36 years. When the maternal age was ≥ 36 years, the aneuploidy rates were 10.7% for rcp carriers, 26.3% for RT carriers, and 57.1% for the control group. The cumulative aneuploidy rates of chromosome translocation carriers were significantly lower than the control group. No ICE was observed in cleavage and blastocyst stage embryos obtained from these carriers. Additionally, the risk of chromosomal numerical abnormalities was observed in each of the 23 pairs of autosomes or sex chromosomes from day 3 and day 5 embryos. There was not enough evidence to prove that ICE was present in embryos derived from both rcp and RT translocation carriers, regardless of the maternal age. However, chromosomal numerical abnormalities were noticed in 23 pairs of autosomes and sex chromosomes in parental structurally normal chromosomes. Thus, 24-chromosomal analysis with an aCGH/SNP microarray PGD protocol is required to decrease the risks of failure to diagnose aneuploidy in structurally normal chromosomes.

Importance of genetic diversity assessment in crop plants and its recent advances: an overview of its analytical perspectives.

PubMed

Govindaraj, M; Vetriventhan, M; Srinivasan, M

2015-01-01

The importance of plant genetic diversity (PGD) is now being recognized as a specific area since exploding population with urbanization and decreasing cultivable lands are the critical factors contributing to food insecurity in developing world. Agricultural scientists realized that PGD can be captured and stored in the form of plant genetic resources (PGR) such as gene bank, DNA library, and so forth, in the biorepository which preserve genetic material for long period. However, conserved PGR must be utilized for crop improvement in order to meet future global challenges in relation to food and nutritional security. This paper comprehensively reviews four important areas; (i) the significance of plant genetic diversity (PGD) and PGR especially on agriculturally important crops (mostly field crops); (ii) risk associated with narrowing the genetic base of current commercial cultivars and climate change; (iii) analysis of existing PGD analytical methods in pregenomic and genomic era; and (iv) modern tools available for PGD analysis in postgenomic era. This discussion benefits the plant scientist community in order to use the new methods and technology for better and rapid assessment, for utilization of germplasm from gene banks to their applied breeding programs. With the advent of new biotechnological techniques, this process of genetic manipulation is now being accelerated and carried out with more precision (neglecting environmental effects) and fast-track manner than the classical breeding techniques. It is also to note that gene banks look into several issues in order to improve levels of germplasm distribution and its utilization, duplication of plant identity, and access to database, for prebreeding activities. Since plant breeding research and cultivar development are integral components of improving food production, therefore, availability of and access to diverse genetic sources will ensure that the global food production network becomes more sustainable. The pros and cons of the basic and advanced statistical tools available for measuring genetic diversity are briefly discussed and their source links (mostly) were provided to get easy access; thus, it improves the understanding of tools and its practical applicability to the researchers.

Importance of Genetic Diversity Assessment in Crop Plants and Its Recent Advances: An Overview of Its Analytical Perspectives

PubMed Central

Govindaraj, M.; Vetriventhan, M.; Srinivasan, M.

2015-01-01

The importance of plant genetic diversity (PGD) is now being recognized as a specific area since exploding population with urbanization and decreasing cultivable lands are the critical factors contributing to food insecurity in developing world. Agricultural scientists realized that PGD can be captured and stored in the form of plant genetic resources (PGR) such as gene bank, DNA library, and so forth, in the biorepository which preserve genetic material for long period. However, conserved PGR must be utilized for crop improvement in order to meet future global challenges in relation to food and nutritional security. This paper comprehensively reviews four important areas; (i) the significance of plant genetic diversity (PGD) and PGR especially on agriculturally important crops (mostly field crops); (ii) risk associated with narrowing the genetic base of current commercial cultivars and climate change; (iii) analysis of existing PGD analytical methods in pregenomic and genomic era; and (iv) modern tools available for PGD analysis in postgenomic era. This discussion benefits the plant scientist community in order to use the new methods and technology for better and rapid assessment, for utilization of germplasm from gene banks to their applied breeding programs. With the advent of new biotechnological techniques, this process of genetic manipulation is now being accelerated and carried out with more precision (neglecting environmental effects) and fast-track manner than the classical breeding techniques. It is also to note that gene banks look into several issues in order to improve levels of germplasm distribution and its utilization, duplication of plant identity, and access to database, for prebreeding activities. Since plant breeding research and cultivar development are integral components of improving food production, therefore, availability of and access to diverse genetic sources will ensure that the global food production network becomes more sustainable. The pros and cons of the basic and advanced statistical tools available for measuring genetic diversity are briefly discussed and their source links (mostly) were provided to get easy access; thus, it improves the understanding of tools and its practical applicability to the researchers. PMID:25874132

The Indirect Effect of Positive Parenting on the Relationship Between Parent and Sibling Bereavement Outcomes After the Death of a Child.

PubMed

Morris, Adam T; Gabert-Quillen, Crystal; Friebert, Sarah; Carst, Nancy; Delahanty, Douglas L

2016-01-01

Families are referred to pediatric palliative care (PPC) programs when a child is diagnosed with a medical condition associated with less than a full life expectancy. When a child dies, PPC programs typically offer a range of bereavement interventions to these families, often focusing on parents. Currently, it is unclear which factors increase the likelihood that bereaved siblings will experience negative outcomes, limiting the development of empirically supported interventions that can be delivered in PPC programs. The present study explored the relationship between parents' and surviving sibling's mental health symptoms (i.e., post-traumatic stress disorder [PTSD], prolonged grief disorder (PGD), and depression symptoms) after a child's death. Additionally, the extent to which parent functioning indirectly impacted sibling functioning through parenting behaviors (i.e., positive parenting and parent involvement) was also examined, with a specific focus on differences based on parent gender. Sixty bereaved parents and siblings (aged 8-18) who enrolled in a PPC program from 2008 to 2013 completed measures of PTSD, PGD, and depression related to the loss of a child/sibling. Siblings also completed a measure of general parenting behaviors. Maternal, but not paternal, symptoms of PTSD and PGD were directly associated with sibling outcomes. Paternal symptoms were associated with sibling symptoms indirectly, through parenting behaviors (i.e., via decreasing positive parenting). These results underscore the importance of examining both maternal and paternal influences after the death of a child, demonstrate differential impact of maternal vs. paternal symptoms on siblings, and stress the importance of addressing postloss symptoms from a family systems perspective. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

On the use of PGD for optimal control applied to automated fibre placement

NASA Astrophysics Data System (ADS)

Bur, N.; Joyot, P.

2017-10-01

Automated Fibre Placement (AFP) is an incipient manufacturing process for composite structures. Despite its concep-tual simplicity it involves many complexities related to the necessity of melting the thermoplastic at the interface tape-substrate, ensuring the consolidation that needs the diffusion of molecules and control the residual stresses installation responsible of the residual deformations of the formed parts. The optimisation of the process and the determination of the process window cannot be achieved in a traditional way since it requires a plethora of trials/errors or numerical simulations, because there are many parameters involved in the characterisation of the material and the process. Using reduced order modelling such as the so called Proper Generalised Decomposition method, allows the construction of multi-parametric solution taking into account many parameters. This leads to virtual charts that can be explored on-line in real time in order to perform process optimisation or on-line simulation-based control. Thus, for a given set of parameters, determining the power leading to an optimal temperature becomes easy. However, instead of controlling the power knowing the temperature field by particularizing an abacus, we propose here an approach based on optimal control: we solve by PGD a dual problem from heat equation and optimality criteria. To circumvent numerical issue due to ill-conditioned system, we propose an algorithm based on Uzawa's method. That way, we are able to solve the dual problem, setting the desired state as an extra-coordinate in the PGD framework. In a single computation, we get both the temperature field and the required heat flux to reach a parametric optimal temperature on a given zone.

Modulation of platelet aggregation by areca nut and betel leaf ingredients: roles of reactive oxygen species and cyclooxygenase.

PubMed

Jeng, Jiiang-Huei; Chen, Shiao-Yun; Liao, Chang-Hui; Tung, Yuan-Yii; Lin, Bor-Ru; Hahn, Liang-Jiunn; Chang, Mei-Chi

2002-05-01

There are 2 to 6 billion betel quid (BQ) chewers in the world. Areca nut (AN), a BQ component, modulates arachidonic acid (AA) metabolism, which is crucial for platelet function. AN extract (1 and 2 mg/ml) stimulated rabbit platelet aggregation, with induction of thromboxane B2 (TXB2) production. Contrastingly, Piper betle leaf (PBL) extract inhibited AA-, collagen-, and U46619-induced platelet aggregation, and TXB2 and prostaglandin-D2 (PGD2) production. PBL extract also inhibited platelet TXB2 and PGD2 production triggered by thrombin, platelet activating factor (PAF), and adenosine diphosphate (ADP), whereas little effect on platelet aggregation was noted. Moreover, PBL is a scavenger of O2(*-) and *OH, and inhibits xanthine oxidase activity and the (*)OH-induced PUC18 DNA breaks. Deferoxamine, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) and neomycin prevented AN-induced platelet aggregation and TXB2 production. Indomethacin, genistein, and PBL extract inhibited only TXB2 production, but not platelet aggregation. Catalase, superoxide dismutase, and dimethylthiourea (DMT) showed little effect on AN-induced platelet aggregation, whereas catalase and DMT inhibited the AN-induced TXB2 production. These results suggest that AN-induced platelet aggregation is associated with iron-mediated reactive oxygen species production, calcium mobilization, phospholipase C activation, and TXB2 production. PBL inhibited platelet aggregation via both its antioxidative effects and effects on TXB2 and PGD2 production. Effects of AN and PBL on platelet aggregation and AA metabolism is crucial for platelet activation in the oral mucosa and cardiovascular system in BQ chewers.

Sci—Fri PM: Dosimetry—01: Radiation-induced refraction artefacts in the optical CT readout of polymer gel dosimeters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Campbell, Warren G; Jirasek, Andrew; Wells, Derek M

2014-08-15

Polymer gel dosimeters (PGDs) are a desirable tool for the verification of advanced radiotherapy treatments. Fully 3D, deformable, and tissue-equivalent, the PGD polymerizes wherever it absorbs dose. To measure the dose absorbed by a PGD, optical computed tomography (CT) can be used to evaluate, in full 3D, the opacity distribution that coincides with polymerization. In addition to an increase in opacity with dose, an increase in refractive index (RI) is also known to occur in irradiated polymer gels. The increase in RI is slight and was previously assumed insignificant. This work reveals the effects that radiation-induced RI changes can havemore » on the optical CT readout of PGDs. A fan-beam optical CT scanner was used to image a cylindrical PGD irradiated by a pair of 3×3 cm{sup 2}, 6 MV photon beams in an orthogonal arrangement. Investigative scans were performed to evaluate refraction errors occurring: i) within the plane, and ii) out of the plane of the fan-beam. In-plane refraction was shown to cause distinct streaking artefacts along dose gradients (i.e. RI gradients) due to higher intensity rays being refracted into more opaque regions. Out-of-plane refraction was shown to produce severe, widespread artefacts due to rays missing the detector array. An iterative Savitzky-Golay filtering technique was developed to reduce both types of artefacts by specifically targeting structured errors in sinogram space. Results introduce a new category of imaging artefacts to be aware of when using optical CT for PGD readout.« less

Leukocyte Telomere Length in the Neonatal Offspring of Mothers with Gestational and Pre-Gestational Diabetes.

PubMed

Gilfillan, Christopher; Naidu, Pratyusha; Gunawan, Florence; Hassan, Fadwa; Tian, Pei; Elwood, Ngaire

2016-01-01

Telomeres undergo shortening with cell division, accelerated by increased oxidative stress. We aimed to demonstrate shortened telomeres in the offspring of mothers who have diabetes as a consequence of exposure to increased oxidative stress during intrauterine development. We examined the level of glycaemia (glucose, HbA1c, fructosamine), oxidative stress (lipid peroxidation) and the levels of antioxidant enzymes (Superoxide dismutase (SOD) and Selenium dependent glutathione peroxidase) and correlate these findings with mean telomere length (TL) in maternal and foetal blood in groups of pregnant women with pre-gestational diabetes (PGD), gestational diabetes (GD) and a euglycaemic control group. Foetal and maternal glucose, maternal HbA1c, and foetal insulin and C-peptide were higher in the PGD group with the GD group being intermediate. Markers of oxidative stress did not vary between groups with the exception of foetal SOD activity that was highest in the GD group. There were no detectable differences in maternal or foetal TL between study groups. An exploratory analysis looking at correlations between glycaemic and oxidative stress parameters and TL revealed a negative correlation between maternal and foetal glucose and TL across the whole study population. This relationship held for the short-term marker of glycaemic control, fructosamine. We were unable to show significant telomere shortening in the offspring of mothers with PGD or GD. Exploratory analysis revealed a relationship between foetal TL and short-term glycaemia particularly in PGD. It is possible that increased telomerase activity can compensate for long-term increased oxidative stress but not for short-term dysglycaemia.

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy.

PubMed

Harper, Joyce; Geraedts, Joep; Borry, Pascal; Cornel, Martina C; Dondorp, Wybo J; Gianaroli, Luca; Harton, Gary; Milachich, Tanya; Kääriäinen, Helena; Liebaers, Inge; Morris, Michael; Sequeiros, Jorge; Sermon, Karen; Shenfield, Françoise; Skirton, Heather; Soini, Sirpa; Spits, Claudia; Veiga, Anna; Vermeesch, Joris Robert; Viville, Stéphane; de Wert, Guido; Macek, Milan

2014-08-01

How has the interface between genetics and assisted reproduction technology (ART) evolved since 2005? The interface between ART and genetics has become more entwined as we increase our understanding about the genetics of infertility and we are able to perform more comprehensive genetic testing. In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and ART and published an extended background paper, recommendations and two Editorials. An interdisciplinary workshop was held, involving representatives of both professional societies and experts from the European Union Eurogentest2 Coordination Action Project. In March 2012, a group of experts from the European Society of Human Genetics, the European Society of Human Reproduction and Embryology and the EuroGentest2 Coordination Action Project met to discuss developments at the interface between clinical genetics and ART. As more genetic causes of reproductive failure are now recognized and an increasing number of patients undergo testing of their genome prior to conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and PGD may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from RCTs to substantiate that the technique is both effective and efficient. Whole genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving, but still remains very heterogeneous and often contradictory. The lack of legal harmonization and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe, and beyond. This continually evolving field requires communication between the clinical genetics and IVF teams and patients to ensure that they are fully informed and can make well-considered choices. Funding was received from ESHRE, ESHG and EuroGentest2 European Union Coordination Action project (FP7 - HEALTH-F4-2010-26146) to support attendance at this meeting. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Purification and biochemical characterization of glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and glutathione reductase from rat lung and inhibition effects of some antibiotics.

PubMed

Adem, Sevki; Ciftci, Mehmet

2016-12-01

G6PD, 6PGD and GR have been purified separately in the single step from rat lung using 2', 5'-ADP Sepharose 4B affinity chromatography. The purified enzymes showed a single band on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The molecular weights of the enzymes were estimated to be 134 kDa for G6PD, 107 kDa for 6PGD and 121 kDa for GR by Sephadex G-150 gel filtration chromatography, and the subunit molecular weights was respectively found to be 66, 52 and 63 kDa by SDS-PAGE. Optimum pH, stable pH, optimum ionic strength, optimum temperature, KM and Vmax values for substrates were determined. Product inhibition studies were also performed. The enzymes were inhibited by levofloxacin, furosemide, ceftazidime, cefuroxime and gentamicin as in vitro with IC50 values in the range of 0.07-30.13 mM. In vivo studies demonstrated that lung GR was inhibited by furosemide and lung 6PGD was inhibited by levofloxacin.

Prevalence of psychiatric disorders and functional impairment after loss of a family member: a longitudinal study after the 2004 Tsunami.

PubMed

Kristensen, Pål; Weisaeth, Lars; Hussain, Ajmal; Heir, Trond

2015-01-01

Bereavement following disasters is a devastating experience for family members. The aim of this study was to examine the long-term mental health effects of losing a loved one in a natural disaster. Ninety-four Norwegians aged 18-80 years who lost close family members in the 2004 Southeast Asian tsunami were evaluated 2 and 6 years after the disaster. The participants were either staying in an affected area at the time of the disaster (i.e., directly exposed) or not (i.e., not directly exposed). The prevalence of psychiatric disorders was assessed by the MINI International Neuropsychiatric Interview (M.I.N.I). Prolonged grief disorder (PGD) was self-reported using the Inventory of Complicated Grief (ICG), and functional impairment was self-reported using the Work and Social Adjustment Scale (WSAS). We did not identify a significant decrease in the prevalence of PGD, posttraumatic stress disorder (PTSD), or major depressive disorder (MDD) from 2 to 6 years. Approximately, one-third of the bereaved (36%) had a psychiatric disorder 6 years after the tsunami. The most common disorder was PGD (12%) followed by general anxiety disorder (GAD, 11%), agoraphobia (11%), and MDD (10%). The prevalence of PTSD and MDD was higher among family members who were directly exposed to the disaster compared to those who were not (21 vs. 0%, and 25 vs. 3%). PGD was associated with functional impairment independent of other disorders. Loss of a close family member in a natural disaster can have a substantial adverse long-term effect on mental health and everyday functioning. © 2014 Wiley Periodicals, Inc.

Use of Lung Allografts From Donation After Cardiac Death Donors: A Single-Center Experience.

PubMed

Costa, Joseph; Shah, Lori; Robbins, Hilary; Raza, Kashif; Sreekandth, Sowmya; Arcasoy, Selim; Sonett, Joshua R; D'Ovidio, Frank

2018-01-01

Lung transplantation remains the only treatment for end-stage lung disease. Availability of suitable lungs does not parallel this growing trend. Centers using donation after cardiac death (DCD) donor lungs report comparable outcomes with those from brain-dead donors. Donor assessment protocols and consistent surgical teams have been advocated when considering using the use of DCD donors. We present our experience using lungs from Maastricht category III DCD donors. Starting 2007 to July 2016, 73 DCD donors were assessed, 44 provided suitable lungs that resulted in 46 transplants. A 2012 to October 2016 comparative cohort of 379 brain-dead donors were assessed. Recipient and donor characteristics and primary graft dysfunction (PGD) and survival were monitored. Seventy-three DCD (40% dry run rate) donors assessed yielded 46 transplants (23 double, 6 right, and 17 left). Comparative cohort of 379 brain-dead donors yielded 237 transplants (112 double, 43 right, and 82 left). One- and 3-year recipient survival was 91% and 78% for recipients of DCD lungs and 91% and 75% for recipients of lungs from brain-dead donors, respectively. PGD 2 and 3 in DCD recipients at 72 hours was 4 of 46 (9%) and 6 of 46 (13%), respectively. Comparatively, brain-dead donor recipient cohort at 72 hours with PGD 2 and 3 was 23 of 237 (10%) and 41 of 237 (17%), respectively. Our experience reaffirms the use of lungs from DCD donors as a viable source with favorable outcomes. Recipients from DCD donors showed equivalent PGD rate at 72 hours and survival compared with recipients from brain-dead donors. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Waterborne Zn influenced Zn uptake and lipid metabolism in two intestinal regions of juvenile goby Synechogobius hasta.

PubMed

Ling, Shi-Cheng; Luo, Zhi; Chen, Guang-Hui; Zhang, Dian-Guang; Liu, Xu

2018-02-01

The present study explored the influence of Zn addition in the water on Zn transport and lipid metabolism of two intestinal regions in goby Synechogobius hasta. Zn contents in water were 0.004 (control), 0.181 and 0.361mg Zn L -1 , respectively. The experiment lasted for 28 days. TG and Zn contents, mRNA contents of genes of Zn transport and lipid metabolism, and enzyme activity from anterior and mid-intestine tissues were analyzed. In anterior intestine, Zn addition in the water increased Zn contents, and mRNA concentrations of ZIP4, ZIP5, ATGL, PPARα, ZNF202 and KLF7, decreased TG contents, 6PGD and G6PD activities, and mRNA contents of 6PGD, G6PD, FAS, PPARγ, ICDH and KLF4. In mid-intestine tissue, the highest Zn and TG contents were observed for 0.18mg Zn/l group, in parallel with the highest expressions of ZnT1, ZIP4, ZIP5, 6PGD, FAS, ICDH, PPARγ, PPARα, ZNF202, KLF4 and KLF7, and with the highest FAS, 6PGD and G6PD activities. Thus, in the anterior intestine, Zn addition increased lipolysis and decreased lipogenesis, and accordingly reduced TG content. However, the highest mid-intestinal TG content in 0.18mg Zn/l group was due to the up-regulated lipogenesis. Although lipolysis was also increased, the incremental lipid synthesis was enough to compensate for lipid degradation, which led TG accumulation. Our results, for the first time, show an anterior/mid functional regionalization of the intestine in lipid metabolism and Zn transport of S. hasta following Zn exposure. Copyright © 2017 Elsevier Inc. All rights reserved.

Detection of SEA-type α-thalassemia in embryo biopsies by digital PCR.

PubMed

Lee, Ta-Hsien; Hsu, Ya-Chiung; Chang, Chia Lin

2017-08-01

Accurate and efficient pre-implantation genetic diagnosis (PGD) based on the analysis of single or oligo-cells is needed for timely identification of embryos that are affected by deleterious genetic traits in in vitro fertilization (IVF) clinics. Polymerase chain reaction (PCR) is the backbone of modern genetic diagnoses, and a spectrum of PCR-based techniques have been used to detect various thalassemia mutations in prenatal diagnosis (PND) and PGD. Among thalassemias, SEA-type α-thalassemia is the most common variety found in Asia, and can lead to Bart's hydrops fetalis and serious maternal complications. To formulate an efficient digital PCR for clinical diagnosis of SEA-type α-thalassemia in cultured embryos, we conducted a pilot study to detect the α-globin and SEA-type deletion alleles in blastomere biopsies with a highly sensitive microfluidics-based digital PCR method. Genomic DNA from embryo biopsy samples were extracted, and crude DNA extracts were first amplified by a conventional PCR procedure followed by a nested PCR reaction with primers and probes that are designed for digital PCR amplification. Analysis of microfluidics-based PCR reactions showed that robust signals for normal α-globin and SEA-type deletion alleles, together with an internal control gene, can be routinely generated using crude embryo biopsies after a 10 6 -fold dilution of primary PCR products. The SEA-type deletion in cultured embryos can be sensitively diagnosed with the digital PCR procedure in clinics. The adoption of this robust PGD method could prevent the implantation of IVF embryos that are destined to develop Bart's hydrops fetalis in a timely manner. The results also help inform future development of a standard digital PCR procedure for cost-effective PGD of α-thalassemia in a standard IVF clinic. Copyright © 2017. Published by Elsevier B.V.

Low-flow venovenous CO₂ removal in association with lung protective ventilation strategy in patients who develop severe progressive respiratory acidosis after lung transplantation.

PubMed

Ruberto, F; Bergantino, B; Testa, M C; D'Arena, C; Zullino, V; Congi, P; Paglialunga, S G; Diso, D; Venuta, F; Pugliese, F

2013-09-01

Primary graft dysfunction (PGD) might occur after lung transplantation. In some severe cases, conventional therapies like ventilatory support, administration of inhaled nitric oxide (iNO), and intravenous prostacyclins are not sufficient to provide an adequate gas exchange. The aim of our study was to evaluate the use of a lung protective ventilation strategy associated with a low-flow venovenous CO2 removal treatment to reduce ventilator-associated injury in patients that develop severe PGD after lung transplantation. From January 2009 to January 2011, 3 patients developed PGD within 24 hours after lung transplantation. In addition to conventional medical treatment, including hemodynamic support, iNO and prostaglandin E1 (PGE1), we initiated a ventilatory protective strategy associated with low-flow venovenous CO2 removal treatment (LFVVECCO2R). Hemodynamic and respiratory parameters were assessed at baseline as well as after 3, 12, 24, and 48 hours. No adverse events were registered. Despite decreased baseline elevated pulmonary positive pressures, application of a protective ventilation strategy with LFVVECCO2R reduced PaCO2 and pulmonary infiltrates as well as increased pH values and PaO2/FiO2 ratios. Every patient showed simultaneous improvement of clinical and hemodynamic conditions. They were weaned from mechanical ventilation and extubated after 24 hours after the use of the low-flow venovenous CO2 removal device. The use of LFVVECCO2R together with a protective lung ventilation strategy during the perioperative period of lung transplantation may be a valid clinical strategy for patients with PGD and severe respiratory acidosis occured despite adequate mechanical ventilation. Copyright © 2013 Elsevier Inc. All rights reserved.

Attitudes of palliative care clinical staff toward prolonged grief disorder diagnosis and grief interventions.

PubMed

Davis, Esther L; Deane, Frank P; Barclay, Gregory D; Bourne, Joan; Connolly, Vivienne

2017-07-03

The provision of psychological support to caregivers is an important part of the role of the clinical staff working in palliative care. Staff knowledge and attitudes may determine their openness to referring caregivers to a psychological intervention. We recently developed a self-help intervention for grief and psychological distress among caregivers and were interested in exploring the extent to which staff knowledge and attitudes might affect future implementation. The aims of our study were to: (1) examine the acceptability of self-help psychological intervention for caregivers among palliative care clinical staff; (2) examine potential attitudinal barriers toward prolonged grief disorder (PGD) as a diagnosis and interventions for grief; and (3) bolster staff confidence in skills and knowledge in identifying and managing caregiver psychological distress. An anonymous survey was distributed among clinical staff at two inpatient units and two community health services that assessed the acceptability of self-help interventions for caregivers, attitudes about PGD diagnosis and grief intervention, and staff confidence in skills and knowledge in assessing caregiver psychological distress. Overall, clinical staff were positively oriented toward self-help for caregivers and intervention for grief. They were also basically confident in their skills and knowledge. While it was positive PGD attitudes that were associated with acceptability of self-help for caregivers, it was both positive and negative PGD attitudes that were associated more specifically with a willingness to refer caregivers to such an intervention. Our findings are useful in highlighting the issues to be considered in the implementation of a self-help intervention within the healthcare service. Clinical staff seemed positively oriented toward engaging with a psychological intervention for caregivers and likely to act as key allies in implementation.

Rapid mapping of chromosomal breakpoints: from blood to BAC in 20 days.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Chun-Mei; Kwan, Johnson; Weier, Jingly F.

2009-02-25

Structural chromosome aberrations and associated segmental or chromosomal aneusomies are major causes of reproductive failure in humans. Despite the fact that carriers of reciprocal balanced translocation often have no other clinical symptoms or disease, impaired chromosome homologue pairing in meiosis and karyokinesis errors lead to over-representation of translocations carriers in the infertile population and in recurrent pregnancy loss patients. At present, clinicians have no means to select healthy germ cells or balanced zygotes in vivo, but in vitro fertilization (IVF) followed by preimplantation genetic diagnosis (PGD) offers translocation carriers a chance to select balanced or normal embryos for transfer. Althoughmore » a combination of telomeric and centromeric probes can differentiate embryos that are unbalanced from normal or unbalanced ones, a seemingly random position of breakpoints in these IVF-patients poses a serious obstacle to differentiating between normal and balanced embryos, which for most translocation couples, is desirable. Using a carrier with reciprocal translocation t(4;13) as an example, we describe our state-of-the-art approach to the preparation of patient-specific DNA probes that span or 'extent' the breakpoints. With the techniques and resources described here, most breakpoints can be accurately mapped in a matter of days using carrier lymphocytes, and a few extra days are allowed for PGD-probe optimization. The optimized probes will then be suitable for interphase cell analysis, a prerequisite for PGD since blastomeres are biopsied from normally growing day 3 - embryos regardless of their position in the mitotic cell cycle. Furthermore, routine application of these rapid methods should make PGD even more affordable for translocation carriers enrolled in IVF programs.« less

Indomethacin causes prostaglandin D(2)-like and eotaxin-like selective responses in eosinophils and basophils.

PubMed

Stubbs, Victoria E L; Schratl, Petra; Hartnell, Adele; Williams, Timothy J; Peskar, Bernhard A; Heinemann, Akos; Sabroe, Ian

2002-07-19

We investigated the actions of a panel of nonsteroidal anti-inflammatory drugs on eosinophils, basophils, neutrophils, and monocytes. Indomethacin alone was a potent and selective inducer of eosinophil and basophil shape change. In eosinophils, indomethacin induced chemotaxis, CD11b up-regulation, respiratory burst, and L-selectin shedding but did not cause up-regulation of CD63 expression. Pretreatment of eosinophils with indomethacin also enhanced subsequent eosinophil shape change induced by eotaxin, although treatment with higher concentrations of indomethacin resulted in a decrease in the expression of the major eosinophil chemokine receptor, CCR3. Indomethacin activities and cell selectivity closely resembled those of prostaglandin D(2) (PGD(2)). Eosinophil shape change in response to eotaxin was inhibited by pertussis toxin, but indomethacin- and PGD(2)-induced shape change responses were not. Treatment of eosinophils with specific inhibitors of phospholipase C (U-73122), phosphatidylinositol 3-kinase (LY-294002), and p38 mitogen-activated protein kinase (SB-202190) revealed roles for these pathways in indomethacin signaling. Indomethacin and its analogues may therefore provide a structural basis from which selective PGD(2) receptor small molecule antagonists may be designed and which may have utility in the treatment of allergic inflammatory disease.

Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

PubMed

Kida, Taiki; Ayabe, Shinya; Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

2016-01-01

Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

Redox cofactors insertion in prokaryotic molybdoenzymes occurs via a conserved folding mechanism

PubMed Central

Arias-Cartin, Rodrigo; Ceccaldi, Pierre; Schoepp-Cothenet, Barbara; Frick, Klaudia; Blanc, Jean-Michel; Guigliarelli, Bruno; Walburger, Anne; Grimaldi, Stéphane; Friedrich, Thorsten; Receveur-Brechot, Véronique; Magalon, Axel

2016-01-01

A major gap of knowledge in metalloproteins is the identity of the prefolded state of the protein before cofactor insertion. This holds for molybdoenzymes serving multiple purposes for life, especially in energy harvesting. This large group of prokaryotic enzymes allows for coordination of molybdenum or tungsten cofactors (Mo/W-bisPGD) and Fe/S clusters. Here we report the structural data on a cofactor-less enzyme, the nitrate reductase respiratory complex and characterize the conformational changes accompanying Mo/W-bisPGD and Fe/S cofactors insertion. Identified conformational changes are shown to be essential for recognition of the dedicated chaperone involved in cofactors insertion. A solvent-exposed salt bridge is shown to play a key role in enzyme folding after cofactors insertion. Furthermore, this salt bridge is shown to be strictly conserved within this prokaryotic molybdoenzyme family as deduced from a phylogenetic analysis issued from 3D structure-guided multiple sequence alignment. A biochemical analysis with a distantly-related member of the family, respiratory complex I, confirmed the critical importance of the salt bridge for folding. Overall, our results point to a conserved cofactors insertion mechanism within the Mo/W-bisPGD family. PMID:27886223

Stable expression of lipocalin-type prostaglandin D synthase in cultured preadipocytes impairs adipogenesis program independently of endogenous prostanoids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hossain, Mohammad Salim; Chowdhury, Abu Asad; Rahman, Mohammad Sharifur

Lipocalin-type prostaglandin D synthase (L-PGDS) expressed preferentially in adipocytes is responsible for the synthesis of PGD{sub 2} and its non-enzymatic dehydration products, PGJ{sub 2} series, serving as pro-adipogenic factors. However, the role of L-PGDS in the regulation of adipogenesis is complex because of the occurrence of several derivatives from PGD{sub 2} and their distinct receptor subtypes as well as other functions such as a transporter of lipophilic molecules. To manipulate the expression levels of L-PGDS in cultured adipocytes, cultured preadipogenic 3T3-L1 cells were transfected stably with a mammalian expression vector having cDNA encoding murine L-PGDS oriented in the sense direction.more » The isolated cloned stable transfectants with L-PGDS expressed higher levels of the transcript and protein levels of L-PGDS, and synthesized PGD{sub 2} from exogenous arachidonic acid at significantly higher levels. By contrast, the synthesis of PGE{sub 2} remained unchanged, indicating no influence on the reactions of cyclooxygenase (COX) and PGE synthase. Furthermore, the ability of those transfectants to synthesize {Delta}{sup 12}-PGJ{sub 2} increased more greatly during the maturation phase. The sustained expression of L-PGDS in cultured stable transfectants hampered the storage of fats during the maturation phase of adipocytes, which was accompanied by the reduced gene expression of adipocyte-specific markers reflecting the down-regulation of the adipogenesis program. The suppressed adipogenesis was not rescued by either exogenous aspirin or peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists including troglitazone and {Delta}{sup 12}-PGJ{sub 2}. Taken together, the results indicate the negative regulation of the adipogenesis program by the enhanced expression of L-PGDS through a cellular mechanism involving the interference of the PPAR{gamma} signaling pathway without the contribution of endogenous pro-adipogenic prostanoids. -- Highlights: Black-Right-Pointing-Pointer Cultured preadipocytes were transfected with sense lipocalin-type PGD synthase. Black-Right-Pointing-Pointer The cloned transfectants had a higher ability to synthesize PGD{sub 2} and PGJ{sub 2} series. Black-Right-Pointing-Pointer The sustained expression of sense L-PGDS hampered the storage of fats. Black-Right-Pointing-Pointer Adipogenesis program was suppressed independently of endogenous prostanoids.« less

Setting up equine embryo gender determination by preimplantation genetic diagnosis in a commercial embryo transfer program.

PubMed

Herrera, C; Morikawa, M I; Bello, M B; von Meyeren, M; Centeno, J Eusebio; Dufourq, P; Martinez, M M; Llorente, J

2014-03-15

Preimplantation genetic diagnosis (PGD) allows identifying genetic traits in early embryos. Because in some equine breeds, like Polo Argentino, females are preferred to males for competition, PGD can be used to determine the gender of the embryo before transfer and thus allow the production of only female pregnancies. This procedure could have a great impact on commercial embryo production programs. The present study was conducted to adapt gender selection by PGD to a large-scale equine embryo transfer program. To achieve this, we studied (i) the effect on pregnancy rates of holding biopsied embryos for 7 to 10 hours in holding medium at 32 °C before transfer, (ii) the effect on pregnancy rates of using embryos of different sizes for biopsy, and (iii) the efficiency of amplification by heating biopsies before polymerase chain reaction. Equine embryos were classified by size (≤300, 300-1000, and >1000 μm), biopsied, and transferred 1 to 2 or 7 to 10 hours after flushing. Some of the biopsy samples obtained were incubated for 10 minutes at 95 °C and the rest remained untreated. Pregnancy rates were recorded at 25 days of gestation; fetal gender was determined using ultrasonography and compared with PGD results. Holding biopsied embryos for 7 to 10 hours before transfer produced pregnancy rates similar to those for biopsied embryos transferred within 2 hours (63% and 57%, respectively). These results did not differ from pregnancy rates of nonbiopsied embryos undergoing the same holding times (50% for 7-10 hours and 63% for 1-2 hours). Pregnancy rates for biopsied and nonbiopsied embryos did not differ between size groups or between biopsied and nonbiopsied embryos within the same size group (P > 0.05). Incubating biopsy samples for 10 minutes at 95 °C before polymerase chain reaction significantly increased the diagnosis rate (78.5% vs. 45.5% for treated and nontreated biopsy samples respectively). Gender determination using incubated biopsy samples matched the results obtained using ultrasonography in all pregnancies assessed (11/11, 100%); untreated biopsy samples were correctly diagnosed in 36 of 41 assessed pregnancies (87.8%), although the difference between treated and untreated biopsy samples was not significant. Our results demonstrated that biopsied embryos can remain in holding medium before being transferred, until gender diagnosis by PGD is complete (7-10 hours), without affecting pregnancy rates. This simplifies the management of an embryo transfer program willing to incorporate PGD for gender selection, by transferring only embryos of the desired sex. Embryo biopsy can be performed in a clinical setting on embryos of different sizes, without affecting their viability. Additionally, we showed that pretreating biopsy samples with a short incubation at 95 °C improved the overall efficiency of embryo sex determination. Copyright © 2014 Elsevier Inc. All rights reserved.

Resolving a genetic paradox throughout preimplantation genetic diagnosis for autosomal dominant severe congenital neutropenia.

PubMed

Malcov, Mira; Reches, Adi; Ben-Yosef, Dalit; Cohen, Tania; Amit, Ami; Dgany, Orly; Tamary, Hannah; Yaron, Yuval

2010-03-01

Severe congenital neutropenia is an inherited disease characterized by low peripheral blood neutrophils, amenable to bone marrow transplantation. Genetic analysis in the family here described detected a ELA2 splice-site mutation in the affected child and also in his asymptomatic father. The parents requested preimplantation genetic diagnosis (PGD), coupled with HLA matching, to obtain a suitable bone marrow donor for the affected child. A PGD protocol was developed, based on multiplex nested PCR for direct analysis of the ELA2 mutation, flanking polymorphic markers and HLA typing. The amplification efficiency of the mutation was > 90% in single leukocytes from the affected child but only 67% in the father. Analysis of single haploid sperm cells from the father demonstrated three different sperm-cell populations: (1) sperm cells harboring the ELA2 mutation on the 'affected' haplotype, (2) sperm cells without the ELA2 mutation on the 'normal' haplotype, and (3) sperm cells without the ELA2 mutation on the 'affected' haplotype. These data demonstrate that the ELA2 mutation in the father occurred de novo during his embryonic development, resulting in somatic as well as germ-line mosaicism. This conclusion was also taken into consideration when PGD was performed. Copyright (c) 2010 John Wiley & Sons, Ltd.

Polymer gel dosimeters for pretreatment radiotherapy verification using the three-dimensional gamma evaluation and pass rate maps.

PubMed

Hsieh, Ling-Ling; Shieh, Jiunn-I; Wei, Li-Ju; Wang, Yi-Chun; Cheng, Kai-Yuan; Shih, Cheng-Ting

2017-05-01

Polymer gel dosimeters (PGDs) have been widely studied for use in the pretreatment verification of clinical radiation therapy. However, the readability of PGDs in three-dimensional (3D) dosimetry remain unclear. In this study, the pretreatment verifications of clinical radiation therapy were performed using an N-isopropyl-acrylamide (NIPAM) PGD, and the results were used to evaluate the performance of the NIPAM PGD on 3D dose measurement. A gel phantom was used to measure the dose distribution of a clinical case of intensity-modulated radiation therapy. Magnetic resonance imaging scans were performed for dose readouts. The measured dose volumes were compared with the planned dose volume. The relative volume histograms showed that relative volumes with a negative percent dose difference decreased as time elapsed. Furthermore, the histograms revealed few changes after 24h postirradiation. For the 3%/3mm and 2%/2mm criteria, the pass rates of the 12- and 24-h dose volumes were higher than 95%, respectively. This study thus concludes that the pass rate map can be used to evaluate the dose-temporal readability of PGDs and that the NIPAM PGD can be used for clinical pretreatment verifications. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Perceived Discrimination and Longitudinal Change in Kidney Function Among Urban Adults.

PubMed

Beydoun, May A; Poggi-Burke, Angedith; Zonderman, Alan B; Rostant, Ola S; Evans, Michele K; Crews, Deidra C

2017-09-01

Perceived discrimination has been associated with psychosocial distress and adverse health outcomes. We examined associations of perceived discrimination measures with changes in kidney function in a prospective cohort study, the Healthy Aging in Neighborhoods of Diversity across the Life Span. Our study included 1620 participants with preserved baseline kidney function (estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m) (662 whites and 958 African Americans, aged 30-64 years). Self-reported perceived racial discrimination and perceived gender discrimination (PGD) and a general measure of experience of discrimination (EOD) ("medium versus low," "high versus low") were examined in relation to baseline, follow-up, and annual rate of change in eGFR using multiple mixed-effects regression (γbase, γrate) and ordinary least square models (γfollow). Perceived gender discrimination "high versus low PGD" was associated with a lower baseline eGFR in all models (γbase = -3.51 (1.34), p = .009 for total sample). Among white women, high EOD was associated with lower baseline eGFR, an effect that was strengthened in the full model (γbase = -5.86 [2.52], p = .020). Overall, "high versus low" PGD was associated with lower follow-up eGFR (γfollow = -3.03 [1.45], p = .036). Among African American women, both perceived racial discrimination and PGD were linked to lower follow-up kidney function, an effect that was attenuated with covariate adjustment, indicating mediation through health-related, psychosocial, and lifestyle factors. In contrast, EOD was not linked to follow-up eGFR in any of the sex by race groups. Perceived racial and gender discrimination are associated with lower kidney function assessed by glomerular filtration rate and the strength of associations differ by sex and race groups. Perceived discrimination deserves further investigation as a psychosocial risk factors for kidney disease.

Teaching about Russia.

ERIC Educational Resources Information Center

Jones, Dianne

1985-01-01

By focusing on goegraphy, music, art, and literature, one teacher teaches her students about the history of Russian culture without having to fight student predjudice against the Soviet government. (PGD)

The therapeutic potential of CRTH2/DP2 beyond allergy and asthma.

PubMed

Jandl, Katharina; Heinemann, Akos

2017-11-01

Prostaglandin (PG) D 2 has been in the focus of research for quite a long time, but its biological effects and its roles in human disease are still not fully characterized. When in 2001 a second major PGD 2 receptor termed chemoattractant receptor homologue expressed on Th2 cells (CRTH2; alternative name DP2) was discovered, diverse investigations started to shed more light on the complex and often controversial actions of the prostaglandin. With various immunomodulating effects, such as induction of migration, activation, and cytokine release of leukocytes observed both in vivo and in vitro, CRTH2 has emerged as a promising target for the treatment of allergic diseases. However, with more and more research being performed on CRTH2, it has also become clear that its biological actions are far more diverse than expected at the beginning. In this review, we aim to summarize the roles that PGD 2 - and CRTH2 in particular - might play in diseases of the central nervous system, kidney, intestine, lung, hair and skin, bone and cartilage, and in cancer. Based on current data we propose that blocking CRTH2 might be a potential therapeutic approach to numerous conditions beyond classical allergic diseases and asthma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weier, Jingly F.; Ferlatte, Christy; Baumgartner, Adolf

Numerical chromosome aberrations in gametes typically lead to failed fertilization, spontaneous abortion or a chromosomally abnormal fetus. By means of preimplantation genetic diagnosis (PGD), we now can screen human embryos in vitro for aneuploidy before transferring the embryos to the uterus. PGD allows us to select unaffected embryos for transfer and increases the implantation rate in in vitro fertilization programs. Molecular cytogenetic analyses using multi-color fluorescence in situ hybridization (FISH) of blastomeres have become the major tool for preimplantation genetic screening of aneuploidy. However, current FISH technology can test for only a small number of chromosome abnormalities and hitherto failedmore » to increase the pregnancy rates as expected. We are in the process of developing technologies to score all 24 chromosomes in single cells within a 3 day time limit, which we believe is vital to the clinical setting. Also, human placental cytotrophoblasts (CTBs) at the fetal-maternal interface acquire aneuploidies as they differentiate to an invasive phenotype. About 20-50% of invasive CTB cells from uncomplicated pregnancies were found aneuploidy, suggesting that the acquisition of aneuploidy is an important component of normal placentation, perhaps limiting the proliferative and invasive potential of CTBs. Since most invasive CTBs are interphase cells and possess extreme heterogeneity, we applied multi-color FISH and repeated hybridizations to investigate individual CTBs. In summary, this study demonstrates the strength of Spectral Imaging analysis and repeated hybridizations, which provides a basis for full karyotype analysis of single interphase cells.« less

Multiple displacement amplification on single cell and possible PGD applications.

PubMed

Hellani, Ali; Coskun, Serdar; Benkhalifa, Moncef; Tbakhi, Abelghani; Sakati, Nadia; Al-Odaib, Ali; Ozand, Pinar

2004-11-01

Multiple displacement amplification (MDA) is a technique used in the amplification of very low amounts of DNA and reported to yield large quantities of high-quality DNA. We used MDA to amplify the whole genome directly from a single cell. The most common techniques used in PGD are PCR and fluorescent in-situ hybridization (FISH). There are many limitations to these techniques including, the number of chromosomes diagnosed for FISH or the quality of DNA issued from a single cell PCR. This report shows, for the first time, use of MDA for single cell whole genome amplification. A total of 16 short tandem repeats (STRs) were amplified successfully with a similar pattern to the genomic DNA. Furthermore, allelic drop out (ADO) derived from MDA was assessed in 40 single cells by analysing (i) heterozygosity for a known beta globin mutation (IVSI-5 C-G) and by studying (ii) the heterozygous loci present in the STRs. ADO turned out to be 10.25% for the beta globin gene sequencing and 5% for the fluorescent PCR analysis of STRs. Moreover, the amplification accuracy of MDA permitted the detection of trisomy 21 on a single cell using comparative genome hybridization-array. Altogether, these data suggest that MDA can be used for single cell molecular karyotyping and the diagnosis of any single gene disorder in PGD.

Successful application of preimplantation genetic diagnosis for beta-thalassaemia and sickle cell anaemia in Italy.

PubMed

Chamayou, S; Alecci, C; Ragolia, C; Giambona, A; Siciliano, S; Maggio, A; Fichera, M; Guglielmino, A

2002-05-01

In Italy, the autosomal recessive diseases beta-thalassaemia and sickle cell anaemia are so widespread that in some regions they can be defined as 'social diseases'. In this study, nine clinical applications of preimplantation genetic diagnosis (PGD) were performed for beta-thalassaemia and sickle cell anaemia on seven Sicilian couples and carriers of beta-globin gene mutations. The studied mutations were: Cd39, HbS, IVS1 nt1, IVS1 nt6 and IVS1 nt110. ICSI was performed with partner's sperm on 131 out of 147 retrieved oocytes, and this resulted in 72 zygotes; 32 embryos were successfully biopsied on day 3. The biopsied blastomeres were lysed and the beta-globin alleles amplified by nested PCR. The mutation diagnosis was performed by restriction enzyme digestion and reverse dot-blot. The amplification efficacy was 97.2%. The genotype study of non-transferred and surplus embryos showed that the allele drop-out rate was 8.6%. Seventeen embryos were transferred in utero on day 4. All couples received an embryo transfer; of the four pregnancies obtained, three resulted in live births and one miscarried at 11 weeks. Prenatal diagnosis at the 11th week and miscarriage material analysis confirmed the PGD results. These studies represent the first successful application of PGD for beta-thalassaemia and sickle cell anaemia in Italy.

First report on an X-linked hypohidrotic ectodermal dysplasia family with X chromosome inversion: Breakpoint mapping reveals the pathogenic mechanism and preimplantation genetics diagnosis achieves an unaffected birth.

PubMed

Wu, Tonghua; Yin, Biao; Zhu, Yuanchang; Li, Guangui; Ye, Lijun; Liang, Desheng; Zeng, Yong

2017-12-01

To investigate the etiology of X-linked hypohidrotic ectodermal dysplasia (XLHED) in a family with an inversion of the X chromosome [inv(X)(p21q13)] and to achieve a healthy birth following preimplantation genetic diagnosis (PGD). Next generation sequencing (NGS) and Sanger sequencing analysis were carried out to define the inversion breakpoint. Multiple displacement amplification, amplification of breakpoint junction fragments, Sanger sequencing of exon 1 of ED1, haplotyping of informative short tandem repeat markers and gender determination were performed for PGD. NGS data of the proband sample revealed that the size of the possible inverted fragment was over 42Mb, spanning from position 26, 814, 206 to position 69, 231, 915 on the X chromosome. The breakpoints were confirmed by Sanger sequencing. A total of 5 blastocyst embryos underwent trophectoderm biopsy. Two embryos were diagnosed as carriers and three were unaffected. Two unaffected blastocysts were transferred and a singleton pregnancy was achieved. Following confirmation by prenatal diagnosis, a healthy baby was delivered. This is the first report of an XLHED family with inv(X). ED1 is disrupted by the X chromosome inversion in this XLHED family and embryos with the X chromosomal abnormality can be accurately identified by means of PGD. Copyright © 2017. Published by Elsevier B.V.

The status of preimplantation genetic diagnosis in Japan: a criticism.

PubMed

Munné, Santiago; Cohen, Jacques

2004-09-01

Advances in preimplantation genetic diagnosis (PGD) are occurring worldwide. New clinics specializing in this approach to the control of disease genes or imbalanced chromosome numbers in human preimplantation embryos continue to increase. One exception is Japan, where the Japanese Society of Obstetrics and Gynecology disapproves of this practice because it discriminates against people with genetic abnormalities. Yet, some doctors there wish to introduce this method to help their couples to improved forms of IVF. This paper stresses the rights of patients to have a healthy baby, if necessary by the use of PGD. It argues against prohibition, since it complements the current nature of prenatal diagnosis and avoids the need for abortions in case of afflicted embryos. Consideration is also given to other attempts at restriction that have failed.

Tuberous Sclerosis Syndrome

MedlinePlus

... removed and fertilized in a laboratory. When the embryos reach a certain size, 1 cell is removed ... question. The parents can then choose to transfer embryos which do not have the mutation. PGD has ...

Ventricular assist device elicits serum natural IgG that correlates with the development of primary graft dysfunction following heart transplantation.

PubMed

See, Sarah B; Clerkin, Kevin J; Kennel, Peter J; Zhang, Feifan; Weber, Matthew P; Rogers, Kortney J; Chatterjee, Debanjana; Vasilescu, Elena R; Vlad, George; Naka, Yoshifumi; Restaino, Susan W; Farr, Maryjane A; Topkara, Veli K; Colombo, Paolo C; Mancini, Donna M; Schulze, P Christian; Levin, Bruce; Zorn, Emmanuel

2017-08-01

Pre-transplant sensitization is a limiting factor in solid-organ transplantation. In heart transplants, ventricular assist device (VAD) implantation has been associated with sensitization to human leukocyte antigens (HLA). The effect of VAD on non-HLA antibodies is unclear. We have previously shown that polyreactive natural antibodies (Nabs) contribute to pre-sensitization in kidney allograft recipients. Here we assessed generation of Nabs after VAD implantation in pre-transplant sera and examined their contribution to cardiac allograft outcome. IgM and IgG Nabs were tested in pre-transplant serum samples collected from 206 orthotopic heart transplant recipients, including 128 patients with VAD (VAD patients) and 78 patients without VAD (no-VAD patients). Nabs were assessed by testing serum reactivity to apoptotic cells by flow cytometry and to the generic oxidized epitope, malondialdehyde, by enzyme-linked immunosorbent assay. No difference was observed in serum levels of IgM Nabs between VAD and no-VAD patients. However, serum IgG Nabs levels were significantly increased in VAD compared with no-VAD patients. This increase was likely due to the presence of the VAD, as revealed by lower serum IgG Nabs levels before implantation. Elevated pre-transplant IgG Nabs level was associated with development of primary graft dysfunction (PGD). Our study demonstrates that VAD support elicits IgG Nabs reactive to apoptotic cells and oxidized epitopes. These findings further support broad and non-specific B-cell activation by VAD, resulting in IgG sensitization. Moreover, the association of serum IgG Nabs levels with development of PGD suggests a possible role for these antibodies in the inflammatory reaction accompanying this complication. Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Population data of five genetic markers in the Turkish population: comparison with four American population groups.

PubMed

Kurtuluş-Ulküer, M; Ulküer, U; Kesici, T; Menevşe, S

2002-09-01

In this study, the phenotype and allele frequencies of five enzyme systems were determined in a total of 611 unrelated Turkish individuals and analyzed by using the exact and the chi 2 test. The following five red cell enzymes were identified by cellulose acetate electrophoresis: phosphoglucomutase (PGM), adenosine deaminase (ADA), phosphoglucose isomerase (PGI), adenylate kinase (AK), and 6-phosphogluconate dehydrogenase (6-PGD). The ADA, PGM and AK enzymes were found to be polymorphic in the Turkish population. The results of the statistical analysis showed, that the phenotype frequencies of the five enzyme under study are in Hardy-Weinberg equilibrium. Statistical analysis was performed in order to examine whether there are significant differences in the phenotype frequencies between the Turkish population and four American population groups. This analysis showed, that there are some statistically significant differences between the Turkish and the other groups. Moreover, the observed phenotype and allele frequencies were compared with those obtained in other population groups of Turkey.

Help Is Available on Tax-Deferred Annuity Programs.

ERIC Educational Resources Information Center

School Administrator, 1985

1985-01-01

Briefly reviews different types of tax-deferred annuities (TDA's) and describes the National Education Association's TDA Studies--comparative analyses of specific fixed, variable, and qualified mutual fund annuity packages. (PGD)

Lung donor treatment protocol in brain dead-donors: A multicenter study.

PubMed

Miñambres, Eduardo; Pérez-Villares, Jose Miguel; Chico-Fernández, Mario; Zabalegui, Arturo; Dueñas-Jurado, Jose María; Misis, Maite; Mosteiro, Fernando; Rodriguez-Caravaca, Gil; Coll, Elisabeth

2015-06-01

The shortage of lung donors for transplantation is the main limitation among patients awaiting this type of surgery. We previously demonstrated that an intensive lung donor-treatment protocol succeeded in increasing the lung procurement rate. We aimed to validate our protocol for centers with or without lung transplant programs. A quasi-experimental study was performed to compare lung donor rate before (historical group, 2010 to 2012) and after (prospective group, 2013) the application of a lung management protocol for donors after brain death (DBDs) in six Spanish hospitals. Lung donor selection criteria remained unchanged in both periods. Outcome measures for lung recipients were early survival and primary graft dysfunction (PGD) rates. A total of 618 DBDs were included: 453 in the control period and 165 in the protocol period. Donor baseline characteristics were similar in both periods. Lung donation rate in the prospective group was 27.3%, more than twice that of the historical group (13%; p < 0.001). The number of lungs retrieved, grafts transplanted, and transplants performed more than doubled over the study period. No differences in early recipients' survival between groups were observed (87.6% vs. 84.5%; p = 0.733) nor in the rate of PGD. Implementing our intensive lung donor-treatment protocol increases lung procurement rates. This allows more lung transplants to be performed without detriment to either early survival or PGD rate. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

PGH1, the Precursor for the Anti-Inflammatory Prostaglandins of the 1-series, Is a Potent Activator of the Pro-Inflammatory Receptor CRTH2/DP2

PubMed Central

Schröder, Ralf; Xue, Luzheng; Konya, Viktoria; Martini, Lene; Kampitsch, Nora; Whistler, Jennifer L.; Ulven, Trond; Heinemann, Akos; Pettipher, Roy; Kostenis, Evi

2012-01-01

Prostaglandin H1 (PGH1) is the cyclo-oxygenase metabolite of dihomo-γ-linolenic acid (DGLA) and the precursor for the 1-series of prostaglandins which are often viewed as “anti-inflammatory”. Herein we present evidence that PGH1 is a potent activator of the pro-inflammatory PGD2 receptor CRTH2, an attractive therapeutic target to treat allergic diseases such as asthma and atopic dermatitis. Non-invasive, real time dynamic mass redistribution analysis of living human CRTH2 transfectants and Ca2+ flux studies reveal that PGH1 activates CRTH2 as PGH2, PGD2 or PGD1 do. The PGH1 precursor DGLA and the other PGH1 metabolites did not display such effect. PGH1 specifically internalizes CRTH2 in stable CRTH2 transfectants as assessed by antibody feeding assays. Physiological relevance of CRTH2 ligation by PGH1 is demonstrated in several primary human hematopoietic lineages, which endogenously express CRTH2: PGH1 mediates migration of and Ca2+ flux in Th2 lymphocytes, shape change of eosinophils, and their adhesion to human pulmonary microvascular endothelial cells under physiological flow conditions. All these effects are abrogated in the presence of the CRTH2 specific antagonist TM30089. Together, our results identify PGH1 as an important lipid intermediate and novel CRTH2 agonist which may trigger CRTH2 activation in vivo in the absence of functional prostaglandin D synthase. PMID:22442685

Segregation of mtDNA Throughout Human Embryofetal Development: m.3243A > G as a Model System

PubMed Central

Monnot, Sophie; Gigarel, Nadine; Samuels, David C; Burlet, Philippe; Hesters, Laetitia; Frydman, Nelly; Frydman, René; Kerbrat, Violaine; Funalot, Benoit; Martinovic, Jelena; Benachi, Alexandra; Feingold, Josué; Munnich, Arnold; Bonnefont, Jean-Paul; Steffann, Julie

2011-01-01

Mitochondrial DNA (mtDNA) mutations cause a wide range of serious diseases with high transmission risk and maternal inheritance. Tissue heterogeneity of the heteroplasmy rate (“mutant load”) accounts for the wide phenotypic spectrum observed in carriers. Owing to the absence of therapy, couples at risk to transmit such disorders commonly ask for prenatal (PND) or preimplantation diagnosis (PGD). The lack of data regarding heteroplasmy distribution throughout intrauterine development, however, hampers the implementation of such procedures. We tracked the segregation of the m.3243A > G mutation (MT-TL1 gene) responsible for the MELAS syndrome in the developing embryo/fetus, using tissues and cells from eight carrier females, their 38 embryos and 12 fetuses. Mutant mtDNA segregation was found to be governed by random genetic drift, during oogenesis and somatic tissue development. The size of the bottleneck operating for m.3243A > G during oogenesis was shown to be individual-dependent. Comparison with data we achieved for the m.8993T > G mutation (MT-ATP6 gene), responsible for the NARP/Leigh syndrome, indicates that these mutations differentially influence mtDNA segregation during oogenesis, while their impact is similar in developing somatic tissues. These data have major consequences for PND and PGD procedures in mtDNA inherited disorders. Hum Mutat 32:116–125, 2011. © 2010 Wiley-Liss, Inc. PMID:21120938

West-Coast Wide Expansion and Testing of the Geodetic Alarm System (G-larmS)

NASA Astrophysics Data System (ADS)

Ruhl, C. J.; Grapenthin, R.; Melgar, D.; Aranha, M. A.; Allen, R. M.

2016-12-01

The Geodetic Alarm System (G-larmS) was developed in collaboration between the Berkeley Seismological Laboratory (BSL) and New Mexico Tech for real-time Earthquake Early Warning (EEW). G-larmS has been in continuous operation at the BSL since 2014 using event triggers from the ShakeAlert EEW system and real-time position time series from a fully triangulated network consisting of BARD, PBO and USGS stations across northern California (CA). G-larmS has been extended to include southern CA and Cascadia, providing continuous west-coast wide coverage. G-larmS currently uses high rate (1 Hz), low latency (< 5 s), accurate positioning (cm level) time series data from a regional GPS network and P-wave event triggers from the ShakeAlert EEW system. It extracts static offsets from real-time GPS time series upon S-wave arrival and performs a least squares inversion on these offsets to determine slip on a finite fault. A key issue with geodetic EEW approaches is that unlike seismology-based algorithms that are routinely tested using frequent small-magnitude events, geodetic systems are not regularly exercised. Scenario ruptures are therefore important for testing the performance of G-larmS. We discuss results from scenario events on several large faults (capable of M>6.5) in CA and Cascadia built from realistic 3D geometries. Synthetic long-period 1Hz displacement waveforms were obtained from a new stochastic kinematic slip distribution generation method. Waveforms are validated by direct comparison to peak P-wave displacement scaling laws and to PGD GMPEs obtained from high-rate GPS observations of large events worldwide. We run the scenarios on real-time streams to systematically test the recovery of slip and magnitude by G-larmS. In addition to presenting these results, we will discuss new capabilities, such as implementing 2D geometry and the applicability of these results to GPS enhanced tsunami warning systems.

On Teacher Career Development: A Conversation with Phillip Schlechty.

ERIC Educational Resources Information Center

Brandt, Ron

1985-01-01

Briefly discusses Phillip Schlechty's view on teacher career development with university cooperation, needs for systematic faculty development, appropriate administrator roles, encouragement of professionalism, the use of differentiated staffing patterns, and appropriate attitudes toward reform. (PGD)

Ham on Regal.

ERIC Educational Resources Information Center

Hubbard, Russ

1985-01-01

Teachers at Ferris High School in Spokane, Washington, are joined by the parents of high school students in the production of elaborate annual shows that both create a sense of community and raise approximately $10,000 a year for the school. (PGD)

[The Cagliari (Italy) Court authorizes the preimplantation genetic diagnosis].

PubMed

Jorqui Azofra, María

2007-01-01

Today, preimplantation genetic diagnosis (PGD) has been greatly accepted within the framework of positive law of many European countries. Nevertheless, in other countries, such as Italy, it is forbidden by law. The ruling of the Civil Court of Cagliari which has authorized its use to a Sardinian couple, has opened, in this way, a small crack to be able to asses possible modifications to the Italian regulation on this matter. This article analyses the ruling of the Civil Court of Cagliari (Italy) from an ethical and legal perspective. The criteria which is used to analyse the legitimacy or illegitimacy of the practice of PGD is analysed. That is, on reasons which could justify or not the transfer of embryos in vitro to the woman. With this objective in mind, the Italian and Spanish normative models which regulates this controversial subject are looked at. As a conclusion, a critical evaluation of the arguments presented is made.

Inhibition effects of some metal ions on the rat liver 6-phosphogluconate dehydrogenase

NASA Astrophysics Data System (ADS)

Adem, Şevki; Kayhan, Naciye

2016-04-01

6-phosphogluconate dehydrogenase is an enzyme in the pentose phosphate path. The main functions of the pathway are the manufacture of the reduced coenzyme NADPH and the formation of ribose 5-phosphate for nucleic acid synthesis and nucleotide. Both NADPH and ribose 5-phosphate involve a critical biochemical process. Metals have been recognized as important toxic agents for living for a long time. It has been considered that they lead to in the emergence of many diseases. To evaluate whether metals is effect towards rat liver 6PGD, we apply various concentrations of metals and enzyme inhibition was analyzed using enzyme activity assays. The IC50 values of Pb+2, Cr+3, Co+2, Ni+2, Cd+2, and Va+2, metals on rat liver 6PGD were calculated as 138,138, 169, 214, 280, and 350 µM, respectively.

Preimplantation genetic diagnosis (PGD) according to medical ethics and medical law

PubMed Central

Lutz, Emine Elif Vatanoğlu

2012-01-01

Assisted reproductive techniques not only nourish great and sometimes illusive hopes of couples who yearn for babies, but also spark new debates by reversing opinions, beliefs and values. Applications made to infertility clinics are increasing due to the influences such as broadcasts made by the media concerning assisted reproductive techniques and other infertility treatments, increase in the knowledge that people have about these problems, late marriages and postponement of childbearing age owing to sociological changes. Pre-implantation genetic diagnosis (PGD) is a technique applied to couples who are known to carry genetic diseases or who have children with genetic diseases. This technique is conducted by doctors in Turkey for its important contribution to decreasing the risk of genetic diseases and in order to raise healthy generations. In this paper, the general ethical debates and the legal situation in Turkey will be discussed. PMID:24627675

Prediction value of anti-Mullerian hormone (AMH) serum levels and antral follicle count (AFC) in hormonal contraceptive (HC) users and non-HC users undergoing IVF-PGD treatment.

PubMed

Bas-Lando, Maayan; Rabinowitz, Ron; Farkash, Rivka; Algur, Nurit; Rubinstein, Esther; Schonberger, Oshrat; Eldar-Geva, Talia

2017-10-01

Use of hormone contraceptives (HC) is very popular in the reproductive age and, therefore, evaluation of ovarian reserve would be a useful tool to accurately evaluate the reproductive potential in HC users. We conducted a retrospective cohort study of 41 HC users compared to 57 non-HC users undergoing IVF-preimplantation genetic diagnosis (PGD) aiming to evaluate the effect of HC on the levels of anti-Mullerian hormone (AMH), small (2-5 mm), large (6-10 mm) and total antral follicle count (AFC) and the ability of these markers to predict IVF outcome. Significant differences in large AFC (p = 0.04) and ovarian volume (p < 0.0001) were seen, however, there were no significant differences in small and total AFC or in serum AMH and FSH levels. Oocyte number significantly correlated with AMH and total AFC in HC users (p < 0.001) while in non-HC users these correlations were weaker. In HC users, the significant predictors of achieving <6 and >18 oocytes were AFC (ROC-AUC; 0.958, p = 0.001 and 0.883, p = 0.001) and AMH (ROC-AUC-0.858, p = 0.01 and 0.878, p = 0.001), respectively. The predictive values were less significant in non-HC users. These findings are important in women treated for PGD, in ovum donors and for assessing the fertility prognosis in women using HC and wishing to postpone pregnancy.

Results of clinical lung transplant from uncontrolled non-heart-beating donors.

PubMed

de Antonio, David Gómez; Marcos, Roberto; Laporta, Rosalía; Mora, Gema; García-Gallo, Cristina; Gámez, Pablo; Córdoba, Mar; Moradiellos, Javier; Ussetti, Piedad; Carreño, María C; Núñez, José R; Calatayud, Joaquín; Del Río, Francisco; Varela, Andrés

2007-05-01

The scarcity of grafts for lung transplant and the growing number of candidates expecting an organ has led to an increase of deaths in patients waiting for lung transplantation. Non-heart-beating donors (NHBD) represent a promising source of grafts for those who are involved in clinical lung transplantation. We present the results of our series of 17 out-of-hospital NHBD lung transplantations performed since 2002. We have collected data from 17 donors and recipients involved in NHBD lung transplants since 2002, as well as data referring to the type of procedure and peri-operative events. We describe the incidence of post-operative complications with special attention to primary graft disfunction (PGD), bronchial healing, bronchiolitis obliterans syndrome (BOS), and survival. We used Kaplan-Meier method to obtain the survival curve. G2-G3 PGD was reported in 9 patients (53%), with a complete restoration of the partial pressure of arterial oxygen/fraction of inspired oxygen ratio in 170 hours for G2 and 168 hours for G3. There were no deaths directly related to PGD. Acute rejection was detected in 7 patients (41%), 4 of which exceeded grade 1. The incidence of BOS after transplantation was 1 (7%) of 14 patients during the first year, 2 (11%) of 9 in the second year, and 2 (50%) of 4 in the third year. Hospital mortality rate was 17%. The survival rates were 82% at 3 months, 69%, at 1 year, and 58% at 3 years. Mid-term results confirm the adequacy of uncontrolled NHBD as a promising complementary source of lung donors for clinical transplant.

Efficacy of an outpatient treatment for prolonged grief disorder: a randomized controlled clinical trial.

PubMed

Rosner, Rita; Pfoh, Gabriele; Kotoučová, Michaela; Hagl, Maria

2014-01-01

Abnormal forms of grief, currently referred to as complicated grief or prolonged grief disorder, have been discussed extensively in recent years. While the diagnostic criteria are still debated, there is no doubt that prolonged grief is disabling and may require treatment. To date, few interventions have demonstrated efficacy. We investigated whether outpatients suffering from prolonged grief disorder (PGD) benefit from a newly developed integrative cognitive behavioural therapy for prolonged grief (PG-CBT). A total of 51 patients were randomized into two groups, stratified by the type of death and their relationship to the deceased; 24 patients composed the treatment group and 27 patients composed the wait list control group (WG). Treatment consisted of 20-25 sessions. Main outcome was change in grief severity; secondary outcomes were reductions in general psychological distress and in comorbidity. Patients on average had 2.5 comorbid diagnoses in addition to PGD. Between group effect sizes were large for the improvement of grief symptoms in treatment completers (Cohen׳s d=1.61) and in the intent-to-treat analysis (d=1.32). Comorbid depressive symptoms also improved in PG-CBT compared to WG. The completion rate was 79% in PG-CBT and 89% in WG. The major limitations of this study were a small sample size and that PG-CBT took longer than the waiting time. PG-CBT was found to be effective with an acceptable dropout rate. Given the number of bereaved people who suffer from PGD, the results are of high clinical relevance. Copyright © 2014 Elsevier B.V. All rights reserved.

Establishing the role of pre-implantation genetic diagnosis with human leucocyte antigen typing: what place do "saviour siblings" have in paediatric transplantation?

PubMed

Samuel, G N; Strong, K A; Kerridge, I; Jordens, C F C; Ankeny, R A; Shaw, P J

2009-04-01

Not all children in need of a haematopoietic stem cell transplant have a suitable relative or unrelated donor available. Recently, in vitro fertilisation (IVF) with pre-implantation genetic diagnosis (PGD) for human leucocyte antigen (HLA) tissue typing has been used to selectively transfer an IVF embryo in order to produce a child who may provide umbilical cord blood for transplantation to an ill sibling. Such children are sometimes called "saviour siblings". To examine the published clinical and epidemiological evidence relevant to the use of this technology, with the aim of clarifying those situations where IVF and PGD for HLA typing should be discussed with parents of an ill child. A critical analysis of published literature on comparative studies of umbilical cord blood versus other sources of stem cells for transplantation; comparative studies of matched unrelated donor versus matched related donor transplantation; and the likelihood of finding an unrelated stem cell donor. IVF and PGD for HLA typing is only applicable when transplantation is non-urgent and parents are of reproductive age. Discussions regarding this technology may be appropriate where no suitable related or unrelated donor is available for a child requiring a transplant, or where no suitable related donor is available and transplantation is only likely to be entertained with a matched sibling donor. Discussion may also be considered in the management of any child lacking a matched related donor who requires a non-urgent transplant or may require a transplant in the future.

School Plays: Raising the Curtain Again.

ERIC Educational Resources Information Center

Zirkel, Perry A.; Gluckman, Ivan B.

1986-01-01

Federal courts upheld the rights of two school boards to cancel planned student plays. One play was intended as part of a secondary school's curriculum and the other was an extracurricular activity for third graders. Both plays contained controversial material. (PGD)

On Ethnographic Intent.

ERIC Educational Resources Information Center

Wolcott, Harry F.

1985-01-01

Defines the essence of ethnographic research as describing and interpreting cultural behavior. Clarifies why some characteristics of ethnography are not defining characteristics, considers what is meant by "culture," examines the ethnographic process, and discusses the application of ethnographic methods in the educational setting. (PGD)

A Vote for 'Messiness'.

ERIC Educational Resources Information Center

Sizer, Theodore R.

1985-01-01

A fictional letter "written" in 2005 laments the success of educational movements that, in the name of productivity, have placed increasing authority over curriculum in the hands of central government, leading to a homogenization of thinking and a dulling of creativity. (PGD)

Early Risers Benefit from Scholars Program.

ERIC Educational Resources Information Center

Jackson, Maria L.; Russell, Ernest L.

1987-01-01

The 7 O'Clock Scholars Program for gifted and talented students at Pontiac (Michigan) Central Senior High School brings speakers from a nearby university to speak to interested high school students during 50-minute sessions before regular classes begin. (PGD)

Quantifying the timescales of Archean UHT metamorphism through U-Pb monazite and zircon petrochronology

NASA Astrophysics Data System (ADS)

Guevara, V.; MacLennan, S. A.; Schoene, B.; Dragovic, B.; Caddick, M. J.; Kylander-Clark, A. R.; Couëslan, C. G.

2016-12-01

Unraveling the timescales of metamorphism is crucial to understanding the mechanisms behind mass/heat transfer through Earth's crust. Though such mechanisms and their durations are becoming well constrained in modern (Phanerozoic) settings, the drivers of metamorphism in the ancient geologic record remain more enigmatic. The development of accessory phase petrochronology has allowed metamorphic evolution to be closely linked to isotopic dates, ultimately improving quantification of metamorphic durations. While in-situ petrochronological methods preserve textural and spatial context, they often lack the temporal resolution required to accurately quantify metamorphic duration in Archean terranes. Here we combine in-situ U-Pb monazite (mnz) and zircon (zrn) laser ablation split-stream (LASS) and high-precision ID-TIMS-TEA petrochronology of distinct grain domains to resolve the timescales of ultrahigh temperature (UHT) metamorphism in the Archean Pikwitonei granulite domain (PGD). The PGD encompasses >1.5x105 km2 of granulite-facies rocks on the NW edge of the Superior Province. Themodynamic modelling of a pelite from the western part of the PGD suggests peak P-T conditions of >8 kbar, 900-940 °C and UHT decompression to 8 kbar followed by cooling. LASS analysis of zrn inclusions in garnet (grt) yields a date of 2701 Ma, with Ti in zrn thermometry yielding T of 800-900 °C. LASS analysis of mnz yields dates of 2720-2680 Ma for low HREE domains with no to shallow negative Eu anomalies, suggestive of growth during plagioclase (plg) breakdown and grt stability. ID-TIMS analysis of a mnz fragment with a strong negative Eu anomaly, suggestive of growth during plg stability, gives a concordant 207Pb/206Pb date of 2666 Ma, consistent with LASS results of 2660-2640 Ma for chemically similar domains. ID-TIMS analyses of zrn rims yield a range of 207Pb/206Pb dates from 2671 to 2656 Ma (±<1 Ma). Ti in zrn yields 800 °C for these rims, indicating they grew at similar T. Together, these data indicate a metamorphic cycle in the PGD to/from UHT over a minimum of 35 Ma, with at least 12 Ma of slow cooling near 800 °C in the lower crust following UHT decompression. This evolution is inconsistent with punctuated thermal pulses due to focused fluid flow or magmatism, instead requiring a long-lived source of crustal heating.

[The gene pool of Belgorod oblast population: study of biochemical gene markers in populations of Ukraine and Belarus and the position of the Belgorod population in the Eastern Slavic gene pool system].

PubMed

Lependina, I N; Churnosov, M I; Artamentova, L A; Ishchuk, M A; Tegako, O V; Balanovskaia, E V

2008-04-01

The characteristics of the gene pools of indigenous populations of Ukraine and Belarus have been studied using 28 alleles of 10 loci of biochemical gene markers (HP, GC, TF, PI, C'3, ACP1, GLO1, PGM1, ESD, and 6-PGD). The gene pools of the Russian and Ukrainian indigenous populations of Belgorod oblast (Russia) and the indigenous populations of Ukraine and Belarus have been compared. Cluster analysis, multidimensional scaling, and factor analysis of the obtained data have been used to determine the position of the Belgorod population gene pool in the Eastern Slavic gene pool system.

Let Children Start School When They're Ready!

ERIC Educational Resources Information Center

Parsons, Cynthia

1985-01-01

Any given child should attend school full time when three parties agree that the time is right: the child, his or her parents, and the school officials. Arbitrary starting dates based on calendar age are outmoded and educationally unsound. (PGD)

Has Your School Had a "Fire Sale" Lately?

ERIC Educational Resources Information Center

Woodward, Dave

1987-01-01

Videotapes can provide useful records for insurance purposes when schools suffer fire or other calamitous damage. This article describes the production, editing, and storage of videotaped records of the contents of school rooms that contain specialized equipment or materials. (PGD)

Under Constant Attack: Personal Reflections of a Teacher Educator.

ERIC Educational Resources Information Center

Hunter, Elizabeth

1985-01-01

The personal reminiscences of a teacher educator ready to retire touch on changing attitudes toward education and the consequences of those attitudes: the shifting character of the bitter criticism teacher educators must endure whatever the current educational fashion. (PGD)

The Entrepreneurial Approach to Participation in Community Redevelopment Activities.

ERIC Educational Resources Information Center

Wickert, Donald M.

1985-01-01

Discusses the use of tax increment financing to fund public redevelopment or urban rehabilitation projects and the opportunity for school districts to take advantage of such projects to supplement reduced property tax revenues in areas of declining valuation. (PGD)

Activation of rat intestinal mucosal mast cells by fat absorption.

PubMed

Ji, Yong; Sakata, Yasuhisa; Yang, Qing; Li, Xiaoming; Xu, Min; Yoder, Stephanie; Langhans, Wolfgang; Tso, Patrick

2012-06-01

Previous studies have linked certain types of gut mucosal immune cells with fat intake. We determined whether fat absorption activates intestinal mucosal mast cells (MMC), a key component of the gut mucosal immune system. Conscious intestinal lymph fistula rats were used. The mesenteric lymph ducts were cannulated, and the intraduodenal (i.d.) tubes were installed for the infusion of Liposyn II 20% (an intralipid emulsion). Lymphatic concentrations of histamine, rat MMC protease II (RMCPII), a specific marker of rat intestinal MMC degranulation, and prostaglandin D(2) (PGD(2)) were measured by ELISA. Intestinal MMC degranulation was visualized by immunofluorescent microscopy of jejunum sections taken at 1 h after Liposyn II gavage. Intraduodenal bolus infusion of Liposyn II 20% (4.4 kcal/3 ml) induced approximately a onefold increase in lymphatic histamine and PGD(2), ∼20-fold increase in lymphatic RMCPII, but only onefold increase in peripheral serum RMCPII concentrations. Release of RMCPII into lymph increased dose dependently with the amount of lipid fed. In addition, i.d. infusion of long-chain triacylglycerol trilinolein (C18:2 n-6, the major composite in Liposyn II) significantly increased the lymphatic RMCPII concentration, whereas medium-chain triacylglycerol tricaprylin (C8:0) did not alter lymph RMCPII secretion. Immunohistochemistry image revealed the degranulation of MMC into lamina propria after lipid feeding. These novel findings indicate that intestinal MMC are activated and degranulate to release MMC mediators to the circulation during fat absorption. This action of fatty acid is dose and chain length dependent.

Activation of rat intestinal mucosal mast cells by fat absorption

PubMed Central

Sakata, Yasuhisa; Yang, Qing; Li, Xiaoming; Xu, Min; Yoder, Stephanie; Langhans, Wolfgang; Tso, Patrick

2012-01-01

Previous studies have linked certain types of gut mucosal immune cells with fat intake. We determined whether fat absorption activates intestinal mucosal mast cells (MMC), a key component of the gut mucosal immune system. Conscious intestinal lymph fistula rats were used. The mesenteric lymph ducts were cannulated, and the intraduodenal (i.d.) tubes were installed for the infusion of Liposyn II 20% (an intralipid emulsion). Lymphatic concentrations of histamine, rat MMC protease II (RMCPII), a specific marker of rat intestinal MMC degranulation, and prostaglandin D2 (PGD2) were measured by ELISA. Intestinal MMC degranulation was visualized by immunofluorescent microscopy of jejunum sections taken at 1 h after Liposyn II gavage. Intraduodenal bolus infusion of Liposyn II 20% (4.4 kcal/3 ml) induced approximately a onefold increase in lymphatic histamine and PGD2, ∼20-fold increase in lymphatic RMCPII, but only onefold increase in peripheral serum RMCPII concentrations. Release of RMCPII into lymph increased dose dependently with the amount of lipid fed. In addition, i.d. infusion of long-chain triacylglycerol trilinolein (C18:2 n-6, the major composite in Liposyn II) significantly increased the lymphatic RMCPII concentration, whereas medium-chain triacylglycerol tricaprylin (C8:0) did not alter lymph RMCPII secretion. Immunohistochemistry image revealed the degranulation of MMC into lamina propria after lipid feeding. These novel findings indicate that intestinal MMC are activated and degranulate to release MMC mediators to the circulation during fat absorption. This action of fatty acid is dose and chain length dependent. PMID:22461027

Why English Teachers Are Responsible for the X-Cars.

ERIC Educational Resources Information Center

Smith, Beverly J.

1985-01-01

The problems plaguing a frequently-recalled car provide satirical evidence that permitting students to get by with bad habits in school may enable them to continue their bad habits at work, forcing a wider public to suffer from the results. (PGD)

Amniotic Fluid Eicosanoids in Preterm and Term Births: Effects of Risk Factors for Spontaneous Preterm Labor

PubMed Central

Menon, Ramkumar; Fortunato, Stephen J.; Milne, Ginger L.; Brou, Lina; Carnevale, Claudine; Sanchez, Stephanie C.; Hubbard, Leah; Lappas, Martha; Drobek, Cayce Owens; Taylor, Robert N.

2012-01-01

OBJECTIVE To evaluate amniotic fluid (AF) arachidonic acid metabolites using enzymatic and nonenzymatic (lipid peroxidation) pathways in spontaneous preterm birth and term births, and to estimate whether prostanoid concentrations correlate with risk factors (race, cigarette smoking, and microbial invasion of amniotic cavity) associated with preterm birth. METHODS In a case-control study, AF was collected at the time of labor or during cesarean delivery. AF samples were subjected to gas chromatography, negative ion chemical ionization, and mass spectrometry for prostaglandin (PG)E2, PGF2α, and PGD2, 6-keto-PGF1α (6-KPGF1α, thromboxane (TXB2), and F2-isoprostane (F2-IsoP). Primary analysis examined differences between prostanoid concentrations in preterm birth (n=133) compared with term births (n=189). Secondary stratified analyses (by race, cigarette smoking and microbial invasion of amniotic cavity) compared eicosanoid concentrations in three epidemiological risk factors. RESULTS AF F2-IsoP, PGE2, and PGD2 were significantly higher at term than in PTB, whereas PGF2 α was higher in PTB 6-KPGF1α and TXB2 concentrations were not different. Data stratified by race (African American or Caucasian) showed no significant disparity among prostanoid concentrations. Regardless of gestational age status, F2-IsoP was threefold higher in smokers, and other eicosanoids were also higher in smokers compared to non-smokers. Preterm birth with microbial invasion of amniotic cavity had significantly higher F2-IsoP compared to preterm birth without microbial invasion of amniotic cavity. CONCLUSIONS Most AF eicosanoid concentrations (F2-isoP PGE2 and PGD2), are higher at term than in preterm birth. The only AF eicosanoid that is not higher at term is PGF2α. PMID:21691170

Improving the quality of reconstructed X-ray CT images of polymer gel dosimeters: zero-scan coupled with adaptive mean filtering.

PubMed

Kakakhel, M B; Jirasek, A; Johnston, H; Kairn, T; Trapp, J V

2017-03-01

This study evaluated the feasibility of combining the 'zero-scan' (ZS) X-ray computed tomography (CT) based polymer gel dosimeter (PGD) readout with adaptive mean (AM) filtering for improving the signal to noise ratio (SNR), and to compare these results with available average scan (AS) X-ray CT readout techniques. NIPAM PGD were manufactured, irradiated with 6 MV photons, CT imaged and processed in Matlab. AM filter for two iterations, with 3 × 3 and 5 × 5 pixels (kernel size), was used in two scenarios (a) the CT images were subjected to AM filtering (pre-processing) and these were further employed to generate AS and ZS gel images, and (b) the AS and ZS images were first reconstructed from the CT images and then AM filtering was carried out (post-processing). SNR was computed in an ROI of 30 × 30 for different pre and post processing cases. Results showed that the ZS technique combined with AM filtering resulted in improved SNR. Using the previously-recommended 25 images for reconstruction the ZS pre-processed protocol can give an increase of 44% and 80% in SNR for 3 × 3 and 5 × 5 kernel sizes respectively. However, post processing using both techniques and filter sizes introduced blur and a reduction in the spatial resolution. Based on this work, it is possible to recommend that the ZS method may be combined with pre-processed AM filtering using appropriate kernel size, to produce a large increase in the SNR of the reconstructed PGD images.

Inhibition by prostaglandin E(2) of anaphylatoxin C5a- but not zymosan-induced prostanoid release from rat Kupffer cells.

PubMed

Pestel, Sabine; Jungermann, Kurt; Götze, Otto; Schieferdecker, Henrike L

2002-04-01

The proinflammatory anaphylatoxin C5a induces the release of prostanoids, ie, prostaglandins (PG) and thromboxane (TX), from the resident liver macrophages (Kupffer cells [KC]). Because KC themselves express prostanoid receptors, prostanoids--besides having paracrine functions--might regulate their own release in an autocrine loop. So far, such a possible feedback regulation has not been investigated systematically, probably because of methodological difficulties to measure newly synthesized prostanoids in the presence of added prostanoids. Here, after prelabeling of phospholipids with [(14)C]arachidonate, cellularly formed [(14)C]prostanoids were determined in the presence of added unlabelled prostanoids by thin layer chromatography. In cultured KC, recombinant rat C5a (rrC5a) rapidly increased PGD(2), PGE(2), and TXA(2) release, which was strongly reduced by PGE(2), but neither by PGD(2) nor by the TXA(2) analog U46619. The inhibitory effect of PGE(2) was mimicked by cAMP, indicating that the G(s)-coupled PGE(2) receptors type 2 or 4 were involved. Zymosan also enhanced prostanoid release from KC, but with slightly slower kinetics; this action was neither inhibited by PGE(2) nor by cAMP. Also in perfused rat livers, rrC5a enhanced prostanoid release from KC as shown by prostanoid overflow and thereby indirectly increased glucose output from hepatocytes. Again, PGE(2), but not PGD(2), inhibited rrC5a-elicited prostanoid overflow. This resulted in a complete inhibition of rrC5a-induced, prostanoid-mediated glucose output. Thus, PGE(2) can inhibit specifically the C5a-induced prostanoid release from KC via a feedback mechanism and thereby limit prostanoid-mediated hepatocellular defense reactions, eg, glucose release.

Clinical lung transplantation from uncontrolled non-heart-beating donors revisited.

PubMed

Gomez-de-Antonio, David; Campo-Cañaveral, Jose Luis; Crowley, Silvana; Valdivia, Daniel; Cordoba, Mar; Moradiellos, Javier; Naranjo, Jose Manual; Ussetti, Piedad; Varela, Andrés

2012-04-01

The aim of our study is to review and update the long-term results from our previously published series of lung transplantation in uncontrolled non-heart-beating donors (NHBDs). A prospective collection of data was undertaken from all lung transplants performed among uncontrolled NHBDs between 2002 and December 2009. The statistical analysis was performed using SPSS software and survival was estimated using the Kaplan-Meier method. Twenty-nine lung transplants were performed. Mean total ischemic times for the first and second lung were 575 minutes (SD 115.6) and 701 minutes (SD 111.3), respectively. Primary graft dysfunction (PGD) G1, G2 and G3 occurred in 5 cases (17%), 5 cases (17%) and 11 cases (38%), respectively. Overall hospital mortality rate was 17% (5 patients). Statistical analysis revealed a statistically significant association of mortality with ischemic times and with PGD. In terms of overall survival, 3-month, 1-year, 2-year and 5-year survival rates were 78%, 68%, 57% and 51%, respectively, and the conditional survival rates in those who survived the first 3 months were 86%, 72% and 65%, respectively. The cumulative incidence of bronchiolitis obliterans syndrome (BOS) was 11%, 35% and 45% at 1, 3 and 5 years, respectively. Lung transplantation from uncontrolled non-heart-beating donors shows acceptable results for both mid- and long-term survival and BOS; however, the higher rates of PGD and its impact on early mortality must make us more demanding with respect to the acceptance criteria and methods of evaluation used with these donors. Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Application of portable gas detector in point and scanning method to estimate spatial distribution of methane emission in landfill.

PubMed

Lando, Asiyanthi Tabran; Nakayama, Hirofumi; Shimaoka, Takayuki

2017-01-01

Methane from landfills contributes to global warming and can pose an explosion hazard. To minimize these effects emissions must be monitored. This study proposed application of portable gas detector (PGD) in point and scanning measurements to estimate spatial distribution of methane emissions in landfills. The aims of this study were to discover the advantages and disadvantages of point and scanning methods in measuring methane concentrations, discover spatial distribution of methane emissions, cognize the correlation between ambient methane concentration and methane flux, and estimate methane flux and emissions in landfills. This study was carried out in Tamangapa landfill, Makassar city-Indonesia. Measurement areas were divided into basic and expanded area. In the point method, PGD was held one meter above the landfill surface, whereas scanning method used a PGD with a data logger mounted on a wire drawn between two poles. Point method was efficient in time, only needed one person and eight minutes in measuring 400m 2 areas, whereas scanning method could capture a lot of hot spots location and needed 20min. The results from basic area showed that ambient methane concentration and flux had a significant (p<0.01) positive correlation with R 2 =0.7109 and y=0.1544 x. This correlation equation was used to describe spatial distribution of methane emissions in the expanded area by using Kriging method. The average of estimated flux from scanning method was 71.2gm -2 d -1 higher than 38.3gm -2 d -1 from point method. Further, scanning method could capture the lower and higher value, which could be useful to evaluate and estimate the possible effects of the uncontrolled emissions in landfill. Copyright © 2016 Elsevier Ltd. All rights reserved.

Leukotriene E4 activates peroxisome proliferator-activated receptor gamma and induces prostaglandin D2 generation by human mast cells.

PubMed

Paruchuri, Sailaja; Jiang, Yongfeng; Feng, Chunli; Francis, Sanjeev A; Plutzky, Jorge; Boyce, Joshua A

2008-06-13

Cysteinyl leukotrienes (cys-LTs) are potent inflammatory lipid mediators, of which leukotriene (LT) E(4) is the most stable and abundant in vivo. Although only a weak agonist of established G protein-coupled receptors (GPCRs) for cys-LTs, LTE(4) potentiates airway hyper-responsiveness (AHR) by a cyclooxygenase (COX)-dependent mechanism and induces bronchial eosinophilia. We now report that LTE(4) activates human mast cells (MCs) by a pathway involving cooperation between an MK571-sensitive GPCR and peroxisome proliferator-activated receptor (PPAR)gamma, a nuclear receptor for dietary lipids. Although LTD(4) is more potent than LTE(4) for inducing calcium flux by the human MC sarcoma line LAD2, LTE(4) is more potent for inducing proliferation and chemokine generation, and is at least as potent for upregulating COX-2 expression and causing prostaglandin D(2) (PGD(2)) generation. LTE(4) caused phosphorylation of extracellular signal-regulated kinase (ERK), p90RSK, and cyclic AMP-regulated-binding protein (CREB). ERK activation in response to LTE(4), but not to LTD(4), was resistant to inhibitors of phosphoinositol 3-kinase. LTE(4)-mediated COX-2 induction, PGD(2) generation, and ERK phosphorylation were all sensitive to interference by the PPARgamma antagonist GW9662 and to targeted knockdown of PPARgamma. Although LTE(4)-mediated PGD(2) production was also sensitive to MK571, an antagonist for the type 1 receptor for cys-LTs (CysLT(1)R), it was resistant to knockdown of this receptor. This LTE(4)-selective receptor-mediated pathway may explain the unique physiologic responses of human airways to LTE(4) in vivo.

Regulation and mechanism of leptin on lipid metabolism in ovarian follicle cells from yellow catfish Pelteobagrus fulvidraco.

PubMed

Zhang, Li-Han; Tan, Xiao-Ying; Wu, Kun; Zhuo, Mei-Qin; Song, Yu-Feng; Chen, Qing-Ling

2015-10-01

The present study was conducted to determine the effect of leptin on lipid metabolism in ovarian follicle cells of yellow catfish Pelteobagrus fulvidraco. For that purpose, primary ovarian follicle cells were isolated from yellow catfish, cultured and subjected to different treatments (control, 0.1% DMSO, 500ng/ml leptin, 500ng/ml leptin plus 100μM wortmannin, 500ng/ml leptin plus 50nM AG490, respectively) for 48h. Intracellular triglyceride (TG) content, the activities (CPT I, FAS, G6PD, and 6PGD) and/or expression level of several enzymes (CPT I, FAS, G6PD, 6PGD, ACCa and ACCb), as well as the mRNA expression of transcription factors (PPARα, PPARγ and SREBP-1) involved in lipid metabolism were determined. Recombinant human leptin (rt-hLEP) incubation significantly reduced intracellular TG content, activities and mRNA levels of FAS, G6PD and 6PGD, SREBP-1 and PPARγ, but enhanced activity and mRNA level of CPT I, PPARα and ACCa. Specific inhibitors AG490 and wortmannin of JAK-STAT and IRS-PI3K signaling pathways prevented leptin-induced changes, indicating that JAK-STAT and IRS-PI3K signaling pathways were involved in the process of leptin-induced changes of lipid metabolism. Based on these observations above, for the first time, our study indicated that leptin reduced lipid deposition by activating lipolysis and suppressing lipogenesis in ovarian follicles of yellow catfish, and both JAK-STAT and IRS-PI3K signaling pathways were involved in the changes of leptin-induced lipid metabolism. Copyright © 2015 Elsevier Inc. All rights reserved.

Characterization and modulation of canine mast cell derived eicosanoids

PubMed Central

Lin, Tzu-Yin; London, Cheryl A.

2013-01-01

Mast cells play an important role in both innate and acquired immunity as well as several pathological conditions including allergy, arthritis and neoplasia. They influence these processes by producing a variety of mediators including cytokines, chemokines and eicosanoids. Very little is currently known about the spectrum of inflammatory mediators, particularly eicosanoids (prostaglandins and leukotrienes), produced by canine mast cells. This is important since modulating mast cell derived eicosanoids may help in the treatment of autoimmune and inflammatory disorders. The purpose of this study was to investigate the spectrum of eicosanoids produced by normal canine mast cells and to evaluate the effects of cytokines and non-steroidal anti-inflammatory mediators (NSAIDS) on eicosanoid production and release. Canine bone marrow derived cultured mast cells (cBMCMCs) expressed COX-1, COX-2, and 5-LOX and synthesized and released PGD2, PGE2, LTB4, and LTC4 following activation by a variety of stimuli. The selective COX-2 NSAIDs carprofen (Rimadyl®) and deracoxib (Deramaxx®) inhibited PGD2 and PGE2 production but only slightly inhibited LTB4 and LTC4. The mixed COX-1/COX-2 inhibitor piroxicam blocked PGD2 and PGE2 production, but upregulated LTC4 following treatment while tepoxilan (Zubrin®), a pan COX/LOX inhibitor, markedly reduced the production of all eicosanoids. The LOX inhibitor nordihydroguaiaretic acid (NDGA) prevented LTB4/LTC4 release and BMBMC degranulation. Pre-incubation of cBMCMCs with IL-4 and SCF sensitized these cells to degranulation in response to substance P. In conclusion, canine BMCMCs produce an array of eicosanoids similar to those produced by mast cells from other species. Tepoxilan appeared to be the most effective NSAID for blocking eicosanoid production and thus may be useful for modulating mast cell mediated responses in dogs. PMID:20036014

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnston, H; UT Southwestern Medical Center, Dallas, TX; Hilts, M

Purpose: To commission a multislice computed tomography (CT) scanner for fast and reliable readout of radiation therapy (RT) dose distributions using CT polymer gel dosimetry (PGD). Methods: Commissioning was performed for a 16-slice CT scanner using images acquired through a 1L cylinder filled with water. Additional images were collected using a single slice machine for comparison purposes. The variability in CT number associated with the anode heel effect was evaluated and used to define a new slice-by-slice background image subtraction technique. Image quality was assessed for the multislice system by comparing image noise and uniformity to that of the singlemore » slice machine. The consistency in CT number across slices acquired simultaneously using the multislice detector array was also evaluated. Finally, the variability in CT number due to increasing x-ray tube load was measured for the multislice scanner and compared to the tube load effects observed on the single slice machine. Results: Slice-by-slice background subtraction effectively removes the variability in CT number across images acquired simultaneously using the multislice scanner and is the recommended background subtraction method when using a multislice CT system. Image quality for the multislice machine was found to be comparable to that of the single slice scanner. Further study showed CT number was consistent across image slices acquired simultaneously using the multislice detector array for each detector configuration of the slice thickness examined. In addition, the multislice system was found to eliminate variations in CT number due to increasing x-ray tube load and reduce scanning time by a factor of 4 when compared to imaging a large volume using a single slice scanner. Conclusion: A multislice CT scanner has been commissioning for CT PGD, allowing images of an entire dose distribution to be acquired in a matter of minutes. Funding support provided by the Natural Sciences and Engineering Research Council of Canada (NSERC)« less

Marketing Policy and Its Cost in a College of Higher Education.

ERIC Educational Resources Information Center

Riley, Eric

1984-01-01

Discusses the development of advertising and publicity strategies and policy for student recruitment purposes at a college of education in the United Kingdom between 1972 and 1982. Covers changes in staff attitudes, selection of media, organization of administration, and cost factors. (PGD)

New Technology and the Curriculum.

ERIC Educational Resources Information Center

Conklin, Joyce

1987-01-01

Hillsdale High School, in San Mateo, California, installed the nation's first 15-computer Macintosh laboratory donated by Apple Computer, Inc. This article describes the lab and the uses to which it has been put, including computer education, word processing, preparation of student publications, and creative writing instruction. (PGD)

Constitutional Due Process and Educational Administration.

ERIC Educational Resources Information Center

Uerling, Donald F.

1985-01-01

Discusses substantive and procedural due process as required by the United States Constitution and interpreted by the Supreme Court, with particular reference to situations arising in educational environments. Covers interests protected by due process requirements, the procedures required, and some special considerations that may apply. (PGD)

A Program Based on Maslow's Hierarchy Helps Students in Trouble.

ERIC Educational Resources Information Center

Yates, Mary Ruth; And Others

1980-01-01

Describes the program at Alabama's Huntsville Alternative School, where severe behavioral problems are dealt with by promoting positive self-concepts in students through acceptance, trust, warmth, concern, firmness, consistency, humor, and the meeting of human needs as identified by Abraham Maslow. (Author/PGD)

Regional assignment of seven genes on chromosome 1 of man by use of man-Chinese hamster somatic cell hybrids. I. Results obtained after hybridization of human cells carrying reciprocal translocations involving chromosome 1.

PubMed

Jongsma, A P; Burgerhout, W G

1977-01-01

Regional localization studies of genes coding for human PGD, PPH1, PGM1, UGPP, GuK1, Pep-C, and FH, which have been assigned to chromosome 1, were performed with man-Chinese hamster somatic cell hybrids, Informative hybrids that retained fragments of the human chromosome 1 were produced by fusion of hamster cells with human cells carrying reciprocal translocations involving chromosome 1. Analysis of the hybrids that retained one of the translocation chromosomes or de novo rearrangements involving the human 1 revealed the following gene positions: PGD and PPH1 in 1pter leads to 1p32, PGM1 in 1p32 leads to 1p22, UGPP and GuK1 in 1q21 leads to 1q42, FH in 1qter leads to 1q42, and Pep-C probably in 1q42.

Selecting for Disabilities: Selection Versus Modification.

PubMed

Shaw, Joshua

2018-04-01

This essay considers one argument used to defend parents who use preimplantation genetic diagnosis (PGD) to select for deafness and other disabilities. Some bioethicists have argued that a distinction should be drawn between genetically modifying embryos to possess disabilities and using PGD to select embryos that already present markers of them, and that the former is unethical because it inflicts avoidable harms onto the resulting children, whereas the latter is permissible because it allows children with potentially impaired abilities to exist. This essay raises doubts about whether a meaningful moral distinction can be drawn between modification and selection. Arguments which distinguish modification from selection can be understood in two ways. One is to read them as presenting a No Harm, No Foul argument. Another is to read them as presenting a Harming Versus Letting Be argument. Neither succeeds, however, either in establishing a meaningful moral distinction between modification and selection, or in showing that the second is morally permissible in contradistinction to the first.

Intense Non-Linear Soft X-Ray Emission from a Hydride Target during Pulsed D Bombardment

NASA Astrophysics Data System (ADS)

Miley, George H.; Yang, Yang; Lipson, Andrei; Haque, Munima; Percel, Ian; Romer, Michael

Radiation emission from low-energy nuclear radiation (LENR) electrodes (both charged-particle and X-rays) represents an important feature of LENR in general. Here, calibration, measurement techniques, and soft X-ray emission results from deuterium bombardment of a Pd target (cathode) placed in a pulsed deuterium glow discharge (PGD) are described. An X-ray intensity of 13.4 mW/cm2 and a dose of 3.3 μJ/cm2 were calculated over a 0.5 ms pulse time from AXUV photodiode radiation detector measurements. A most striking feature is that X-ray energies >600 V are observed with a discharge voltage only about half of that value. To further investigate this phenomenon, emission during room temperature D-desorption from electrolytically loaded Pd:Dx cathodes was also studied. The X-ray emission energy observed was quite similar to the PGD case. However, the intensity in this case was almost 13 orders of magnitude lower due to the much lower deuterium fluxes involved.

Preimplantation genetic haplotyping a new application for diagnosis of translocation carrier's embryos- preliminary observations of two robertsonian translocation carrier families.

PubMed

Shamash, Jana; Rienstein, Shlomit; Wolf-Reznik, Haike; Pras, Elon; Dekel, Michal; Litmanovitch, Talia; Brengauz, Masha; Goldman, Boleslav; Yonath, Hagith; Dor, Jehoshua; Levron, Jacob; Aviram-Goldring, Ayala

2011-01-01

Preimplantation genetic diagnosis using fluorescence in-situ hybridization (PGD-FISH) is currently the most common reproductive solution for translocation carriers. However, this technique usually does not differentiate between embryos carrying the balanced form of the translocation and those carrying the homologous normal chromosomes. We developed a new application of preimplantation genetic haplotyping (PGH) that can identify and distinguish between all forms of the translocation status in cleavage stage embryos prior to implantation. Polymorphic markers were used to identify and differentiate between the alleles that carry the translocation and those that are the normal homologous chromosomes. Embryos from two families of robertsonian translocation carriers were successfully analyzed using polymorphic markers haplotyping. Our preliminary results indicate that the PGH is capable of distinguishing between normal, balanced and unbalanced translocation carrier embryos. This method will improve PGD and will enable translocation carriers to avoid transmission of the translocation and the associated medical complications to offspring.

Preimplantation genetic diagnosis, reproductive freedom, and deliberative democracy.

PubMed

Farrelly, Colin

2009-04-01

In this paper I argue that the account of deliberative democracy advanced by Amy Gutmann and Dennis Thompson (1996, 2004) is a useful normative theory that can help enhance our deliberations about public policy in morally pluralistic societies. More specifically, I illustrate how the prescriptions of deliberative democracy can be applied to the issue of regulating non-medical uses of pre-implantation genetic diagnosis (PGD), such as gender selection. Deliberative democracy does not aim to win a philosophical debate among rival first-order theories, such as libertarianism, egalitarianism or feminism. Rather, it advances a second-order analysis that strives to help us determine what would constitute a reasonable balance between the conflicting fundamental values that arise in the context of regulating PGD. I outline a theoretical model (called the Reasonable Genetic Intervention Model) that brings these issues to the fore. Such a model incorporates the concern for both procedural and substantive principles; and it does so in way that takes provisionality seriously.

Leishmania in the Old World: 1. The geographical and hostal distribution of L. major zymodemes.

PubMed

Le Blancq, S M; Schnur, L F; Peters, W

1986-01-01

135 stocks of Leishmania major from man, reservoir hosts and sandflies were characterized using thin-layer starch-gel electrophoresis of 13 enzymes: MDH, 6PGD, GD, SOD, ASAT, ALAT, PK, PGM, ES, NH, PEPD, MPI, GPI. Homogeneity in this species was demonstrated by identical electrophoretic mobilities in nine enzymes. Polymorphism in four enzymes: 6PGD, GPI, PEPD, ES, gave six zymodemes among the collection. Stocks from sandflies and several species of burrowing rodents were indistinguishable from those from man in the same areas. Stocks of Leishmania from North-West India were identified as L. major. In some foci the distribution of zymodemes has some correlation with the presence of particular rodent reservoir hosts. The enzymic homogeneity of L. major throughout its geographical and host range appears to be correlated with the close association between L. major and sandflies of the subgenus Phlebotomus. The status of L. major as a distinct species is supported.

Ibuprofen results in alterations of human fetal testis development

PubMed Central

Ben Maamar, Millissia; Lesné, Laurianne; Hennig, Kristin; Desdoits-Lethimonier, Christèle; Kilcoyne, Karen R.; Coiffec, Isabelle; Rolland, Antoine D.; Chevrier, Cécile; Kristensen, David M.; Lavoué, Vincent; Antignac, Jean-Philippe; Le Bizec, Bruno; Dejucq-Rainsford, Nathalie; Mitchell, Rod T.; Mazaud-Guittot, Séverine; Jégou, Bernard

2017-01-01

Among pregnant women ibuprofen is one of the most frequently used pharmaceutical compounds with up to 28% reporting use. Regardless of this, it remains unknown whether ibuprofen could act as an endocrine disruptor as reported for fellow analgesics paracetamol and aspirin. To investigate this, we exposed human fetal testes (7–17 gestational weeks (GW)) to ibuprofen using ex vivo culture and xenograft systems. Ibuprofen suppressed testosterone and Leydig cell hormone INSL3 during culture of 8–9 GW fetal testes with concomitant reduction in expression of the steroidogenic enzymes CYP11A1, CYP17A1 and HSD17B3, and of INSL3. Testosterone was not suppressed in testes from fetuses younger than 8 GW, older than 10–12 GW, or in second trimester xenografted testes (14–17 GW). Ex vivo, ibuprofen also affected Sertoli cell by suppressing AMH production and mRNA expression of AMH, SOX9, DHH, and COL2A1. While PGE2 production was suppressed by ibuprofen, PGD2 production was not. Germ cell transcripts POU5F1, TFAP2C, LIN28A, ALPP and KIT were also reduced by ibuprofen. We conclude that, at concentrations relevant to human exposure and within a particular narrow ‘early window’ of sensitivity within first trimester, ibuprofen causes direct endocrine disturbances in the human fetal testis and alteration of the germ cell biology. PMID:28281692

Biodegradation of propylene glycol and associated hydrodynamic effects in sand.

PubMed

Bielefeldt, Angela R; Illangasekare, Tissa; Uttecht, Megan; LaPlante, Rosanna

2002-04-01

At airports around the world, propylene glycol (PG) based fluids are used to de-ice aircraft for safe operation. PG removal was investigated in 15-cm deep saturated sand columns. Greater than 99% PG biodegradation was achieved for all flow rates and loading conditions tested, which decreased the hydraulic conductivity of the sand by 1-3 orders of magnitude until a steady-state minimum was reached. Under constant loading at 120 mg PG/d for 15-30 d, the hydraulic conductivity (K) decreased by 2-2.5 orders of magnitude when the average linear velocity of the water was 4.9-1.4 cm/h. Variable PG loading in recirculation tests resulted in slower conductivity declines and lower final steady-state conductivity than constant PG feeding. After significant sand plugging, endogenous periods of time without PG resulted in significant but partial recovery of the original conductivity. Biomass growth also increased the dispersivity of the sand.

United States Immigration Policy and Indirect Immigration of Professionals.

ERIC Educational Resources Information Center

Agarwal, Vinod B.; Winkler, Donald R.

1985-01-01

The number of foreign professionals (including college students) who have entered the United States with nonimmigrant status but who have their visas adjusted to immigrant status is steadily increasing. This study explores the relationship between the frequency of such adjustments and changes in immigration policy. (PGD)

Military and VA General Dentistry Training: A National Resource.

ERIC Educational Resources Information Center

Atchison, Kathryn A.; Bachand, William; Buchanan, C. Richard; Lefever, Karen H.; Lin, Sylvia; Engelhardt, Rita

2002-01-01

Compared the program characteristics of the postgraduate general dentistry (PGD) training programs sponsored by the military and the Veterans Health Administration (VA). Gathered information on program infrastructure and emphasis, resident preparation prior to entering the program, and patients served and types of services provided. Programs…

Organizational Health--How to Measure a School's Level of Health and Take Remedial Action.

ERIC Educational Resources Information Center

Childers, John H., Jr.

1985-01-01

Reviews interrelated factors affecting a school's organizational health and describes nine steps administrators can take to enhance the school's climate. Suggests using the Organizational Health Instrument or a similar diagnostic tool to collect data on the school's organizational health. (PGD)

Dealing with Academic, Social, and Emotional Problems.

ERIC Educational Resources Information Center

Mahan, Guy; Johnson, Charles

1983-01-01

A study of over 100 dropouts from schools in the western suburbs of Chicago (Illinois) permitted researchers to develop this descriptive overview of the school experiences and family situations typical among dropouts and to offer suggestions for helping potential dropouts stay in school and adjust successfully. (PGD)

The Four-Day Week--What Are the Advantages for Schools?

ERIC Educational Resources Information Center

Richburg, Robert W.; Sjogren, Douglas D.

1983-01-01

Experience in 12 Colorado school districts suggests that implementation of a four-day school week can offer several benefits, including savings in fuel costs, decreased absenteeism, improved efficiency in activity-oriented classes, increased staff development time, and a flexible "fifth day" for extracurricular activities. (PGD)

The Changing College Admissions Scene.

ERIC Educational Resources Information Center

Sjogren, Cliff

1983-01-01

Discusses the status of college admissions and some of the forces that influenced college admissions policies during each of four three-year periods: the Sputnik Era (1957-60), the Postwar Baby Boom Era (1964-67), the "New Groups" Era (1971-74), and the Stable Enrollment Era (1978-81). (PGD)

Potassium permanganate is not an effective pond disinfectant to control Dero digitata

USDA-ARS?s Scientific Manuscript database

Proliferative gill disease (PGD) is a major problem in cultured channel catfish, Ictalurus punctatus. This parasite requires Dero digitata to complete its life cycle. It is believed potassium permanganate disinfects ponds and reduces D. digitata populations, but this practice has not been verified...

School-Business Partnerships: Trojan Horse or Manna from Heaven?

ERIC Educational Resources Information Center

Burke, Michael A.

1986-01-01

Recent national initiatives have renewed interest in the development of cooperative programs involving participation by businesses in school activities. This article reviews potential problems and benefits in school-business partnerships and identifies six steps that must be followed if such partnerships are to be successful. (PGD)

Designing and Implementing Performance-Based Career Ladder Plans.

ERIC Educational Resources Information Center

Hawley, Willis D.

1985-01-01

Reviews the factors that any teacher motivation plan must incorporate to be effective and outlines 11 principles that should be followed in designing career ladder plans to meet teacher needs, increase teacher competence, and facilitate effective instruction. Warns against potential pitfalls in career ladder plans. (PGD)

Alternative Learning Centers: Another Option for Discipline Programs.

ERIC Educational Resources Information Center

Pare, John A.

1983-01-01

Describes the operation and effectiveness of the Alternative Learning Center program administered by James Madison Memorial High School in Madison (Wisconsin). The center permits the school to remove students committing breaches of school discipline from their classes without removing them from the educational environment altogether. (PGD)

Structure in the Classroom: How Much Should Be Provided?

ERIC Educational Resources Information Center

Diamond, Stanley C.

1987-01-01

Reviews the range of thought concerning the extent to which the student's educational experience should be formally structured and externally imposed or informal and structurally controlled by the student. Recommends allowing students to make choices to the extent that they are comfortable and learning remains functional and effective. (PGD)

False Premises, False Promises: The Mythical Character of Public Discourse about Education.

ERIC Educational Resources Information Center

Hawley, Willis D.

1985-01-01

Available research disproves a number of myths concerning educational quality, but the myths continue to influence educational reform efforts. The three categories of reform that could actually prove effective all affect teachers directly: salary raises, improved working conditions, and alterations in the professional structure of teaching. (PGD)

Reconceptualize Schools with a Micro-Society.

ERIC Educational Resources Information Center

Altman-Winfrey, Fran

1985-01-01

Describes the support given by a Miami (Florida) area chamber of commerce to a group of junior high school students starting a school-based junior chamber of commerce. Visits by chamber members to the school and by students to chamber meetings and local businesses were part of the program. (PGD)

Teacher-Controlled Evaluation in a Career Ladder Program.

ERIC Educational Resources Information Center

Peterson, Ken; Mitchell, Anthony

1985-01-01

Teachers in Utah's Park City School District select which of several types of information they wish to gather as evidence of their own teaching ability and effectiveness. The teachers are trained in information gathering methods, and the dossiers they develop serve as the basis for evaluations and promotions. (PGD)

Will Carl Perkins's Legacy Survive Ronald Reagan's Policies?

ERIC Educational Resources Information Center

Jennings, Jack

1985-01-01

Discusses the political battles over federal support of education in the Congress since Reagan's election to the Presidency, including the reaction to the impact of the report of the National Commission on Excellence in Education. Contrasts the activities and attitudes of Reagan and Kentucky's late Democratic Congressman Carl Perkins. (PGD)

Implementation of Chapter 2 of ECIA in Texas.

ERIC Educational Resources Information Center

Katzman, Martin T.

1985-01-01

Examines the impact during a period of extensive curricular and school finance reform in Texas of the implementation of the block grant provisions of Chapter 2 of the Education Consolidation and Improvement Act. Considers governmental response, effects on transaction costs and resource allocation, and the potential for further savings. (PGD)

Use of preimplantation genetic diagnosis and preimplantation genetic screening in the United States: a Society for Assisted Reproductive Technology Writing Group paper.

PubMed

Ginsburg, Elizabeth S; Baker, Valerie L; Racowsky, Catherine; Wantman, Ethan; Goldfarb, James; Stern, Judy E

2011-10-01

To comprehensively report Society for Assisted Reproductive Technology (SART) member program usage of preimplantation genetic testing (PGT), preimplantation genetic diagnosis (PGD) for diagnosis of specific conditions, and preimplantation genetic screening for aneuploidy (PGS). Retrospective study. United States SART cohort data. Women undergoing a PGT cycle in which at least one embryo underwent biopsy. PGT. PGT use, indications, and delivery rates. Of 190,260 fresh, nondonor assisted reproductive technology (ART) cycles reported to SART CORS in 2007-2008, 8,337 included PGT. Of 6,971 cycles with a defined indication, 1,382 cycles were for genetic diagnosis, 3,645 for aneuploidy screening (PGS), 527 for translocation, and 1,417 for elective sex election. Although the total number of fresh, autologous cycles increased by 3.6% from 2007 to 2008, the percentage of cycles with PGT decreased by 5.8% (4,293 in 2007 and 4,044 in 2008). As a percentage of fresh, nondonor ART cycles, use dropped from 4.6% (4,293/93,433) in 2007 to 4.2% (4,044/96,827) in 2008. The primary indication for PGT was PGS: cycles performed for this indication decreased (-8.0%). PGD use for single-gene defects (+3.2%), elective sex selection (+5.3%), and translocation analysis (+0.5%) increased. PGT usage varied significantly by geographical region. PGT usage in the United States decreased between 2007 and 2008 owing to a decrease in PGS. Use of elective sex selection increased. High transfer cancellation rates correlated with reduced live-birth rates for some PGT indications. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Polymer gel dosimetry for measuring the dose near thin high-Z materials irradiated with high energy photon beams.

PubMed

Warmington, Leighton L; Gopishankar, N; Broadhurst, John H; Watanabe, Yoichi

2016-12-01

To investigate the feasibility of three-dimensional (3D) dose measurements near thin high-Z materials placed in a water-like medium by using a polymer gel dosimeter (PGD) when the medium was irradiated with high energy photon beams. PGD is potentially a useful tool for this application because it can record the dose around a small object made of a high-Z material in a continuous 3D medium. In this study, the authors manufactured a methacrylic acid-based normoxic PGD, nMAG. Two 0.5 mm thick lead foils (1 × 1 cm) were placed in foil supports with 0.7 cm separation in a 1000 ml polystyrene container filled with nMAG. The authors used two foil configurations, i.e., orthogonal and parallel. In the orthogonal configuration, two foils were placed in the direction orthogonal to the beam axis. The parallel configuration had two foils arranged in parallel to the beam axis. The phantom was irradiated with an 18 MV photon beam of 5 × 5 cm field size. It was imaged with a three-Tesla (3 T) magnetic resonance imaging (MRI) scanned using the Car-Purcell-Meiboom-Gill pulse sequence. The spin-spin relaxation time (R2) to-dose calibration data were obtained by using small vials filled with nMAG and exposing to known doses. The DOSXYZnrc Monte Carlo (MC) code was used to get the expected dose distributions. More than 35 × 10 6 of histories were simulated so that the average error was less than 1%. An in-house matlab-based software was used to obtain the dose distributions from the measured R2 data as well as to compare the measurements and the MC predictions. The dose change due to the presence of the foils was studied by comparing the dose distributions with and without foils (or the reference). For the orthogonal configuration, the measured dose along the beam axis showed an increase in the upstream side of the first foil, between the foils, and on the downstream side of the second foil. The range of increased dose area was 1.1 cm in the upstream of the first foil. However, in the downstream of the second foil, it was 0.2 cm, beyond which the dose fell below the reference dose by 10%. The dose profile between the foils showed a well-like shape with the minimum dose still larger than the reference dose by 1.8%. The minimum dose point was closer to the first foil than to the second foil. For the parallel configuration, the dose between foils was the largest at the center. The increased dose area opposite to the gap between foils extended outward to 1 cm. The spatial dose distributions of PGD and MC showed the same geometrical patterns except for the points inside the foils for both orthogonal and parallel foil arrangements. The authors demonstrated that the nMAG PGD with MRI could be used to measure the 3D dosimetric structures at the mm-scale in the vicinity of the foil. The current study provided more accurate 3D spatial dose distribution than the previous studies. Furthermore, the measurements were validated by the MC simulation.

Local mediator release after antigen challenge of a bronchial segment in allergic dogs.

PubMed

Reiss, T F; Rubinstein, I; Emery, D L; Gold, W M; Boushey, H A

1989-12-01

To investigate the local intraluminal bronchial response to an antigenic stimulus, we developed a bronchoscopic double-balloon system to challenge and lavage a segment of the left main-stem bronchus. We studied whether fluid from above or below the occlusion balloons leaked into the bronchial segment. Lavage was performed before and after placement of red and blue pigments proximal and distal to the inflated balloons, respectively, and the recovered lavage fluid was analyzed visually and spectrophotometrically in three experiments. There was no evidence for pigment leakage into the segment. In six anesthetized ragweed-allergic dogs, local ragweed antigen challenges were performed. After balloon inflation in the left main-stem bronchus, we performed two baseline lavages of the interballoon segment, introduced a ragweed antigen solution, and performed two postchallenge lavages. The recovered fluid was analyzed for the concentrations of prostaglandin D2 (PGD2; radioimmunoassay) and histamine (fluorometric technique) and for total and differential cell counts. Antigen challenge was associated with a significant increase in PGD2 concentration in the recovered fluid, rising from a median of 178 pg/ml (range, 157-647) before to 919 pg/ml (range, 149-2,452) after challenge. Median histamine concentrations were 3.1 ng/ml (range, 1-5.4 ng/ml) before and 5.6 ng/ml (range, 1-16.2) after challenge (P = not significant). In four dogs, a control challenge with the antigen vehicle alone showed no change in either mediator. Changes in cell counts after challenge were inconsistent.(ABSTRACT TRUNCATED AT 250 WORDS)

Real-time simulation of biological soft tissues: a PGD approach.

PubMed

Niroomandi, S; González, D; Alfaro, I; Bordeu, F; Leygue, A; Cueto, E; Chinesta, F

2013-05-01

We introduce here a novel approach for the numerical simulation of nonlinear, hyperelastic soft tissues at kilohertz feedback rates necessary for haptic rendering. This approach is based upon the use of proper generalized decomposition techniques, a generalization of PODs. Proper generalized decomposition techniques can be considered as a means of a priori model order reduction and provides a physics-based meta-model without the need for prior computer experiments. The suggested strategy is thus composed of an offline phase, in which a general meta-model is computed, and an online evaluation phase in which the results are obtained at real time. Results are provided that show the potential of the proposed technique, together with some benchmark test that shows the accuracy of the method. Copyright © 2013 John Wiley & Sons, Ltd.

A Threat to Accreditation: Defamation Judgment against an Accreditation Team Member.

ERIC Educational Resources Information Center

Flygare, Thomas J.

1980-01-01

Delaware Law School founder Alfred Avins successfully sued accreditation team member James White for defamation as a result of comments made in 1974 and 1975. An appeals brief claims Avins was a "public figure," that he consented to accreditation, and that the accreditation process deserves court protection against such suits. (PGD)

Reporting Child Abuse and Neglect: Your Responsibility and Your Protections.

ERIC Educational Resources Information Center

Beezer, Bruce

1985-01-01

Educators are reluctant to report child abuse and neglect because they are not sure how abuse and neglect are defined, they are inadequately informed about the reporting process, and they fear prosecution. Most states make failure to report illegal, and courts tend to support educators making reports in good faith. (PGD)

Parental Choices and Ethical Dilemmas Involving Disabilities: Special Education and the Problem of Deliberately Chosen Disabilities

ERIC Educational Resources Information Center

Kauffman, James M.; Hallahan, Daniel P.

2009-01-01

Ethical issues regarding children with disabilities have long involved their treatment after they are born. These issues remain important, but children may be deliberately created with or without characteristics that are usually thought of as disabilities. Preimplantation genetic diagnosis (PGD) and related technologies that involve human…

Problems and Alternatives in Housing Students: What a School Business Administrator Should Know.

ERIC Educational Resources Information Center

Earthman, Glen I.

1984-01-01

Reviews factors that could influence planning for the provision of educational facilities in the foreseeable future: new enrollment projections, the need to address deferred maintenance problems, recent educational reform efforts, the needs of new programs, recent tax limitation measures, court action, and new approaches to raising funds. (PGD)

In Federal Court, at Least, Comparable Worth Gets a Cool Reception.

ERIC Educational Resources Information Center

Zakariya, Sally Banks

1985-01-01

The concept of comparable worth bases its legal claims in the Equal Pay Act of 1963, the Civil Rights Act of 1964, and a 1981 decision of the United States Supreme Court. Still, assertions that comparable worth should be invoked to correct wage discrimination have usually been rejected in federal courts. (PGD)

Item Specification in the Development of a Diagnostic Gambling Instrument: A Focus Group Approach

ERIC Educational Resources Information Center

Cunningham-Williams, Renee M.; Zayas, Luis E.; Books, Samantha J.; Cottler, Linda B.

2008-01-01

Pathological Gambling Disorder (PGD) is internationally prevalent and contributes to significant disruption and impairment in a gambler's life. For accurate diagnosis and treatment planning, clinicians require standardized criteria as in commonly used DSM and ICD-10 taxonomies, which are conceptually clear, valid, and culturally appropriate. We…

Symbiotic relationships: saviour siblings, family rights and biomedicine.

PubMed

Bennett, Belinda

2005-12-01

It is now possible to combine the use of preimplantation genetic diagnosis (PGD) and tissue matching to select an IVF embryo that will, after birth, be a compatible tissue donor for an existing individual. This article analyses the ethical issues and the regulatory frameworks that intersect around the creation of tissue compatible children.

Transfusion-related acute lung injury (TRALI) in graft by blood donor antibodies against host leukocytes.

PubMed

Goodwin, Jodi; Tinckam, Kathryn; denHollander, Neal; Haroon, Ayesha; Keshavjee, Shaf; Cserti-Gazdewich, Christine M

2010-09-01

It is unknown the extent to which transfusion-related acute lung injury (TRALI) contributes to primary graft dysfunction (PGD), the leading cause of death after lung transplantation. In this case of suspected transfusion-associated acute bilateral graft injury in a 61-year-old idiopathic pulmonary fibrosis patient, recipient sera from before and after transplantation/transfusion, as well as the sera of 22 of the 24 implicated blood donors, were individually screened by Luminex bead assay for the presence of human leukocyte antigen (HLA) antibodies, with recipient and lung donor HLA typing to explore for cognate relationships. A red-cell-unit donor-source anti-Cw6 antibody, cognate with the HLA type of the recipient, was identified. This is the second reported case of TRALI in the setting of lung transplantation, and the first to show an associated interaction between donor antibodies (in a low-plasma volume product) with recipient leukocytes (rather than graft antigens); therefore, it should be considered in the differential diagnosis of PGD. Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Genome editing and assisted reproduction: curing embryos, society or prospective parents?

PubMed

Cavaliere, Giulia

2018-06-01

This paper explores the ethics of introducing genome-editing technologies as a new reproductive option. In particular, it focuses on whether genome editing can be considered a morally valuable alternative to preimplantation genetic diagnosis (PGD). Two arguments against the use of genome editing in reproduction are analysed, namely safety concerns and germline modification. These arguments are then contrasted with arguments in favour of genome editing, in particular with the argument of the child's welfare and the argument of parental reproductive autonomy. In addition to these two arguments, genome editing could be considered as a worthy alternative to PGD as it may not be subjected to some of the moral critiques moved against this technology. Even if these arguments offer sound reasons in favour of introducing genome editing as a new reproductive option, I conclude that these benefits should be balanced against other considerations. More specifically, I maintain that concerns regarding the equality of access to assisted reproduction and the allocation of scarce resources should be addressed prior to the adoption of genome editing as a new reproductive option.

Chromosomal disorders and male infertility

PubMed Central

Harton, Gary L; Tempest, Helen G

2012-01-01

Infertility in humans is surprisingly common occurring in approximately 15% of the population wishing to start a family. Despite this, the molecular and genetic factors underlying the cause of infertility remain largely undiscovered. Nevertheless, more and more genetic factors associated with infertility are being identified. This review will focus on our current understanding of the chromosomal basis of male infertility specifically: chromosomal aneuploidy, structural and numerical karyotype abnormalities and Y chromosomal microdeletions. Chromosomal aneuploidy is the leading cause of pregnancy loss and developmental disabilities in humans. Aneuploidy is predominantly maternal in origin, but concerns have been raised regarding the safety of intracytoplasmic sperm injection as infertile men have significantly higher levels of sperm aneuploidy compared to their fertile counterparts. Males with numerical or structural karyotype abnormalities are also at an increased risk of producing aneuploid sperm. Our current understanding of how sperm aneuploidy translates to embryo aneuploidy will be reviewed, as well as the application of preimplantation genetic diagnosis (PGD) in such cases. Clinical recommendations where possible will be made, as well as discussion of the use of emerging array technology in PGD and its potential applications in male infertility. PMID:22120929

Chromosomal disorders and male infertility.

PubMed

Harton, Gary L; Tempest, Helen G

2012-01-01

Infertility in humans is surprisingly common occurring in approximately 15% of the population wishing to start a family. Despite this, the molecular and genetic factors underlying the cause of infertility remain largely undiscovered. Nevertheless, more and more genetic factors associated with infertility are being identified. This review will focus on our current understanding of the chromosomal basis of male infertility specifically: chromosomal aneuploidy, structural and numerical karyotype abnormalities and Y chromosomal microdeletions. Chromosomal aneuploidy is the leading cause of pregnancy loss and developmental disabilities in humans. Aneuploidy is predominantly maternal in origin, but concerns have been raised regarding the safety of intracytoplasmic sperm injection as infertile men have significantly higher levels of sperm aneuploidy compared to their fertile counterparts. Males with numerical or structural karyotype abnormalities are also at an increased risk of producing aneuploid sperm. Our current understanding of how sperm aneuploidy translates to embryo aneuploidy will be reviewed, as well as the application of preimplantation genetic diagnosis (PGD) in such cases. Clinical recommendations where possible will be made, as well as discussion of the use of emerging array technology in PGD and its potential applications in male infertility.

Cyclo-oxygenase-2 contributes to constitutive prostanoid production in rat kidney and brain

PubMed Central

2005-01-01

Cyclo-oxygenases (COXs) catalyse the synthesis of PGH2 (prostaglandin H2), which serves as the common substrate for the production of PGE2, PGD2, PGF2α, prostacyclin (or PGI2) and TXs (thromboxanes). While COX-1 is the major isoform responsible for prostanoid synthesis in healthy tissues, little information is available on the contribution of constitutive COX-2 to the various prostanoid synthetic pathways under non-inflammatory conditions. To evaluate further the role of COX-2 in prostanoid biosynthesis, rats were acutely treated with the selective COX-1 inhibitor SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] or the selective COX-2 inhibitors MF tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulphonyl)phenyl)-2-(5H)-furanone] and DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2-(5H)-furanone]. Selected tissues were then processed for a complete analysis of their prostanoid content by liquid chromatography MS. Whereas the treatment with SC-560 caused a 60–70% inhibition in the total prostanoid content of most tissues examined, a significant decrease (35–50%) in total prostanoid content following selective COX-2 inhibition was solely detected for kidney and brain tissues. Analysis of the individual prostanoids reveals significant inhibition of 6-oxo-PGF1α, PGE2, PGD2, PGF2α and TXB2 in the kidney and inhibition of all these prostanoids with the exception of PGD2 in the forebrain. These results demonstrate that constitutively expressed COX-2 contributes to the production of prostanoids in kidney and brain for each of the PGE2, PGI2 and TXB2 pathways under non-inflammatory conditions. Approaches to modulate inflammation through specific inhibition of terminal synthases, such as mPGES-1 (microsomal PGE2 synthase-1), thus have the potential to differ from COX-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs with regard to effects on constitutive prostanoid synthesis and on renal function. PMID:16008526

[Treating coeliac disease. How do we measure adherence to the gluten-free diet?

PubMed

Aranda, Elisa A; Araya, Magdalena

Coeliac disease (CD) is a systemic autoimmune disorder triggered by gluten consumption in genetically susceptible individuals. It exhibits several clinical features, such as blood auto-antibodies (anti-endomysial antibodies EMA, anti-transglutaminase antibodies tTG, anti-deamidated gliadin peptides PGD), plus variable degrees of damage in the small intestinal mucosa. In Chile, tTG is positive in 0.76% in individuals >15 years, with the prevalence of CD being estimated at 0.6%. Approximately17% of first-degree relatives of coeliac patients have been reported tTG positive. To date, the gluten free diet (GFD) is the only known treatment for CD. To be effective, this must be lifelong, permanent, and strict. Gluten content in the GFD is not zero, but is limited to a cut-off of 3ppm (ormg/kg of product) in Chile. Mortality higher than that of the general population has been reported among coeliac patients, and poor adherence to GFD is associated with complications (mainly autoimmune processes and cancer). GFD is difficult to maintain strictly and poor adherence is by far the main cause of lack of response to treatment. Follow-up of adherence is also difficult because there are no objective measurements to assess it. In clinical practice determination of serum EMA, tTG and PGD is routinely used for these purposes, although more recently, the interview by an expert dietitian, validated questionnaires and measurement of faecal 33-mer peptide are being assessed as alternatives or complements to measure adherence to GFD. A review is presented with the current concepts on the available tools to follow up patients on GFD, emphasising those available in Chilel. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

A new fluorescent dye accumulation assay for parallel measurements of the ABCG2, ABCB1 and ABCC1 multidrug transporter functions.

PubMed

Szabó, Edit; Türk, Dóra; Telbisz, Ágnes; Kucsma, Nóra; Horváth, Tamás; Szakács, Gergely; Homolya, László; Sarkadi, Balázs; Várady, György

2018-01-01

ABC multidrug transporters are key players in cancer multidrug resistance and in general xenobiotic elimination, thus their functional assays provide important tools for research and diagnostic applications. In this study we have examined the potential interactions of three key human ABC multidrug transporters with PhenGreen diacetate (PGD), a cell permeable fluorescent metal ion indicator. The non-fluorescent, hydrophobic PGD rapidly enters the cells and, after cleavage by cellular esterases, in the absence of quenching metal ions, PhenGreen (PG) becomes highly fluorescent. We found that in cells expressing functional ABCG2, ABCB1, or ABCC1 transporters, cellular PG fluorescence is strongly reduced. This fluorescence signal in the presence of specific transporter inhibitors is increased to the fluorescence levels in the control cells. Thus the PG accumulation assay is a new, unique tool for the parallel determination of the function of the ABCG2, ABCB1, and ABCC1 multidrug transporters. Since PG has very low cellular toxicity, the PG accumulation assay also allows the selection, separation and culturing of selected cell populations expressing either of these transporters.

Genetical Analysis of Chromosomal Interaction Effects on the Activities of the Glucose 6-Phosphate and 6-Phosphogluconate Dehydrogenases in DROSOPHILA MELANOGASTER

PubMed Central

Miyashita, Naohiko; Laurie-Ahlberg, C. C.

1984-01-01

By combining ten second and ten third chromosomes, we investigated chromosomal interaction with respect to the action of the modifier factors on G6PD and 6PGD activities in Drosophila melanogaster. Analysis of variance revealed that highly significant chromosomal interaction exists for both enzyme activities. From the estimated variance components, it was concluded that the variation in enzyme activity attributed to the interaction is as great as the variation attributed to the second chromosome but less than attributed to the third chromosome. The interaction is not explained by the variation of body size (live weight). The interaction is generated from both the lack of correlation of second chromosomes for third chromosome backgrounds and the heterogeneous variance of second chromosomes for different third chromosome backgrounds. Large and constant correlation between G6PD and 6PGD activities were found for third chromosomes with any second chromosome background, whereas the correlations for second chromosomes were much smaller and varied considerably with the third chromosome background. This result suggests that the activity modifiers on the second chromosome are under the influence of third chromosome factors. PMID:6425115

Re-evaluation of thin layer chromatography as an alternative method for the quantification of prostaglandins from rat Kupffer cells.

PubMed

Pestel, Sabine; Jungermann, Kurt; Schieferdecker, Henrike L

2005-01-01

In contrast to conventionally used immunoassays, thin layer chromatography (TLC)--by prelabeling of cells with radioactive arachidonic acid (AA)--allows to differentiate between cellularly built and added prostanoids and thus to investigate feedback effects of prostanoids on their own release. PGD2, TXB2 and PGE2 released from zymosan-stimulated Kupffer cells were separated with distinct RF-values, corresponding to those of the pure substances. Quantification of PGD2 and PGE2 gave comparable results with TLC and immunoassays, but measurement in the presence of added prostanoids was only possible with TLC. Moreover TLC was superior to immunoassays in having a longer linear range while being comparably sensitive. Cellularly built TXB2 in its radioactively labeled form was not detectable by TLC. Inhibition of TXB2 release by externally added AA or technical artifacts were excluded, suggesting that the cellular AA-pools used for prostaglandin and thromboxane synthesis differ in their accessibility for added AA. Thus, TLC is a simple, sensitive and precise method for the quantification of cellularly built prostaglandins but not of thromboxane even in the presence of added prostanoids.

Prostaglandins and Their Receptors in Eosinophil Function and As Therapeutic Targets

PubMed Central

Peinhaupt, Miriam; Sturm, Eva M.; Heinemann, Akos

2017-01-01

Of the known prostanoid receptors, human eosinophils express the prostaglandin D2 (PGD2) receptors DP1 [also D-type prostanoid (DP)] and DP2 (also chemoattractant receptor homologous molecule, expressed on Th2 cells), the prostaglandin E2 receptors EP2 and EP4, and the prostacyclin (PGI2) receptor IP. Prostanoids can bind to either one or multiple receptors, characteristically have a short half-life in vivo, and are quickly degraded into metabolites with altered affinity and specificity for a given receptor subtype. Prostanoid receptors signal mainly through G proteins and naturally activate signal transduction pathways according to the G protein subtype that they preferentially interact with. This can lead to the activation of sometimes opposing signaling pathways. In addition, prostanoid signaling is often cell-type specific and also the combination of expressed receptors can influence the outcome of the prostanoid impulse. Accordingly, it is assumed that eosinophils and their (patho-)physiological functions are governed by a sensitive prostanoid signaling network. In this review, we specifically focus on the functions of PGD2, PGE2, and PGI2 and their receptors on eosinophils. We discuss their significance in allergic and non-allergic diseases and summarize potential targets for drug intervention. PMID:28770200

Impact of Topography on Seismic Amplification During the 2005 Kashmir Earthquake

NASA Astrophysics Data System (ADS)

Khan, S.; van der Meijde, M.; van der Werff, H.; Shafique, M.

2016-12-01

This study assesses topographic amplification of seismic response during the 2005 Kashmir Earthquake in northern Pakistan. Topography scatters seismic waves, which causes variation in seismic response on the surface of the earth. During the Kashmir earthquake, topography induced amplification was suspected to have had major influence on the damage of infrastructure. We did a 3-dimensional simulation of the event using SPECFEM3D software. We first analyzed the impact of data resolution (mesh and Digital Elevation Model) on the derived seismic response. ASTER GDEM elevation data was used to build a 3D finite element mesh, and the parameters (latitude, longitude, depth, moment tensor) of the Kashmir earthquake were used in simulating the event. Our results show amplification of seismic response on ridges and de-amplification in valleys. It was also found that slopes facing away from the source receive an amplified seismic response when compared to slopes facing towards the source. The PGD would regularly fall within the range 0.23-5.8 meters. The topographic amplification causes local changes in the range of -2.50 to +3.50 meters; causing the PGD to fall in the range of 0.36-7.85 meters.

Frequency of primary glomerular disease in northeastern China.

PubMed

Wu, Yi-Qi; Wang, Zheng; Xu, Hua-Feng; Jin, Xiao-Ming; Zhou, Hai-Zhou

2011-08-01

Most frequently reported Chinese renal biopsy data have originated from southeastern China. The present study analyzed the renal biopsy data from northeastern China. The records of 1550 consecutive native patients who were diagnosed with primary glomerular diseases (PGD) after renal biopsy at our hospital during 2005-2009 were used. These patients were divided into four age groups for stratified analysis: <15, 15-44, 45-59, and ≥60 years old. Among PGD, minimal change disease (MCD) was the most common histologically diagnosed disease (30.7%), followed by IgA nephropathy (IgAN), mesangial proliferative glomerulonephritis (MsPGN), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), focal segmental glomerulosclerosis (FSGS), and endocapillary proliferative glomerulonephritis (EnPGN). MCD was the disease most frequently observed (43.7%) in the <15-year-old group. MsPGN was the most common disease in the elderly group (38.1%). MsPGN was more prevalent in females (27.8%), whereas MCD was more prevalent in males (35.3%). Primary glomerular diseases constituted the most commonly encountered group of diseases with a high prevalence of MCD, which predominantly affected males and young adults. The prevalence of MCD was high in northeastern China. Further study is necessary to expand the epidemiologic data available for renal disease in China.

Anti-inflammatory activity of 6-hydroxy-2,7-dimethoxy-1,4-henanthraquinone from tuberous roots of yam (Dioscorea batatas) through inhibition of prostaglandin D₂ and leukotriene C₄ production in mouse bone marrow-derived mast cells.

PubMed

Jin, Meihua; Lu, Yue; Yang, Ju Hye; Jo, Tae Hyung; Park, Young In; Lee, Chong-Kil; Park, Sang-Jo; Son, Kun Ho; Chang, Hyeun Wook

2011-09-01

6-Hydroxy-2,7-dimethoxy-1,4-phenanthraquinone (PAQ) isolated from the tuberous roots of Yam (Dioscorea batatas) inhibited cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) dependent prostaglandin D(2) (PGD(2)) generation in mouse bone marrow-derived mast cells in a concentration-dependent manner with IC(50) values of 0.08 μM and 0.27 μM, respectively. In the Western blotting with specific anti-COX-2 antibodies, the decrease of the quantity of PGD(2) was accompanied by a decrease in the COX-2 protein level. But PAQ did not affect COX-1 protein level. In addition, this compound inhibited 5-lipoxygenase (5-LOX) dependent production of leukotriene C(4) in a dose-dependent manner, with an IC(50) of 0.032 μM. These results demonstrate that PAQ has a dual COX-2/5-LOX inhibitory activity. This compound also inhibited the degranulation reaction in a dose-dependent manner with an IC(50) of 2.7 μM. Thus, these results suggest that PAQ may be useful in regulating mast cell-mediated inflammatory diseases.

Thermal mechanism of prepeak formation in Pulsed Glow Discharge

NASA Astrophysics Data System (ADS)

Voronov, Maxim; Hoffmann, Volker; Steingrobe, Tobias; Buscher, Wolfgang; Engelhard, Carsten; Storey, Andrew; Ray, Steven; Hieftje, Gary

2012-10-01

A microsecond Pulsed Glow Discharge (μs PGD) in a Grimm-type source is characterized by the so-called ``prepeak,'' which is a spike in both electrical current and emission intensity at the leading edge of the discharge pulse. The prepeak is followed by synchronized vibrations of the current and the emission. To understand the nature of these phenomena, a microphone was inserted into the discharge chamber. Acoustical waves were detected and found to be in correlation with the measured vibrations. This points to a thermal mechanism for prepeak formation: the gas is heated in the leading edge of the discharge pulse and then expanded. To prove this suggestion, a Monte-Carlo based model was developed to simulate the evolution of Ar concentration, temperature, and flow in time and space. Potentially, the model could be used for gas simulations in a wide range of different applications. Here, the model is incorporated into an existing but modified model of the μs PGD in a Grimm-type plasma excitation source. Results of the simulations confirm that the thermal mechanism is responsible for the formation of the electrical prepeak and the pressure waves.

DNA Probe Pooling for Rapid Delineation of Chromosomal Breakpoints

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Chun-Mei; Kwan, Johnson; Baumgartner, Adolf

2009-01-30

Structural chromosome aberrations are hallmarks of many human genetic diseases. The precise mapping of translocation breakpoints in tumors is important for identification of genes with altered levels of expression, prediction of tumor progression, therapy response, or length of disease-free survival as well as the preparation of probes for detection of tumor cells in peripheral blood. Similarly, in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) for carriers of balanced, reciprocal translocations benefit from accurate breakpoint maps in the preparation of patient-specific DNA probes followed by a selection of normal or balanced oocytes or embryos. We expedited the process of breakpointmore » mapping and preparation of case-specific probes by utilizing physically mapped bacterial artificial chromosome (BAC) clones. Historically, breakpoint mapping is based on the definition of the smallest interval between proximal and distal probes. Thus, many of the DNA probes prepared for multi-clone and multi-color mapping experiments do not generate additional information. Our pooling protocol described here with examples from thyroid cancer research and PGD accelerates the delineation of translocation breakpoints without sacrificing resolution. The turnaround time from clone selection to mapping results using tumor or IVF patient samples can be as short as three to four days.« less

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop.

PubMed

Lama, Vibha N; Belperio, John A; Christie, Jason D; El-Chemaly, Souheil; Fishbein, Michael C; Gelman, Andrew E; Hancock, Wayne W; Keshavjee, Shaf; Kreisel, Daniel; Laubach, Victor E; Looney, Mark R; McDyer, John F; Mohanakumar, Thalachallour; Shilling, Rebecca A; Panoskaltsis-Mortari, Angela; Wilkes, David S; Eu, Jerry P; Nicolls, Mark R

2017-05-04

Lung transplantation, a cure for a number of end-stage lung diseases, continues to have the worst long-term outcomes when compared with other solid organ transplants. Preclinical modeling of the most common and serious lung transplantation complications are essential to better understand and mitigate the pathophysiological processes that lead to these complications. Various animal and in vitro models of lung transplant complications now exist and each of these models has unique strengths. However, significant issues, such as the required technical expertise as well as the robustness and clinical usefulness of these models, remain to be overcome or clarified. The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in March 2016 to review the state of preclinical science addressing the three most important complications of lung transplantation: primary graft dysfunction (PGD), acute rejection (AR), and chronic lung allograft dysfunction (CLAD). In addition, the participants of the workshop were tasked to make consensus recommendations on the best use of these complimentary models to close our knowledge gaps in PGD, AR, and CLAD. Their reviews and recommendations are summarized in this report. Furthermore, the participants outlined opportunities to collaborate and directions to accelerate research using these preclinical models.

Diagnosis of Fanconi Anemia: Mutation Analysis by Multiplex Ligation-Dependent Probe Amplification and PCR-Based Sanger Sequencing

PubMed Central

Gille, Johan J. P.; Floor, Karijn; Kerkhoven, Lianne; Ameziane, Najim; Joenje, Hans; de Winter, Johan P.

2012-01-01

Fanconi anemia (FA) is a rare inherited disease characterized by developmental defects, short stature, bone marrow failure, and a high risk of malignancies. FA is heterogeneous: 15 genetic subtypes have been distinguished so far. A clinical diagnosis of FA needs to be confirmed by testing cells for sensitivity to cross-linking agents in a chromosomal breakage test. As a second step, DNA testing can be employed to elucidate the genetic subtype of the patient and to identify the familial mutations. This knowledge allows preimplantation genetic diagnosis (PGD) and enables prenatal DNA testing in future pregnancies. Although simultaneous testing of all FA genes by next generation sequencing will be possible in the near future, this technique will not be available immediately for all laboratories. In addition, in populations with strong founder mutations, a limited test using Sanger sequencing and MLPA will be a cost-effective alternative. We describe a strategy and optimized conditions for the screening of FANCA, FANCB, FANCC, FANCE, FANCF, and FANCG and present the results obtained in a cohort of 54 patients referred to our diagnostic service since 2008. In addition, the follow up with respect to genetic counseling and carrier screening in the families is discussed. PMID:22778927

Screening and prevention of neonatal glucose 6-phosphate dehydrogenase deficiency in Guangzhou, China.

PubMed

Jiang, J; Li, B; Cao, W; Jiang, X; Jia, X; Chen, Q; Wu, J

2014-06-09

We aimed to summarize the results of screening protocol and prevention of neonatal glucose 6-phosphate dehydrogenase (G6PD) deficiency during a 22-year-long period to provide a basis of reference for the screening of this disease. About 1,705,569 newborn subjects in Guangzhou City were screened for this deficiency. Specimens were collected according to the conventional method of specimen acquisition for "newborn dried bloodspot screening", preserved, and inspected. The specimens were studied with fluorescent spot test and quantitative fluorescence assay. Diagnosis was performed using the modified NBTG6PD/6PGD ratio method. Bloodspot filter paper specimens were sent to the laboratory within 24 h via EMS Express, and the G6PD test was performed on the same day. The G6PD deficiency-positive rate was 4.2% in the samples screened using the fluorescent spot test, while it was 5% in case of the quantitative fluorescence assay. Neonatal screening for G6PD deficiency for 11,437 cases (6117 boys and 5320 girls) showed positive results in 481 cases. About 420 cases (318 boys and 102 girls) of G6PD deficiency were confirmed with the modified Duchenne NBT ratio method. The total detection rate was 3.7:5.2% for boys and 1.9% for girls. Quantitative fluorescence assay improved the sensitivity and detection rate. Accelerating the speed of sample delivery by using Internet network systems and ensuring online availability of screening results can aid the screening and diagnosis of this deficiency within 1 week of birth.

Reducing process delays for real-time earthquake parameter estimation - An application of KD tree to large databases for Earthquake Early Warning

NASA Astrophysics Data System (ADS)

Yin, Lucy; Andrews, Jennifer; Heaton, Thomas

2018-05-01

Earthquake parameter estimations using nearest neighbor searching among a large database of observations can lead to reliable prediction results. However, in the real-time application of Earthquake Early Warning (EEW) systems, the accurate prediction using a large database is penalized by a significant delay in the processing time. We propose to use a multidimensional binary search tree (KD tree) data structure to organize large seismic databases to reduce the processing time in nearest neighbor search for predictions. We evaluated the performance of KD tree on the Gutenberg Algorithm, a database-searching algorithm for EEW. We constructed an offline test to predict peak ground motions using a database with feature sets of waveform filter-bank characteristics, and compare the results with the observed seismic parameters. We concluded that large database provides more accurate predictions of the ground motion information, such as peak ground acceleration, velocity, and displacement (PGA, PGV, PGD), than source parameters, such as hypocenter distance. Application of the KD tree search to organize the database reduced the average searching process by 85% time cost of the exhaustive method, allowing the method to be feasible for real-time implementation. The algorithm is straightforward and the results will reduce the overall time of warning delivery for EEW.

Colonia Tovar: the history of a semi-isolated Venezuelan population of German ancestry described by HLA class I genes.

PubMed

Gendzekhadze, K; Montagnani, S; Ogando, V; Balbas, O; Mendez-Castellano, H; Layrisse, Z

2003-11-01

The history of Colonia Tovar is very complex, being the home of descendants of only a small fraction of immigrants arriving to the South American continent from a specific region of Germany, with a restricted number of founders, small population size and consanguineous mating, experiencing isolation for 100 years, with later migrations, a low rate of population growth and a high mean number of children per couple. How complex is its genetic structure? Do the highly polymorphic HLA genes reflect its history and confirm the story of this population described by other genes? Several studies have been made in this population, but we describe for the first time the HLA Class I variability in the population of Colonia Tovar using PCR-SSOP. Random genetic drift, founder effect and gene flow could explain the HLA allele and haplotype frequencies observed in this population but alleles at the class I loci were insufficient to identify the German origin of the community established through history. This agrees with findings obtained testing other genetic systems (ACP, AK, ESD, G6PD, GLO, PGM, PGD, ALB, CP, HP, TF), but the HLA-typing results indicate that the original gene pool has been diluted due to gene flow from the surrounding Mestizo population.

PGD and aneuploidy screening for 24 chromosomes: advantages and disadvantages of competing platforms.

PubMed

Bisignano, A; Wells, D; Harton, G; Munné, S

2011-12-01

Diagnosis of embryos for chromosome abnormalities, i.e. aneuploidy screening, has been invigorated by the introduction of microarray-based testing methods allowing analysis of 24 chromosomes in one test. Recent data have been suggestive of increased implantation and pregnancy rates following microarray testing. Preimplantation genetic diagnosis for infertility aims to test for gross chromosome changes with the hope that identification and transfer of normal embryos will improve IVF outcomes. Testing by some methods, specifically single-nucleotide polymorphism (SNP) microarrays, allow for more information and potential insight into parental origin of aneuploidy and uniparental disomy. The usefulness and validity of reporting this information is flawed. Numerous papers have shown that the majority of meiotic errors occur in the egg, while mitotic errors in the embryo affect parental chromosomes at random. Potential mistakes made in assigning an error as meiotic or mitotic may lead to erroneous reporting of results with medical consequences. This study's data suggest that the bioinformatic cleaning used to 'fix' the miscalls that plague single-cell whole-genome amplification provides little improvement in the quality of useful data. Based on the information available, SNP-based aneuploidy screening suffers from a number of serious issues that must be resolved. Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Ray Tolcacher: Peddling His Own Brand of Community Relations, This Principal Has Made His Los Angeles Elementary School an Island of Stability in a Neighborhood of Turmoil.

ERIC Educational Resources Information Center

Savage, David G.

1985-01-01

Ray Tolcacher, the active and highly visible principal of Whelan Elementay School in Lennox, California, won the respect and trust of the Hispanic community served by Whelan by encouraging local residents to use school facilities and by fostering good relations between community members and local police. (PGD)

Investigating source directivity for the 2012 Ml5.9 Emilia (Northern Italy) earthquake by jointly using High-rate GPS and Strong motion data

NASA Astrophysics Data System (ADS)

Avallone, A.; Herrero, A.; Latorre, D.; Rovelli, A.; D'Anastasio, E.

2012-12-01

On May, 20th 2012, the Ferrara and Modena provinces (Emilia Romagna, Northern Italy) were struck by a moderate magnitude earthquake (Ml 5.9). The focal mechanism is consistent with a ~E-W-striking thrust fault. The mainshock was recorded by 29 high-rate sampling (1-Hz) continuous GPS (HRGPS) stations belonging to scientific or commercial networks and by 55 strong motion (SM) stations belonging to INGV (Istituto Nazionale di Geofisica e Vulcanologia) and RAN (Rete Accelerometrica Nazionale) networks, respectively. The spatial distribution of both HRGPS and SM stations with respect to the mainshock location allows a satisfactory azimuthal coverage of the area. To investigate directivity effects during the mainshock occurrence, we analyze the spatial variation of the peak ground displacement (PGD) measured either for HRGPS or SM sites, using different methods. For each HRGPS and SM site, we rotated the horizontal time series to the azimuth direction and we estimated the GPS-related and the SM-related peak ground displacement (G-PGD and S-PGD, respectively) retrieved by transverse component. However, in contrast to GPS displacements, the double integration of the SM data can be affected by the presence of drifts and, thus, they have to be corrected by quasi-manual procedures. To more properly compare the G-PGDs to the S-PGDs, we used the response spectrum. A response spectrum is simply the response of a series of oscillators of varying natural frequency, that are forced into motion by the same input. The asymptotic value of the displacement response spectrum is the peak ground displacement. Thus, for each HRGPS and SM site, we computed the value of this asymptotic trend (G-PGDrs and S-PGDrs, respectively). This method allows simple automatic procedures. The consistency of the PGDs derived from HRGPS and SM is also evaluated for sites where the two instruments are collocated. The PGDs obtained by the two different methods and the two different data types suggest a source directivity effect in the SE (~120°-150°N) direction.

Cysteinyl leukotriene E4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2 and epithelial cytokines.

PubMed

Salimi, Maryam; Stöger, Linda; Liu, Wei; Go, Simei; Pavord, Ian; Klenerman, Paul; Ogg, Graham; Xue, Luzheng

2017-10-01

Group 2 innate lymphoid cells (ILC2s) are a potential innate source of type 2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) and mast cell mediators (prostaglandin D 2 [PGD 2 ]) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs), including leukotriene (LT) C 4 , LTD 4 , and LTE 4 , are metabolites of arachidonic acid and mediate inflammatory responses. Their role in human ILC2s is still poorly understood. We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s. For ex vivo studies, fresh blood from patients with atopic dermatitis and healthy control subjects was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD 2 , IL-33, IL-25, TSLP, and IL-2 alone or in combination on ILC2s were defined by using chemotaxis, apoptosis, ELISA, Luminex, quantitative RT-PCR, and flow cytometric assays. The effect of endogenous cysLTs was assessed by using human mast cell supernatants. Human ILC2s expressed the LT receptor CysLT 1 , levels of which were increased in atopic subjects. CysLTs, particularly LTE 4 , induced migration, reduced apoptosis, and promoted cytokine production in human ILC2s in vitro. LTE 4 enhanced the effect of PGD 2 , IL-25, IL-33, and TSLP, resulting in increased production of type 2 and other proinflammatory cytokines. The effect of LTE 4 was inhibited by montelukast, a CysLT 1 antagonist. Interestingly, addition of IL-2 to LTE 4 and epithelial cytokines significantly amplified ILC2 activation and upregulated expression of the receptors for IL-33 and IL-25. CysLTs, particularly LTE 4 , are important contributors to the triggering of human ILC2s in inflammatory responses, particularly when combined with other ILC2 activators. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chinese herbal medicine formula for acute asthma: A multi-center, randomized, double-blind, proof-of-concept trial.

PubMed

Zhang, Hong Ping; Wang, Lei; Wang, Zhen; Xu, Xian Rong; Zhou, Xian Mei; Liu, Gang; He, Lv Yuan; Wang, Jun; Hsu, Alan; Li, Wei Min; Wang, Gang

2018-07-01

Despite advances in asthma management, exacerbations constitute a significant health economic burden. To observe the efficacy and safety of Chinese herbal medicine formula entitled PingchuanYiqi (PCYQ) granule, on acute asthma and to explore its possible mechanism. This proof-of-concept study consisted of a randomized, double-blind, placebo-controlled trial in patients with acute asthma (n = 300). Participants with acute mild-to-moderate asthma recruited from seven centers in China were randomly assigned to receive PCYQ or placebo. The primary outcomes were PEF (L/min) and total asthma symptom scores. Furthermore, a panel of cytokines including serum IL-4, IL-5, IL-6, IL-8, IL-1β, IL-17A, IFN-α, IFN-β, IFN-γ, CRP, CCL-5, IP-10, and PGD 2 levels was detected using ELISA. The PCYQ (n = 139) significantly improved the morning PEF on day 4 (349.73 ± 93.92 vs. 313.56 ± 92.91 L/min, P = 0.004) and day 7 (360.42 ± 94.39 vs. 329.52 ± 95.97 L/min, P = 0.023), and the evening PEF on day 4 (352.65 ± 95.47 vs. 320.58 ± 95.30 L/min, P = 0.012) and day 7 (360.42 ± 94.39 vs. 336.86 ± 95.59 L/min, P = 0.029) in comparison with the placebo (n = 143). The PCYQ also improved the clinical symptoms scores and reduced the puffs of short-acting β 2 -agonist (all P < 0.05). Furthermore, the PCYQ statistically reduced IL-5, IL-8, IL-1β and PGD 2 in serum. The PCYQ as the Chinese herbal medicine formula significantly improves lung function and symptoms of acute asthma, and reduces SABA dosage possibly via decrease of inflammatory biomarkers such as IL-5, IL-8, IL-1β and PGD 2 . ISRCTN61674768 (http://www.isrctn.com/). Copyright © 2018. Published by Elsevier Ltd.

Effects of recombinant human leptin administration on hepatic lipid metabolism in yellow catfish Pelteobagrus fulvidraco: in vivo and in vitro studies.

PubMed

Song, Yu-Feng; Wu, Kun; Tan, Xiao-Ying; Zhang, Li-Han; Zhuo, Mei-Qin; Pan, Ya-Xiong; Chen, Qi-Liang

2015-02-01

The present study was conducted to investigate the effects and mechanism of leptin influencing lipid metabolism in yellow catfish Pelteobagrus fulvidraco. To this end, hepatic lipid (in vivo experiment) and intracellular triglyceride (TG) (in vitro experiment) content, the activities and/or expression level of several enzymes (CPT-1, 6PGD, G6PD, FAS, ME and ICDH) as well as the mRNA expression of transcription factors (PPARα, PPARγ and SREBP-1) involved in lipid metabolism were determined. Using the primary hepatocytes of yellow catfish, specific inhibitors AG490 (JAK-STAT inhibitor) and wortmannin (IRS-PI3K inhibitor) were used to explore the signaling pathways of leptin effects on lipid metabolism. Intraperitoneal injection of recombinant human leptin (rt-hLEP) significantly reduced hepatic lipid content, activities of lipogenic enzymes (6PGD, G6PD, ME, ICDH and FAS) as well as mRNA levels of 6PGD, G6PD, FAS, PPARγ and SREBP-1 genes, but up-regulated activity and mRNA level of CPT-1 and PPARα. Using primary hepatocytes, rt-hLEP incubation also reduced intracellular TG content, mRNA levels of G6PD and PPARγ genes, but enhanced mRNA levels of PPARα, CPT-1 and SREBP-1. Leptin-induced effects could partially be reversed by specific inhibitors AG490, suggesting that JAK-STAT signaling pathways played important roles in the process of leptin-induced changes in lipid metabolism. Wortmannin significantly suppressed the decrease of TG content induced by leptin, reflecting that IRS-PI3K was involved in the leptin-mediate changes as well. To our knowledge, the present study provides, for the first time, evidence that rt-hLEP can increase lipolysis and reduce lipogenesis at the both enzymatic and molecular levels in fish with the combination of in vivo with in vitro studies, which serves to increase our understanding into the roles and mechanisms of leptin regulating lipid metabolism in fish. Copyright © 2015 Elsevier Inc. All rights reserved.

Rapid magnitude estimation from time-dependent displacement amplitude measured with seismogeodetic instrumentation

NASA Astrophysics Data System (ADS)

Goldberg, D.; Bock, Y.; Melgar, D.

2017-12-01

Earthquake magnitude is a concise metric that illuminates the destructive potential of a seismic event. Rapid determination of earthquake magnitude is currently the main prerequisite for dissemination of a tsunami early warning, thus timely and automated calculation is of high importance. Seismic instrumentation experiences well-documented complications at long periods, making the accurate measurement of ground displacement in the near field unreliable. As a result, the relation between ground motion measured with seismic instrumentation and magnitude saturates, causing underestimation of the size of very large events. In the case of tsunamigenic earthquakes, magnitude underestimation in turn leads to a flawed tsunami inundation assessment, which limits the effectiveness of an early warning, in particular for local tsunamis. Global Navigation Satellite System (GNSS) instrumentation measures the displacement field directly, leading to more accurate magnitude estimates with near-field data. Unlike seismic-only instrumentation, near-field GNSS has been shown to provide an accurate magnitude estimate using the peak ground displacement (PGD) after just 2 minutes [Melgar et al., 2015]. However, GNSS alone is too noisy to detect the first seismic wave arrivals (P-waves), thus it cannot be as timely as a seismic system on its own. Using collocated seismic and geodetic instrumentation, we refine magnitude scaling relations by incorporating a large dataset of earthquakes in Japan. We demonstrate that consideration of the time-dependence of displacement amplitude with respect to P-wave arrival time reduces the time to convergence of the magnitude estimate. We present findings on the growth of events of large magnitude, and demonstrate time-dependent scaling relations that adapt to the amount of recorded data, starting with the P-wave arrival and continuing through PGD. We illustrate real-time, automated implementation of this method, and consider network improvements to advance rapid characterization of large events. Improvement of initial magnitude estimates through integration of geodetic and seismogeodetic observations is a top priority of an ongoing collaboration with NASA and NOAA's National and Pacific Tsunami Warning Centers (NOAA/NASA GNSS Tsunami Team).

[G6PD deficiency among children under 7 years old from Yunnan with unique ethnic minority origin].

PubMed

Yao, Li-qin; Zou, Tuan-biao; Wang, Xing-tian; Quan, Xing; Chen, Qian; Yang, Fa-bin; Hu, Li-sha; Fan, Li-mei; Wang, Min; Feng, Xi-yun; Liu, Jin-tao; Zhao, Zhong-ming

2013-04-01

To investigate the epidemiological status of glucose-6-phosphate dehydrogenase (G6PD) deficiency among children from Yunnan with unique ethnic origins. DNA samples from 11759 children were tested with fluorescent spot test, G6PD/6PGD quantitative ratio assay and hemoglobin electrophoresis. The detection rate of G6PD deficiency was 2.5%, for which boys were significantly greater than girls (3.5% vs. 1.4%, P<0.05). Significant differences were also detected among children from different ethnic groups and different regions. For ethnic Han Chinese, the detection rate was 0.7%, which was lower than the majority of ethnic minorities. By regression analysis, altitude of residence and family history both have significant influence on the calculated rate. Occurrence of G6PD deficiency seems to be influenced by gender. It also varies substantially between different ethnic groups as well as regions, e.g., more common in south. It also showed a declining trend after years of diagnosis and intervention. This survey may provide a valuable basis for counseling of G6PD deficiency in Yunnan.

Biochemical effect of chocolate colouring and flavouring like substances on thyroid function and protein biosynthesis.

PubMed

el-Saadany, S S

1991-01-01

Synthetic chocolate colourant, flavourant and the mixture of both were administered to healthy adult male albino rats to evaluate their effect on the nucleic acids metabolism, i.e. deoxyribonucleic and ribonucleic acids (DNA and RNA), total serum protein, thyroid hormones (T4 and T3) and nuclease enzymes, i.e. cytoplasmic- and mitochondrial deoxyribonuclease and ribonuclease (DNase and RNase) in brain, liver, and kidneys. Also, the activity of the fundamental enzymes of the oxidative pentose phosphate pathway, i.e. cytoplasmic and mitochondrial glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase (G-6-PD and 6-PGD), as well as total lipids and cholesterol contents in the same organs were studied. Ingestion of the studied food additives significantly increased serum protein, RNA and T4 hormone, while, DNA and T3 hormone were insignificantly elevated. In connection with this, the hydrolytic enzymes of nucleic acids (DNase and RNase activities) were stimulated by all studied food additives and in all mentioned organs. The activity of G-6-PD and 6-PGD in both cytoplasmic and mitochondrial fractions of all studied organs were increased. The highest increase was noticed in rats fed on diets supplemented with the mixture of both colourant and flavourant followed by colourant then flavourant, respectively.

Regional assignment of seven genes on chromosome 1 of man by use of man-Chinese hamster somatic cell hybrids. II. Results obtained after induction of breaks in chromosome 1 by X-irradiation.

PubMed

Burgerhout, W G; Smit, S L; Jongsma, A P

1977-01-01

The position of genes coding for PGD, PPH1, UGPP, GuK1, PGM1, Pep-C, and FH on human chromosome 1 was investigated by analysis of karyotype and enzyme phenotypes in man-Chinese hamster somatic cell hybrids carrying aberrations involving chromosome 1. Suitable hybrid cell lines were obtained by X-irradiation of hybrid cells carrying an intact chromosome 1 and by fusion of human cells from a clonal population carrying a translocation involving chromosome 1 with Chinese hamster cells. The latter human cell population had been isolated following X-irradiation of primary Lesch-Nyhan fibroblasts. In addition, products of de novo chromosome breakage in the investigated hybrid lines were utilized. By integrating the results of these analyses with earlier findings in our laboratory, the following positions of genes are deduced: PGD and PPH1 in 1p36 leads to 1p34; PGM1 in 1p32; UGPP in 1q21 leads to 1q23; GuK1 in 1q31 leads to 1q42; Pep-C in 1q42; and FH in 1qter leads to 1q42.

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

PubMed Central

Lama, Vibha N.; Belperio, John A.; Christie, Jason D.; El-Chemaly, Souheil; Fishbein, Michael C.; Gelman, Andrew E.; Hancock, Wayne W.; Keshavjee, Shaf; Kreisel, Daniel; Looney, Mark R.; McDyer, John F.; Shilling, Rebecca A.; Panoskaltsis-Mortari, Angela; Wilkes, David S.; Eu, Jerry P.; Nicolls, Mark R.

2017-01-01

Lung transplantation, a cure for a number of end-stage lung diseases, continues to have the worst long-term outcomes when compared with other solid organ transplants. Preclinical modeling of the most common and serious lung transplantation complications are essential to better understand and mitigate the pathophysiological processes that lead to these complications. Various animal and in vitro models of lung transplant complications now exist and each of these models has unique strengths. However, significant issues, such as the required technical expertise as well as the robustness and clinical usefulness of these models, remain to be overcome or clarified. The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in March 2016 to review the state of preclinical science addressing the three most important complications of lung transplantation: primary graft dysfunction (PGD), acute rejection (AR), and chronic lung allograft dysfunction (CLAD). In addition, the participants of the workshop were tasked to make consensus recommendations on the best use of these complimentary models to close our knowledge gaps in PGD, AR, and CLAD. Their reviews and recommendations are summarized in this report. Furthermore, the participants outlined opportunities to collaborate and directions to accelerate research using these preclinical models. PMID:28469087

A monoclonal antibody specific for Δ12-prostaglandin J2 and its utilization in the immunological assay in cell culture system of adipocytes.

PubMed

Syeda, Pinky Karim; Hossain, Mohammad Salim; Chowdhury, Abu Asad; Rahman, Mohammad Sharifur; Khan, Ferdous; Nishimura, Kohji; Jisaka, Mitsuo; Nagaya, Tsutomu; Shono, Fumiaki; Yokota, Kazushige

2012-10-01

Prostaglandin (PG) D(2) can be produced in adipocytes and dehydrated to PGs of J(2) series, including Δ(12)-PGJ(2) and 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)), which serve as pro-adipogenic prostanoids through the activation of peroxisome proliferator-activated receptor γ. To accomplish the quantification of Δ(12)-PGJ(2) in the cell culture system of adipocytes, the present study aimed to develop a sensitive and specific immunological assay for Δ(12)-PGJ(2). Here, we established a cloned hybridoma cell line secreting a monoclonal antibody specifically recognizing Δ(12)-PGJ(2) and utilized for the development of its solid-phase enzyme-linked immunosorbent assay (ELISA). The immobilized antigen using a conjugate of Δ(12)-PGJ(2) and γ-globulin was competitively allowed to react with the monoclonal antibody in the presence of free Δ(12)-PGJ(2). The assay provided a sensitive calibration curve for Δ(12)-PGJ(2), allowing us to determine a range from 0.16 pg to 0.99 ng with a value of 13 pg at 50% displacement in one assay. The monoclonal antibody showed almost no cross-reactivity with other related prostanoids since PGJ(2) and 15d-PGJ(2) were only recognized with much lower values of 0.5% and 0.2%, respectively. The accuracy for determining Δ(12)-PGJ(2) in the culture medium of adipocytes was confirmed by measurement after the culture medium was fortified with known amounts of authentic Δ(12)-PGJ(2) in a range from 10 to 200 pg/mL. The application of our ELISA revealed that the formation of Δ(12)-PGJ(2) became more pronounced after several hours of incubation of PGD(2) at 37°C in fresh maturation medium of cultured adipocytes. Furthermore, we provide evidence for the increased ability of cultured adipocytes to synthesize endogenous Δ(12)-PGJ(2) during the progression of adipogenesis. These results indicate the reliability and usefulness of our solid-phase ELISA for stable Δ(12)-PGJ(2), reflecting the biosynthesis of unstable PGD(2) in the culture system of adipocytes.

Subgroup-Elimination Transcriptomics Identifies Signaling Proteins that Define Subclasses of TRPV1-Positive Neurons and a Novel Paracrine Circuit

PubMed Central

Isensee, Jörg; Wenzel, Carsten; Buschow, Rene; Weissmann, Robert; Kuss, Andreas W.; Hucho, Tim

2014-01-01

Normal and painful stimuli are detected by specialized subgroups of peripheral sensory neurons. The understanding of the functional differences of each neuronal subgroup would be strongly enhanced by knowledge of the respective subgroup transcriptome. The separation of the subgroup of interest, however, has proven challenging as they can hardly be enriched. Instead of enriching, we now rapidly eliminated the subgroup of neurons expressing the heat-gated cation channel TRPV1 from dissociated rat sensory ganglia. Elimination was accomplished by brief treatment with TRPV1 agonists followed by the removal of compromised TRPV1(+) neurons using density centrifugation. By differential microarray and sequencing (RNA-Seq) based expression profiling we compared the transcriptome of all cells within sensory ganglia versus the same cells lacking TRPV1 expressing neurons, which revealed 240 differentially expressed genes (adj. p<0.05, fold-change>1.5). Corroborating the specificity of the approach, many of these genes have been reported to be involved in noxious heat or pain sensitization. Beyond the expected enrichment of ion channels, we found the TRPV1 transcriptome to be enriched for GPCRs and other signaling proteins involved in adenosine, calcium, and phosphatidylinositol signaling. Quantitative population analysis using a recent High Content Screening (HCS) microscopy approach identified substantial heterogeneity of expressed target proteins even within TRPV1-positive neurons. Signaling components defined distinct further subgroups within the population of TRPV1-positive neurons. Analysis of one such signaling system showed that the pain sensitizing prostaglandin PGD2 activates DP1 receptors expressed predominantly on TRPV1(+) neurons. In contrast, we found the PGD2 producing prostaglandin D synthase to be expressed exclusively in myelinated large-diameter neurons lacking TRPV1, which suggests a novel paracrine neuron-neuron communication. Thus, subgroup analysis based on the elimination rather than enrichment of the subgroup of interest revealed proteins that define subclasses of TRPV1-positive neurons and suggests a novel paracrine circuit. PMID:25551770

Access to medical-assisted reproduction and pgd in Italian law: a deadly blow to an illiberal statute? commentary to the European Court on Human Rights's decision Costa and Pavan v Italy (ECtHR, 28 August 2012, App. 54270/2010).

PubMed

Biondi, Stefano

2013-01-01

This article provides an account of the European Court on Human Rights' Second Section decision in the case Costa and Pavan v Italy. The judgment found that the Italian Statute on Assisted Reproduction (Law 40/2004), and particularly its prohibition to use in vitro fertilisation and pre-implantation genetic diagnosis (PGD) to prevent the birth of children affected by genetically transmissible conditions, breached Article 8 of the European Convention on Human Rights (ECHR). In fact, the statute in question permits only infertile people to access medically assisted reproduction techniques and forbids PGD and embryo selection. The Court regarded that the rationale of these prohibitions-identified by the Italian Government with the need to prevent eugenic practices as well as to protect the health of the unborn and of the woman-was at odds with the fact that Italian law allows pre-natal screening and therapeutic abortions in case foetal abnormalities are diagnosed. In order to clarify the decision's significance, the paper goes on to analyse the rationale of Law 40/2004 in the Italian legal and political context. Emphasis is placed on the fact that this statute is extremely controversial at domestic level, because many of its provisions-including those considered by the Strasbourg Court-are inherently contradictory and contrast with the settled constitutional principles on abortion, as many domestic authorities highlighted. In this context, should the commented decision be confirmed by the Grand Chamber, it may provide a basis to bring consistency back to the Italian regulation of assisted reproduction. Finally, the paper considers the appeal lodged by the Italian Government to the Grand Chamber, and in particular the contention that the European Court had failed to respect Italy's margin of appreciation. In this regard, it is argued that, under Law 40/2004, individuals face illogical and discriminatory restrictions to their right to private and family life and that therefore, even if an outright violation of Article 8 ECHR could not be found, there appears to be at least a breach of Article 8 in conjunction with Article 14 ECHR.

Reproductive Decision-Making in MMR Mutation Carriers After Results Disclosure: Impact of Psychological Status in Childbearing Options.

PubMed

Duffour, Jacqueline; Combes, Audrey; Crapez, Evelyne; Boissière-Michot, Florence; Bibeau, Frédéric; Senesse, Pierre; Ychou, Marc; Courraud, Julie; de Forges, Hélène; Roca, Lise

2016-06-01

Reproductive techniques such as prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD), although debated, are legally forbidden in France in case of Lynch syndrome. The preference of mutation carriers about their reproductive options is not systematically considered in France. We aimed to prospectively assess the reproductive preferences of mismatch repair mutation carriers consulting in our institution (2003-2010, n = 100). We also considered the short- and long-term post-disclosure psychological impact using the Impact of Events Scale-Revised questionnaire to measure the prevalence of posttraumatic stress disorder (PTSD) in those patients. Complete data were obtained for 34 respondents (17 males, 17 females, median age of 33.5 years [22-59]). Seventeen respondents (57 %) preferred spontaneous natural conception versus 28 % and 35 % choosing PND and PGD, respectively. At results disclosure, respondents mainly explained their distress by fear of premature death (43 %) and transmitting mutated genes (42 %). One year later, this last fear remained predominant in 55 % of subjects. None of the main socio-demographical, psychological or medical variables (including fear of transmitting mutations) was significantly associated with the reproductive preferences. Results disclosure had a real and time-decreasing psychological impact on mutation carriers. Reproductive techniques, expected to decrease the hereditary risk, were not significantly preferred to natural conception.

Preimplantation genetic diagnosis for gender selection in the United States

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colls, P.; Silver, L.; Olivera, G.

Preimplantation genetic diagnosis (PGD) of gender selection for non medical reasons has been considered an unethical procedure by several authors and agencies in the Western society on the basis of disrupting the sex ratio, being discriminatory againsts women and disposal of normal embryos of the non desired gender. In this study, the analysis of a large series of PGD procedures for gender selection from a wide geographical area in the United States, shows that in general there is no deviation in preference towards any specific gender except for a preference of males in some ethnic populations of Chinese, Indian andmore » Middle Eastern origin that represent a small percentage of the US population. In cases where only normal embryos of the non-desired gender are available, 45.5% of the couples elect to cancel the transfer, while 54.5% of them are open to have transferred embryos of the non-desired gender, this fact being strongly linked to cultural and ethnical background of the parents. In addition this study adds some evidence to the proposition that in couples with previous children of a given gender there is no biological predisposition towards producing embryos of that same gender. Based on these facts, it seems that objections to gender selection formulated by ethics committees and scientific societies are not well-founded.« less

Control of cell cycle by metabolites of prostaglandin D2 through a non-cAMP mediated mechanism

NASA Technical Reports Server (NTRS)

Hughes-Fulford, M.; Fukushima, M.

1993-01-01

The dehydration products of PGD2, 9-deoxy-9 prostaglandin D2(PGJ2), 9-deoxy-delta 9, delta 12, delta 13 dehydroprostaglandin D2 (delta 12 PGJ2), and PGA2 all contain an unsaturated cyclopentenone structure which is characteristic of prostaglandins which effectively inhibit cell growth. It has been suggested that the action of the inhibitory prostaglandins may be through a cAMP mechanism. In this study, we use S49 wild type (WT) and adenylate cyclase variant (cyc-) cells to show that PGD2 and PGJ2 are not acting via a cyclic AMP mechanism. First, the increase in cyclic AMP in wild type S-49 cells is not proportional to its effects on DNA synthesis. More importantly, when S-49 cyc- cells were exposed to PGJ2, the adenylate cyclase (cyc-) mutant had decreased DNA synthesis with no change in its nominal cAMP content. Short-term (2 hours or less) exposure of the cyc- cells to prostaglandin J2 caused an inhibition of DNA synthesis. PGJ2 caused cytolysis at high concentrations. Long-term exposure (>14 hrs) of the cells to PGJ2, delta 12PGJ2 or delta 12, delta 14PGJ2 caused a cell cycle arrest in G1 demonstrating a cell cycle specific mechanism of action for growth inhibition by naturally occurring biological products independent of cAMP.

Changing direction: the struggle of regulating assisted reproductive technology in Austria.

PubMed

Griessler, Erich; Hager, Mariella

2016-12-01

From 1992 until 2015, Austria had a very restrictive Reproductive Medicine Law (FMedG, 1992) that prohibited a number of treatments such as egg donation, preimplantation genetic diagnosis (PGD), heterologous sperm donation for IVF/intracytoplasmic sperm injection (ICSI) as well as general access to assisted reproductive technology for same-sex couples. As one consequence of this rather prohibitive law, Austrian physicians active in the area of assisted reproductive technology co-operated with, or had daughter institutes in, countries with less restrictive legislation such as the Czech Republic and Slovakia, which are only a few hours' drive away. For a long time, liberalisation of the Reproductive Medicine Law was blocked by the fierce and seemingly unresolvable struggle between the restrictive conservative party (ÖVP) and the permissive social democrats' party (SPÖ). In 2014 the impasse, which had lasted for decades, was finally resolved in favour of a more liberal Reproductive Medicine Law that permits egg donation, PGD in some cases and heterologous sperm donation for IVF/ICSI and lesbian couples. Assisted reproductive technology treatments for single women and surrogate motherhood remain prohibited. The new Reproductive Medicine Law was heavily opposed by the Catholic Church, by some conservatives and by disability associations. By applying the concept of political culture, this paper explains why a liberalisation of the Reproductive Medicine Law was blocked for decades, and how the sudden policy change came about.

Inhibition of histamine and eicosanoid release from dispersed human lung cells in vitro by quinotolast.

PubMed

Okayama, Y; Hiroi, J; Lau, L C; Church, M K

1995-12-01

We have examined the effects of a new anti-allergic drug, quinotolast [sodium 5-(4-oxo-1-phenoxy-4H-quinolizine-3-carboxamido) yetrazolate monohydrate], in inhibiting the release of histamine and the generation of leukotriene (LT) C4 and prostaglandin (PG) D2 from dispersed human lung cells and compared this with those of its active metabolite in the rat, hydroxy quinotolast, and reference drugs, tranilast and sodium cromoglycate (SCG). Quinotolast in the concentration range of 1-100 micrograms/ml inhibited histamine and LTC4 release in a concentration-dependent manner. The inhibitory effect of quinotolast on histamine release from dispersed lung cells was largely independent of the preincubation period, no tachyphylaxis being observed. Hydroxy quinotolast and tranilast showed a weak inhibition of histamine release only when the drugs were added to the cells simultaneously with anti-IgE challenge. Quinotolast, 100 micrograms/ml, and SCG, 1 mM, significantly inhibited PGD2 and LTC4 release. Quinotolast inhibited PGD2 release by 100% and LTC4 release by 54%, whereas SCG inhibited PDG2 release by 33% and LTC4 release by 100%. No cross-tachyphylaxis between quinotolast and SCG was observed. The results demonstrated that quinotolast showed a significant inhibition of inflammatory mediators from human dispersed lung cells, suggesting that quinotolast is a good candidate for a clinical anti-allergic drug.

15-deoxy prostaglandin J2, the nonenzymatic metabolite of prostaglandin D2, induces apoptosis in keratinocytes of human hair follicles: a possible explanation for prostaglandin D2-mediated inhibition of hair growth.

PubMed

Joo, Hyun Woo; Kang, Yoo Ri; Kwack, Mi Hee; Sung, Young Kwan

2016-07-01

Recent studies have shown that prostaglandin D2 (PGD2) and its nonenzymatic metabolite, 15-deoxy-Δ(12,14)-prostaglandin J2 (15-dPGJ2), inhibit in vitro growth of explanted human hair follicles and inhibit hair growth in mice through the GPR44 (DP2). However, the underlying mechanism is still unclear. In this study, we first investigated the expression of DP2 in human hair follicles and in cultured follicular cells. We found that DP2 is strongly expressed in the outer root sheath (ORS) cells and weakly expressed in the dermal papilla (DP) cells. We observed slight growth stimulation when ORS and DP cells were treated with PGD2. We also observed slight growth stimulation when DP and ORS cells were treated with low concentrations (0.5 and 1 μM) of 15-dPGJ2. However, 5 μM 15-dPGJ2 inhibited the viability and caused apoptosis of both cell types. Exposure of cultured human hair follicles to 15-dPGJ2 resulted in significant apoptosis in follicular keratinocytes. Altogether, our data provide an evidence that 15-dPGJ2 promotes apoptosis in follicular keratinocytes and provide rationale for developing remedies for the prevention and treatment of hair loss based on DP2 antagonism.

Synergistic Antiproliferative Effects of Combined γ-Tocotrienol and PPARγ Antagonist Treatment Are Mediated through PPARγ-Independent Mechanisms in Breast Cancer Cells

PubMed Central

Sylvester, Paul W.

2014-01-01

Previous findings showed that the anticancer effects of combined γ-tocotrienol and peroxisome proliferator activated receptor γ (PPARγ) antagonist treatment caused a large reduction in PPARγ expression. However, other studies suggest that the antiproliferative effects of γ-tocotrienol and/or PPARγ antagonists are mediated, at least in part, through PPARγ-independent mechanism(s). Studies were conducted to characterize the role of PPARγ in mediating the effects of combined treatment of γ-tocotrienol with PPARγ agonists or antagonists on the growth of PPARγ negative +SA mammary cells and PPARγ-positive and PPARγ-silenced MCF-7 and MDA-MB-231 breast cancer cells. Combined treatment of γ-tocotrienol with PPARγ antagonist decreased, while combined treatment of γ-tocotrienol with PPARγ agonist increased, growth of all cancer cells. However, treatment with high doses of 15d-PGJ2, an endogenous natural ligand for PPARγ, had no effect on cancer cell growth. Western blot and qRT-PCR studies showed that the growth inhibitory effects of combined γ-tocotrienol and PPARγ antagonist treatment decreased cyclooxygenase (COX-2), prostaglandin synthase (PGDS), and prostaglandin D2 (PGD2) synthesis. In conclusion, the anticancer effects of combined γ-tocotrienol and PPARγ antagonists treatment in PPARγ negative/silenced breast cancer cells are mediated through PPARγ-independent mechanisms that are associated with a downregulation in COX-2, PGDS, and PGD2 synthesis. PMID:24729783

Deletion of cytosolic gating ring decreases gate and voltage sensor coupling in BK channels.

PubMed

Zhang, Guohui; Geng, Yanyan; Jin, Yakang; Shi, Jingyi; McFarland, Kelli; Magleby, Karl L; Salkoff, Lawrence; Cui, Jianmin

2017-03-06

Large conductance Ca 2+ -activated K + channels (BK channels) gate open in response to both membrane voltage and intracellular Ca 2+ The channel is formed by a central pore-gate domain (PGD), which spans the membrane, plus transmembrane voltage sensors and a cytoplasmic gating ring that acts as a Ca 2+ sensor. How these voltage and Ca 2+ sensors influence the common activation gate, and interact with each other, is unclear. A previous study showed that a BK channel core lacking the entire cytoplasmic gating ring (Core-MT) was devoid of Ca 2+ activation but retained voltage sensitivity (Budelli et al. 2013. Proc. Natl. Acad. Sci. USA http://dx.doi.org/10.1073/pnas.1313433110). In this study, we measure voltage sensor activation and pore opening in this Core-MT channel over a wide range of voltages. We record gating currents and find that voltage sensor activation in this truncated channel is similar to WT but that the coupling between voltage sensor activation and gating of the pore is reduced. These results suggest that the gating ring, in addition to being the Ca 2+ sensor, enhances the effective coupling between voltage sensors and the PGD. We also find that removal of the gating ring alters modulation of the channels by the BK channel's β1 and β2 subunits. © 2017 Zhang et al.

Deletion of cytosolic gating ring decreases gate and voltage sensor coupling in BK channels

PubMed Central

Zhang, Guohui; Shi, Jingyi; McFarland, Kelli; Magleby, Karl L.; Salkoff, Lawrence

2017-01-01

Large conductance Ca2+-activated K+ channels (BK channels) gate open in response to both membrane voltage and intracellular Ca2+. The channel is formed by a central pore-gate domain (PGD), which spans the membrane, plus transmembrane voltage sensors and a cytoplasmic gating ring that acts as a Ca2+ sensor. How these voltage and Ca2+ sensors influence the common activation gate, and interact with each other, is unclear. A previous study showed that a BK channel core lacking the entire cytoplasmic gating ring (Core-MT) was devoid of Ca2+ activation but retained voltage sensitivity (Budelli et al. 2013. Proc. Natl. Acad. Sci. USA. http://dx.doi.org/10.1073/pnas.1313433110). In this study, we measure voltage sensor activation and pore opening in this Core-MT channel over a wide range of voltages. We record gating currents and find that voltage sensor activation in this truncated channel is similar to WT but that the coupling between voltage sensor activation and gating of the pore is reduced. These results suggest that the gating ring, in addition to being the Ca2+ sensor, enhances the effective coupling between voltage sensors and the PGD. We also find that removal of the gating ring alters modulation of the channels by the BK channel’s β1 and β2 subunits. PMID:28196879

SP-LL-37, human antimicrobial peptide, enhances disease resistance in transgenic rice.

PubMed

Lee, In Hye; Jung, Yu-Jin; Cho, Yong Gu; Nou, Ill Sup; Huq, Md Amdadul; Nogoy, Franz Marielle; Kang, Kwon-Kyoo

2017-01-01

Human LL-37 is a multifunctional antimicrobial peptide of cathelicidin family. It has been shown in recent studies that it can serve as a host's defense against influenza A virus. We now demonstrate in this study how signal peptide LL-37 (SP-LL-37) can be used in rice resistance against bacterial leaf blight and blast. We synthesized LL-37 peptide and subcloned in a recombinant pPZP vector with pGD1 as promoter. SP-LL-37 was introduced into rice plants by Agrobacterium mediated transformation. Stable expression of SP-LL-37 in transgenic rice plants was confirmed by RT-PCR and ELISA analyses. Subcellular localization of SP-LL-37-GFP fusion protein showed evidently in intercellular space. Our data on testing for resistance to bacterial leaf blight and blast revealed that the transgenic lines are highly resistant compared to its wildtype. Our results suggest that LL-37 can be further explored to improve wide-spectrum resistance to biotic stress in rice.

Muramyl Peptide-Enhanced Sleep: Pharmacological Optimization of Performance

DTIC Science & Technology

1991-06-01

assessed. Exieriment C: Effects of PGE2, PGD2, IFNa, VIP, DSIP, 5- HT , hydrocorti- sone, and MDP, on HLADR expression in HTB16 cells . HTB16 cells were...stimulatory effect of IFNy on MHCII expression in astrocytes, or the cell line we used lacks receptors for 5- HT . It is well known that glucocorticoids... Effects of ICV injection of CCK on sleep-wake activity and brain temperature 92 Fig. 7: Growth curves of glioblastoma cell lines HTBl4, HTE16, and H:0i

Review of studies of polymorphic blood systems in the Aymara indigenous population from Bolivia, Peru, and Chile.

PubMed

Dittmar, M

1995-12-01

A review was made of all studies available from the literature referring to polymorphic blood systems of South American Aymara Indians. 33 original papers published up to 1990 covering a period of 45 years were summarized. Aymara samples were considered from a total of 55 localities in Bolivia, Peru, and Chile. Gene frequencies were tabulated for 21 polymorphic genetic systems comprising blood groups (AB0, MNSs, P, Rh, Lu, K, Le, Fy, Jk, Di), erythrocyte enzyme groups (AcP, 6PGD, PGM1, AK, ADA, EsD), and plasma protein groups (Hp, Tf, Gc, Gm, Km). Weighted average and range over all Aymara samples were computed for each blood system and compared with corresponding mean value and range in South Amerindians in general. Gene frequency distribution in the Aymara population shows ranges of different orders of magnitude in the 21 blood systems, some of them varying widely. Nevertheless the average gene frequencies for the Aymara are well within the range of values reported for South American Indian populations. The assessment of blood systems in the Aymara revealed that information concerning the Lutheran and HLA systems is scarce or nil up to now. Further studies are needed, especially from Peru on erythrocyte enzyme systems, in order to obtain a more complete picture on the variation of blood system polymorphisms in the Aymara population.

Donor age and early graft failure after lung transplantation: a cohort study.

PubMed

Baldwin, M R; Peterson, E R; Easthausen, I; Quintanilla, I; Colago, E; Sonett, J R; D'Ovidio, F; Costa, J; Diamond, J M; Christie, J D; Arcasoy, S M; Lederer, D J

2013-10-01

Lungs from older adult organ donors are often unused because of concerns for increased mortality. We examined associations between donor age and transplant outcomes among 8860 adult lung transplant recipients using Organ Procurement and Transplantation Network and Lung Transplant Outcomes Group data. We used stratified Cox proportional hazard models and generalized linear mixed models to examine associations between donor age and both 1-year graft failure and primary graft dysfunction (PGD). The rate of 1-year graft failure was similar among recipients of lungs from donors age 18-64 years, but severely ill recipients (Lung Allocation Score [LAS] >47.7 or use of mechanical ventilation) of lungs from donors age 56-64 years had increased rates of 1-year graft failure (p-values for interaction = 0.04 and 0.02, respectively). Recipients of lungs from donors <18 and ≥65 years had increased rates of 1-year graft failure (adjusted hazard ratio [HR] 1.23, 95% CI 1.01-1.50 and adjusted HR 2.15, 95% CI 1.47-3.15, respectively). Donor age was not associated with the risk of PGD. In summary, the use of lungs from donors age 56 to 64 years may be safe for adult candidates without a high LAS and the use of lungs from pediatric donors is associated with a small increase in early graft failure. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

A Multicenter Study on Long-Term Outcomes After Lung Transplantation Comparing Donation After Circulatory Death and Donation After Brain Death.

PubMed

van Suylen, V; Luijk, B; Hoek, R A S; van de Graaf, E A; Verschuuren, E A; Van De Wauwer, C; Bekkers, J A; Meijer, R C A; van der Bij, W; Erasmus, M E

2017-10-01

The implementation of donation after circulatory death category 3 (DCD3) was one of the attempts to reduce the gap between supply and demand of donor lungs. In the Netherlands, the total number of potential lung donors was greatly increased by the availability of DCD3 lungs in addition to the initial standard use of donation after brain death (DBD) lungs. From the three lung transplant centers in the Netherlands, 130 DCD3 recipients were one-to-one nearest neighbor propensity score matched with 130 DBD recipients. The primary end points were primary graft dysfunction (PGD), posttransplant lung function, freedom from chronic lung allograft dysfunction (CLAD), and overall survival. PGD did not differ between the groups. Posttransplant lung function was comparable after bilateral lung transplantation, but seemed worse after DCD3 single lung transplantation. The incidence of CLAD (p = 0.17) nor the freedom from CLAD (p = 0.36) nor the overall survival (p = 0.40) were significantly different between both groups. The presented multicenter results are derived from a national context where one third of the lung transplantations are performed with DCD3 lungs. We conclude that the long-term outcome after lung transplantation with DCD3 donors is similar to that of DBD donors and that DCD3 donation can substantially enlarge the donor pool. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Coupling of multi-walled carbon nanotubes/polydimethylsiloxane coated stir bar sorptive extraction with pulse glow discharge-ion mobility spectrometry for analysis of triazine herbicides in water and soil samples.

PubMed

Zou, Nan; Yuan, Chunhao; Liu, Shaowen; Han, Yongtao; Li, Yanjie; Zhang, Jialei; Xu, Xiang; Li, Xuesheng; Pan, Canping

2016-07-29

An analytical method based on stir bar sorptive extraction (SBSE) coupled with pulse glow discharge-ion mobility spectrometry (PGD-IMS) was developed for analysis of three triazine pesticide residues in water and soil samples. An injection port with sealing device and stir bars hold device were designed and constructed to directly position the SBSE fiber including the extracted samples into the heating device, making desorption and detection of analytes proceeded simultaneously. The extraction conditions such as SBSE solid phase material, extraction time, extraction temperature, pH value and salt concentration were optimized. Mixture of MWCNTs-COOH and PDMS were shown to be effective in enriching the triazines. The LODs and LOQs of three triazines were found to be 0.006-0.015μgkg(-1) and 0.02-0.05μgkg(-1), and the linear range was 0.05-10μgL(-1) with determination coefficients from 0.9987 to 0.9993. The SBSE-PGD-IMS method was environmentally friendly without organic solvent consumption in the entire experimental procedures, and it was demonstrated to be a commendable rapid analysis technique for analysis of triazine pesticide residues in environmental samples on site. The proposed method was applied for the analysis of real ground water, surface water and soil samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Sex selection for non-medical indications: a survey of current pre-implantation genetic screening practices among U.S. ART clinics.

PubMed

Capelouto, Sarah M; Archer, Sydney R; Morris, Jerrine R; Kawwass, Jennifer F; Hipp, Heather S

2018-03-01

This study aimed to determine the current percentage of United States (U.S.) assisted reproductive technology (ART) clinics offering sex selection via pre-implantation genetic screening (PGS) for non-medical purposes. The authors conducted website review and telephone interview survey of 493 U.S. ART clinics performing in vitro fertilization (IVF) in 2017. Main outcome measures were pre-implantation genetic screening (PGS)/pre-implantation genetic diagnosis (PGD) practices and non-medical sex selection practices including family balancing. Of the 493 ART clinics in the USA, 482 clinics (97.8%) responded to our telephone interview survey. Among all U.S. ART clinics, 91.9% (n = 449) reported offering PGS and/or PGD. Furthermore, 476 clinics responded to survey questions about sex selection practices. Of those ART clinics, 72.7% (n = 346) reported offering sex selection. More specifically among those clinics offering sex selection, 93.6% (n = 324) reported performing sex selection for family balancing, and 81.2% (n = 281) reported performing for elective purposes (patient preference, regardless of rationale for the request). For couples without infertility, 83.5% (n = 289) of clinics offer sex selection for family balancing and 74.6% (n = 258) for non-specific elective reasons. The majority of U.S. ART clinics offer non-medical sex selection, a percentage that has increased substantially since last reported in 2006.

Erythrocyte membrane-encapsulated celecoxib improves the cognitive decline of Alzheimer's disease by concurrently inducing neurogenesis and reducing apoptosis in APP/PS1 transgenic mice.

PubMed

Guo, Jing-Wen; Guan, Pei-Pei; Ding, Wei-Yan; Wang, Si-Ling; Huang, Xue-Shi; Wang, Zhan-You; Wang, Pu

2017-11-01

Alzheimer's disease (AD) is characterized by the loss of neurogenesis and excessive induction of apoptosis. The induction of neurogenesis and inhibition of apoptosis may be a promising therapeutic approach to combating the disease. Celecoxib (CB), a cyclooxygenase-2 specific inhibitor, could offer neuroprotection. Specifically, the CB-encapsulated erythrocyte membranes (CB-RBCMs) sustained the release of CB over a period of 72 h in vitro and exhibited high brain biodistribution efficiency following intranasal administration, which resulted in the clearance of aggregated β-amyloid proteins (Aβ) in neurons. The high accumulation of the CB-RBCMs in neurons resulted in a decrease in the neurotoxicity of CB and an increase in the migratory activity of neurons, and alleviated cognitive decline in APP/PS1 transgenic (Tg) mice. Indeed, COX-2 metabolic products including prostaglandin E2 (PGE 2 ) and PGD 2 , PGE 2 induced neurogenesis by enhancing the expression of SOD2 and 14-3-3ζ, and PGD 2 stimulated apoptosis by increasing the expression of BIK and decreasing the expression of ARRB1. To this end, the CB-RBCMs achieved better effects on concurrently increasing neurogenesis and decreasing apoptosis than the phospholipid membrane-encapsulated CB liposomes (CB-PSPD-LPs), which are critical for the development and progression of AD. Therefore, CB-RBCMs provide a rational design to treat AD by promoting the self-repairing capacity of the brain. Copyright © 2017 Elsevier Ltd. All rights reserved.

Health care of pregnant women with diabetes in Spain: Approach using a questionnaire.

PubMed

Rubio, José Antonio; Ontañón, Marta; Perea, Verónica; Megia, Ana

2016-03-01

To ascertain how health care for pregnant women with gestational diabetes (GD) and pregestational diabetes (PGD) is organized, and to estimate the number of Pregnancy and Diabetes Units (PDUs) in Spain in 2013. The Spanish Group of Diabetes and Pregnancy (GEDE) developed and agreed on a questionnaire based on the recommendations of the group. The questionnaire was sent to members of the Spanish Society of Diabetes and the Spanish Society of Endocrinology and Nutrition. Eighty-seven questionnaires were received from 81 hospitals, 4 outpatient specialty centers, and 2 primary healthcare centers, which accounted for 51% of the Spanish population and for 39% of births in 2013. GD was mainly diagnosed based on GEDE recommendations (98%), and less than 50% of women were reevaluated after delivery in primary care. Fourteen (26%) of the 53 centers identified as PDUs corresponded to a minimal model. Continuous subcutaneous insulin infusion (CSII) therapy was not available in 30% of centers, and 13% of hospitals had no preconceptional clinics. No nurse support was available in 20% of centers. Care of women with PGD has a fair coverage with PDU, but significant deficits still exist, for instance, in preconception clinic and CSII. However, organization of care for women with GD appears to be adequate. There are aspects in need of improvement such as integration of diabetes educators and coordination with primary care for postpartum reclassification. Copyright © 2015 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Effect of Medialization Thyroplasty on Glottic Airway Anatomy: Cadaver Model.

PubMed

Shinghal, Tulika; Anderson, Jennifer; Chung, Janet; Hong, Aaron; Bharatha, Aditya

2016-11-01

The purpose of this study was to investigate the change in airway dimensions after medialization thyroplasty (MT) using a cadaveric model. Helical computerized tomography (CT) was performed before and after placement of a silastic block in human larynges to investigate the effect on airway anatomy at the level of the glottis. Tissue density (TD) of the medialized vocal fold (VF) was documented to understand the effect on tissue displacement. This is a cadaveric study. Thirteen human cadaveric larynges underwent fine-cut CT scan before and after MT was performed using carved blocks in two sizes (small block and large block [LB]). Clientstream software was used to measure laryngeal dimensions: intraglottic volume (IGV), cross-sectional area (CSA), posterior-glottic diameter (PGD), VF density (in Hounsfield units [HUs]), and anterior-posterior diameter (APD). Eight sequential axial sections 0.625 mm cuts) at the level of the true VFs were analyzed. There was a significant decrease between the three conditions for IGV (P < 0.0001) and CSA (P < 0.0001). TD of the VF was increased after MT as indicated by HU increase (P = 0.0003). APD was not significantly changed. PGD was significantly different between the no block to LB placement (P = 0.0012). MT significantly changes the IGV and CSA at the level of the glottis. Density in the true VF was significantly increased. These findings have important implications for understanding volumetric effects of MT. Copyright © 2015 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Live births after polar body biopsy and frozen-thawed cleavage stage embryo transfer: case report

PubMed Central

Guimarães, Fernando; Roque, Matheus; Valle, Marcello; Kostolias, Alessandra; de Azevedo, Rodrigo A; Martinhago, Ciro D; Sampaio, Marcos; Geber, Selmo

2016-01-01

Pre-implantation genetic diagnosis (PGD) or screening (PGS) technology, has emerged and developed in the past few years, benefiting couples as it allows the selection and transfer of healthy embryos during IVF treatments. These techniques can be performed in oocytes (polar-body biopsy) or embryos (blastomere or trophectoderm biopsy). In this case report, we describe the first two live births to be published in Brazil after a polar-body (PB) biopsy. In case 1, a 42-year-old was submitted to PB biopsy with PGS due to advanced maternal age and poor ovarian reserve. Five MII oocytes underwent first and second polar body biopsy and four cleavage embryos were cryopreserved. The PGS analysis resulted in two euploid embryos (next generation sequence). A frozen-thawed embryo transfer (FET) was performed after endometrial priming and a healthy baby was delivered after a cesarean section (37 weeks, female, 3390g, 47.5 cm). In case 2, a 40-year old patient with balanced translocation and poor ovarian response was submitted to PB biopsy. Two MII oocytes underwent first and second polar body biopsy and two embryos were cryopreserved in cleavage stage. The analysis resulted in one euploid embryo that was transferred after endometrial priming. A preterm healthy baby (34 weeks, female, 2100g, 40 cm) was delivered via cesarean section. In conclusion, although the blastocyst biopsy is the norm when performing PGS/PGD during IVF treatments, other alternatives (as PB biopsy) should be considered in some specific situations. PMID:28050963

Live births after polar body biopsy and frozen-thawed cleavage stage embryo transfer: case report.

PubMed

Guimarães, Fernando; Roque, Matheus; Valle, Marcello; Kostolias, Alessandra; Azevedo, Rodrigo A de; Martinhago, Ciro D; Sampaio, Marcos; Geber, Selmo

2016-12-01

Pre-implantation genetic diagnosis (PGD) or screening (PGS) technology, has emerged and developed in the past few years, benefiting couples as it allows the selection and transfer of healthy embryos during IVF treatments. These techniques can be performed in oocytes (polar-body biopsy) or embryos (blastomere or trophectoderm biopsy). In this case report, we describe the first two live births to be published in Brazil after a polar-body (PB) biopsy. In case 1, a 42-year-old was submitted to PB biopsy with PGS due to advanced maternal age and poor ovarian reserve. Five MII oocytes underwent first and second polar body biopsy and four cleavage embryos were cryopreserved. The PGS analysis resulted in two euploid embryos (next generation sequence). A frozen-thawed embryo transfer (FET) was performed after endometrial priming and a healthy baby was delivered after a cesarean section (37 weeks, female, 3390g, 47.5 cm). In case 2, a 40-year old patient with balanced translocation and poor ovarian response was submitted to PB biopsy. Two MII oocytes underwent first and second polar body biopsy and two embryos were cryopreserved in cleavage stage. The analysis resulted in one euploid embryo that was transferred after endometrial priming. A preterm healthy baby (34 weeks, female, 2100g, 40 cm) was delivered via cesarean section. In conclusion, although the blastocyst biopsy is the norm when performing PGS/PGD during IVF treatments, other alternatives (as PB biopsy) should be considered in some specific situations.

[Short-term outcomes of lung transplant recipients using organs from brain death donors].

PubMed

He, W X; Jiang, C; Liu, X G; Huang, W; Chen, C; Jiang, L; Yang, B; Wu, K; Chen, Q K; Yang, Y; Yu, Y M; Jiang, G N

2016-12-01

Objective: To assess short-term outcomes after lung transplantation with organs procured following brain death. Methods: Between April 2015 and July 2016, all 17 recipients after lung transplantation using organs from brain death donors (DBD) at Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine were enrolled in this study. All patients were male, aging (60±7) years, including 11 chronic obstructive pulmonary disease, 5 idiopathic pulmonary fibrosis, 1 silicosis. Seventeen donors were 16 males and 1 female, with 10 traumatic brain injury, 5 cerebrovascular accident and 2 sudden cardiac death. Of 17 recipients receiving DBD lung transplant, 16 were single lung transplant. Data were collected including intubation duration of mechanical ventilation, hospital length of stay, incidence of pulmonary infection bronchus anastomosis complications, primary graft dysfunction (PGD), and acute rejection, bronchiolitis obliterans syndrome (BOS) as well as mortality of 90-day after lung transplantation. Results: Median duration of intubation were 2 (2) days ( M ( Q R )) in recipients after lung transplantation. The incidence of pulmonary infection and bronchus anastomosis complications were 15/17 and 5/17, respectively. Median length of stay in hospital were 56 (19) days. The ratio of readmission 1 month after discharge were 10/17. Mortality of 90-day post-transplant were 2/17. The incidence of PGD and BOS were 1/17 and 2/17, respectively. Conclusion: Recipients with DBD lung transplantation have an acceptable survival during short-term follow-up, but with higher incidences of complications related to infection post-transplantation.

Earthquake response of storey building in Jakarta using accelerographs data analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Julius, Admiral Musa, E-mail: admiralmusajulius@yahoo.com; Jakarta Geophysics Observatory, Indonesia Agency of Meteorology Climatology and Geophysics; Sunardi, Bambang, E-mail: b.sunardi@gmail.com

As seismotectonic, the Jakarta city will be greatly affected by the earthquake which originated from the subduction zone of the Sunda Strait and south of Java. Some occurrences of earthquakes in these location are often perceived by the occupants in the upper floors of multi-storey buildings in Jakarta but was not perceived by the occupants on the ground floor. The case shows the difference in ground-motion parameters on each floor height. The analysis of the earthquake data recorded by accelerographs on different floors need to be done to know the differences in ground-motion parameters. Data used in this research ismore » accelerograph data installed on several floors in the main building of Meteorology Climatology and Geophysics Agency with a case study of Kebumen earthquake on January 25{sup th} 2014. Parameters analyzed include the Peak Ground Acceleration (PGA), Peak Ground Displacement (PGD), Peak Spectral Acceleration (PSA), Amplification (Ag), and the Effective Duration of earthquake (t{sub e}). Research stages include accelerographs data acquisition in three (3) different floors, conversion and data partition for each component, conversion to units of acceleration, determination of PGA, PGD, PSA, Ag and t{sub e} as well as data analysis. The study shows the value of PGA on the ground floor, 7{sup th} floor and 15{sup th} floors, respectively are 0.016 g, 0.053 g and 0.116 g. PGD on the ground floor, 7{sup th} floor and 15{sup th} floor respectively are 2.15 cm, 2.98 cm and 4.92 cm. PSA on the ground floor, 7{sup th} floor and 15{sup th} floor respectively are 0.067 g, 0.308 g and 0.836 g. Amplification of the peak acceleration value on the ground floor, 7{sup th} floor and 15{sup th} floor to the surface rock are 4.37, 6.07 and 7.30. Effective duration of the earthquake on the ground floor, 7{sup th} floor and 15{sup th} floor respectively are 222.28 s, 202.28 s and 91.58 s. In general, with increasing floor of the building, the value of the peak ground acceleration, peak ground displacement, peak spectral acceleration and amplification growing, contrary to the value of the effective duration of earthquake decreases. The difference in this parameter is strongly influenced by local soil conditions and building construction.« less

[Is preimplantation diagnosis legal?--on the need for harmonizing legislation].

PubMed

Ratzel, Rudolf

2002-07-01

Whether PGD is already legally permitted in Germany today is a moot point. A guidelines draft of the Germany's Federal General Medical Council, the Bundesärztekammer, on pre-implantation genetic diagnostics that--like the earlier findings of the ethics commission of the German federal state of the Rhineland-Palatinate--assumed that the method is admissible, if certain clearly-defined indications are present and a rigorous testing procedure has been established, has given the discussion a new impetus. The discussion is in full swing, with calls by politicians for the legislator to pass a regulation mounting. Of late, though, constitutional objections have been raised against a positive-law regulation. Such a simple legal move to regulate PGD, it is claimed, would violate the constitutionally-guaranteed right to inviolable human dignity. Critics, however, point out that such an absolute inviolability does not exist. According to them, not only the verdicts by the German Federal Constitutional Court, the Bundesverfassungsgericht, on the reform of section 218 of the German Federal Penal Code (StGB)--the paragraph that specifies the conditions under which an abortion is not punished--that relativize (in terms of the indication model) one claim to existence with respect to another, but also the approval in terms of pharmaceutical and medicine-products law of nidation-blocking agents, serve to show this. If the condition of being a human being were made to coincide with the completion of the genetic code upon the completion of the process of fertilisation, then one tended to forget, the critics noted, that this attendant dignity was not properly "infused with life" unless nidation had been successful. Without nidation everything were fragmentary, the total protection of human dignity according to Article 1 Section 1 of the Federal Republic's Basic Law, Germany's constitution, notwithstanding. During every in vitro fertilisation embryo transfer is conditional upon a variety of factors the presence of which is not noted until after fertilisation has taken place. On the part of the embryos, too, certain conditions have to be met whose presence at the moment of fertilisation is not assured. Thus an embryo with, for instance, defects that can be visually detected will not be transferred. With regard to these facts too the opponents of pre-implantation genetic diagnostics must be challenged to answer the question of why an embryo with visually-detectable defects should undoubtedly be allowed to be discarded, but the act of searching for "internal" defects be banned. Thus the fact remains that the mere acceptance of the loss of created embryos does not make artificial insemination a punishable offense, as long as the motive for the act is to bring about pregnancy. To achieve legal security for the couples and the physicians involved the law on the protection of embryos should be changed. The new regulations should determine under which conditions PGD is permissible. As is already the case for other norms that apply to reproductive medicine, but also for the practice of abortion, these regulations should contain an analogous right of refusal for the professionals involved. The laws relating to the healing professions, to the professional chambers, as well as the regulations of the various German federal states (which together constitute the Federal Republic of Germany) that apply to the professions should be amended accordingly.

Natural Disasters: Planning for Psychological First Aid.

PubMed

Wynn, Stephanie T

Natural disasters leave survivors suffering physically, psychologically, and spiritually. An EF4 tornado on April 27, 2011, in Tuscaloosa, Alabama, known as April's Fury, raised the question of how mental health practitioners (MHPs) might respond to address psychological needs, rather than being exclusively assigned to offer physical support immediately following a disaster. This article proposes planning ahead for MHPs to provide psychological first aid (PFA) in the immediate aftermath of a catastrophe. Combating psychological issues early will hopefully help reduce the development of posttraumatic stress disorder (PTSD) or prolonged grief disorder (PGD) in survivors.

Dynamics and ethics of comprehensive preimplantation genetic testing: a review of the challenges.

PubMed

Hens, Kristien; Dondorp, Wybo; Handyside, Alan H; Harper, Joyce; Newson, Ainsley J; Pennings, Guido; Rehmann-Sutter, Christoph; de Wert, Guido

2013-01-01

Genetic testing of preimplantation embryos has been used for preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). Microarray technology is being introduced in both these contexts, and whole genome sequencing of blastomeres is also expeted to become possible soon. The amount of extra information such tests will yield may prove to be beneficial for embryo selection, will also raise various ethical issues. We present an overview of the developments and an agenda-setting exploration of the ethical issues. The paper is a joint endeavour by the presenters at an explorative 'campus meeting' organized by the European Society of Human Reproduction and Embryology in cooperation with the department of Health, Ethics & Society of the Maastricht University (The Netherlands). The increasing amount and detail of information that new screening techniques such as microarrays and whole genome sequencing offer does not automatically coincide with an increasing understanding of the prospects of an embryo. From a technical point of view, the future of comprehensive embryo testing may go together with developments in preconception carrier screening. From an ethical point of view, the increasing complexity and amount of information yielded by comprehensive testing techniques will lead to challenges to the principle of reproductive autonomy and the right of the child to an open future, and may imply a possible larger responsibility of the clinician towards the welfare of the future child. Combinations of preconception carrier testing and embryo testing may solve some of these ethical questions but could introduce others. As comprehensive testing techniques are entering the IVF clinic, there is a need for a thorough rethinking of traditional ethical paradigms regarding medically assisted reproduction.

'Designer babies' almost thirty years on.

PubMed

Handyside, Alan H

2018-06-13

The first pregnancies and live births following IVF and preimplantation genetic testing (PGT), formerly known as preimplantation genetic diagnosis (PGD), were reported in 1990, almost 30 years ago, in several couples at risk of X-linked inherited conditions, which typically only affect boys inheriting the X chromosome with the affected gene from their carrier mothers. At that time, it was only possible to identify the sex of the embryo by amplifying a Y-linked repeat sequence in single cells biopsied at cleavage stages and avoid the transfer of males, half of which would be affected. The extensive publicity surrounding these cases and the perceived risk of using IVF and PGT for desirable characteristics not related to health, such as sex selection, led to the epithet of 'designer babies' which continues to resonate to this day. Here I briefly reflect on how the technology of PGT has evolved over the decades and whether it deserves this reputation. With efficient methods for whole genome amplification and the genomic revolution, we now have highly accurate universal tests which combine marker-based diagnosis of almost any monogenic disorder with the detection of aneuploidy. PGT is now clinically well established and is likely to remain a valuable alternative for couples at risk of having affected children.

Clinical features and management of 33 patients with 46,XX pure gonadal dysgenesis.

PubMed

Huang, He; Wang, Chun-Qing; Tian, Qin-Jie

2016-12-01

The objective of the study is to summarize the clinical characteristics of 33 patients' cohort (46,XX pure gonadal dysgenesis, 46,XX PGD), discuss the management, and propose treatment suggestions. Patients' information, medical history, and medical records were obtained. All patients were closely followed up. At the time of diagnosis, the patients presented 19.53 ± 3.60 years old, 165 ± 6.49 cm height, breast development of Tanner stage I, and infantile female genitalia. High level of follicle-stimulating hormone (87.41 ± 21.50 mIU/mL) and LH (27.10 ± 8.47 mIU/mL) and low level of E2 (8.85 ± 6.13 pg/mL) were observed. Individualized hormone replacement therapy (HRT) was initiated after diagnosis. After 2 years of treatment, all patients had obvious breast development; the uterus showed (2.38 ± 0.60) × (1.38 ± 0.70) × (1.38 ± 0.55) cm growth. The incidence of osteopenia changed from 69.70% to 22.22% and that of osteoporosis changed from 18.18% to 0. Dysgeminoma was found in one patient. We concluded that gonadal dysgenesis in 46,XX PGD causes secondary sexual characteristic absence, tendency of taller, osteoporosis, infertility, and sexual health problems. There is minor chance of tumor occurrence for the patients. Optimal care including HRT and close follow-up are required.

Preimplantation genetic diagnosis (PGD): the Gothenburg experience.

PubMed

Hanson, C; Jakobsson, A H; Sjögren, A; Lundin, K; Nilsson, L; Wahlström, J; Hardarson, T; Stevic, J; Darnfors, C; Janson, P O; Wikland, M; Hamberger, L

2001-04-01

A program for preimplantation genetic diagnosis of pre-embryos from patients with hereditary disorders was set up in our unit at Sahlgrenska University Hospital in 1994. The majority of the patients were carriers of X-chromosome linked disorders; a few patients were translocation carriers. In this paper we describe our experiences of our first 36 cycles, 30 gender determinations and six analyses of embryos with possible translocations. Conventional hormone replacement treatment with intracytoplasmic sperm injection to fertilize the eggs followed by blastomere biopsy and fluorescent in situ hybridization at the eight cell stage was used for sexing as well as detection of translocations. Out of the 30 cycles in 13 patients for gender determination, blastomere biopsies could be carried out in 25 cycles. Transfer of normal female embryos (XX) was performed in 18 cycles, resulting in five pregnancies (pregnancy rate 27.8%) and an implantation rate of 20% per transfer. Three girls have been born. Hence the take home baby rate was 16.7% per transfer and 10% per started cycle. Six cycles (three patients) for detection of translocations in embryos were performed. Diagnosis was possible in four cycles. Transfer of normal embryos was carried out in one cycle. No pregnancy was achieved. Successful PGD in its clinical application demands close collaboration between a large group of specialists. Even so, the success rate is considerably lower than after conventional IVF or ICSI procedures. Taking into account the stress caused to the parents facing late interruption of pregnancy following conventional prenatal diagnosis we are convinced that this technique is well worthwhile continuing and refining.

Effects of nanomaterial saturable absorption on gain-guide soliton in a positive group-dispersion fiber laser: Simulations and experiments

NASA Astrophysics Data System (ADS)

Du, Tuanjie; Wan, Xiaojiao; Yang, Runhua; Li, Weiwei; Ruan, Qiujun; Chen, Nan; Luo, Zhengqian

2018-01-01

In recent years, several kinds of nanomaterials have been discovered, and successfully used as saturable absorbers (SAs) for passively mode-locked fiber lasers. However, it is found that most of nanomaterials-based SAs cannot stably generate gain-guide solitons in positive group-dispersion fiber lasers, which is urgently expected to fully understand the inherent reasons. In this paper, we numerically and experimentally investigate the effects of nanomaterial saturable absorption (e.g. modulation depth and saturation optical power) on gain-guide soliton in positive group-dispersion Er3+-doped fiber laser (PGD-EDFL). By numerically solving the Ginzburg-Landau equation, the evolutions of both the mode-locked optical spectrum and pulse duration as a function of modulation depth and saturation optical power are analyzed, respectively. In experiment, we firstly prepare five nanomaterial SAs with the similar insertion loss, which have the different modulation depth from 1.80% to 23.36%, and the different saturation optical power from 8.8 to 536 W. We then perform the experimental comparison by incorporating the five SAs in a same PGD-EDFL cavity, respectively. The experimental results are in good agreement with the numerical ones. Our result reveals that: (1) a low modulation depth cannot support the formation of gain-guide soliton, (2) as the modulation depth increases, the spectral bandwidth of gain-guide soliton increases, the pulse duration decreases and the pulse chirp becomes large, (3) the saturation optical power has the weak influences on the gain-guide soliton performances.

The H-bond network surrounding the pyranopterins modulates redox cooperativity in the molybdenum-bisPGD cofactor in arsenite oxidase.

PubMed

Duval, Simon; Santini, Joanne M; Lemaire, David; Chaspoul, Florence; Russell, Michael J; Grimaldi, Stephane; Nitschke, Wolfgang; Schoepp-Cothenet, Barbara

2016-09-01

While the molybdenum cofactor in the majority of bisPGD enzymes goes through two consecutive 1-electron redox transitions, previous protein-film voltammetric results indicated the possibility of cooperative (n=2) redox behavior in the bioenergetic enzyme arsenite oxidase (Aio). Combining equilibrium redox titrations, optical and EPR spectroscopies on concentrated samples obtained via heterologous expression, we unambiguously confirm this claim and quantify Aio's redox cooperativity. The stability constant, Ks, of the Mo(V) semi-reduced intermediate is found to be lower than 10(-3). Site-directed mutagenesis of residues in the vicinity of the Mo-cofactor demonstrates that the degree of redox cooperativity is sensitive to H-bonding interactions between the pyranopterin moieties and amino acid residues. Remarkably, in particular replacing the Gln-726 residue by Gly results in stabilization of (low-temperature) EPR-observable Mo(V) with KS=4. As evidenced by comparison of room temperature optical and low temperature EPR titrations, the degree of stabilization is temperature-dependent. This highlights the importance of room-temperature redox characterizations for correctly interpreting catalytic properties in this group of enzymes. Geochemical and phylogenetic data strongly indicate that molybdenum played an essential biocatalytic roles in early life. Molybdenum's redox versatility and in particular the ability to show cooperative (n=2) redox behavior provide a rationale for its paramount catalytic importance throughout the evolutionary history of life. Implications of the H-bonding network modulating Molybdenum's redox properties on details of a putative inorganic metabolism at life's origin are discussed. Copyright © 2016. Published by Elsevier B.V.

Inhibitory Effects of Urothelium-related Factors.

PubMed

Guan, Na N; Gustafsson, Lars E; Svennersten, Karl

2017-10-01

The urothelium of the bladder has long been recognized as a protective barrier between detrusor and urine. In recent years, it has become more evident that the urothelium plays a role as an active source of mediators. The urothelium can release neurotransmitters and modulators such as acetylcholine, ATP, nitric oxide, prostaglandins and neuropeptides. They exert both excitatory and inhibitory effects in modulating urinary tract motility. In addition, several studies have reported the existence of an urothelium-derived unknown inhibitory factor in the urinary bladder. By the use of a new serial cascade superfusion bioassay on guinea pig ureter, recent studies confirm that the guinea pig bladder urothelium releases a substance with inhibitory bioactivity, which was resistant to treatment with nitric oxide synthase inhibitor and cyclooxygenase inhibitor and to adenosine A1/A2 receptor blockade. Lately, a marked and quickly inactivated novel release of PGD 2 from the bladder urothelium was discovered, together with localization of prostaglandin D synthase therein. PGD 2 was found to have an inhibitory influence on nerve-induced contractions in guinea pig urinary bladder and on spontaneous contractions in the out-flow region. An altered release of excitatory and inhibitory factors is likely to play an important part in bladder motility disturbances, of which the prostanoids are a notable group. Due to the fact that the bladder is relaxed 99% of the time, not only excitatory mechanisms in the bladder are necessary to study, but also inhibitory mechanisms need considerable attention, which will contribute to the discovery of new targets to treat bladder motility disorders. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Response to 'No country is an island: comment on the House of Commons report Human Reproductive Technologies and the Law'.

PubMed

Bhargava, Pushpa M

2005-07-01

Edgar Dahl supports sex selection, e.g. through separation of X and Y sperm or through PGD. It is argued in this commentary that while such sex selection would seem reasonable for balancing a family (wanting a daughter if one already has a son, or vice-versa), it is likely to lead to skewing of female-male ratios, not only in India where it is already as low as 0.8 in certain parts, but possibly also in Great Britain as male chauvinism is not a thing of the past anywhere.

Bioethics and Biopolitics: Presents and Futures of Reproduction.

PubMed

Camporesi, Silvia

2017-06-01

This Bioethics and Biopolitics: Presents and Futures of Reproduction symposium draws together a series of articles that were each submitted independently by their authors to the JBI and which explore the biopower axis in the externalization of reproduction in four contexts: artificial gestation (ectogenesis), PGD for sex selection, women's (reproductive) rights, and testicular cryopreservation (TCCP). While one contribution explores a "future" of reproduction, the other three explore a "present," or better, explore different "presents." What may counts as "present," and what may count as "future," has dramatically different connotations depending on the geographical declination of the tense.

Simulation of strong ground motion parameters of the 1 June 2013 Gulf of Suez earthquake, Egypt

NASA Astrophysics Data System (ADS)

Toni, Mostafa

2017-06-01

This article aims to simulate the ground motion parameters of the moderate magnitude (ML 5.1) June 1, 2013 Gulf of Suez earthquake, which represents the largest instrumental earthquake to be recorded in the middle part of the Gulf of Suez up to now. This event was felt in all cities located on both sides of the Gulf of Suez, with minor damage to property near the epicenter; however, no casualties were observed. The stochastic technique with the site-dependent spectral model is used to simulate the strong ground motion parameters of this earthquake in the cities located at the western side of the Gulf of Suez and north Red Sea namely: Suez, Ain Sokhna, Zafarana, Ras Gharib, and Hurghada. The presence of many tourist resorts and the increase in land use planning in the considered cities represent the motivation of the current study. The simulated parameters comprise the Peak Ground Acceleration (PGA), Peak Ground Velocity (PGV), and Peak Ground Displacement (PGD), in addition to Pseudo Spectral Acceleration (PSA). The model developed for ground motion simulation is validated by using the recordings of three accelerographs installed around the epicenter of the investigated earthquake. Depending on the site effect that has been determined in the investigated areas by using geotechnical data (e.g., shear wave velocities and microtremor recordings), the investigated areas are classified into two zones (A and B). Zone A is characterized by higher site amplification than Zone B. The ground motion parameters are simulated at each zone in the considered areas. The results reveal that the highest values of PGA, PGV, and PGD are observed at Ras Gharib city (epicentral distance ∼ 11 km) as 67 cm/s2, 2.53 cm/s, and 0.45 cm respectively for Zone A, and as 26.5 cm/s2, 1.0 cm/s, and 0.2 cm respectively for Zone B, while the lowest values of PGA, PGV, and PGD are observed at Suez city (epicentral distance ∼ 190 km) as 3.0 cm/s2, 0.2 cm/s, and 0.05 cm/s respectively for Zone A, and as 1.3 cm/s2, 0.1 cm/s, and 0.024 cm respectively for Zone B. Also the highest PSA values are observed in Ras Gharib city as 200 cm/s2 and 78 cm/s2 for Zone A and Zone B respectively, while the lowest PSA values are observed in Suez city as 7 cm/s2 and 3 cm/s2 for Zone A and Zone B respectively. These results show a good agreement with the earthquake magnitude, epicentral distances, and site characterizations as well.

Effect of Exposure to Atmospheric Ultrafine Particles on Production of Free Fatty Acids and Lipid Metabolites in the Mouse Small Intestine

PubMed Central

Li, Rongsong; Navab, Kaveh; Hough, Greg; Daher, Nancy; Zhang, Min; Mittelstein, David; Lee, Katherine; Pakbin, Payam; Saffari, Arian; Bhetraratana, May; Sulaiman, Dawoud; Beebe, Tyler; Wu, Lan; Jen, Nelson; Wine, Eytan; Tseng, Chi-Hong; Araujo, Jesus A.; Fogelman, Alan; Sioutas, Constantinos; Navab, Mohamed

2014-01-01

Background: Exposure to ambient ultrafine particulate matter (UFP) is a well-recognized risk factor for cardiovascular and respiratory diseases. However, little is known about the effects of air pollution on gastrointestinal disorders. Objective: We sought to assess whether exposure to ambient UFP (diameter < 180 nm) increased free fatty acids and lipid metabolites in the mouse small intestine. Methods: Ldlr-null mice were exposed to filtered air (FA) or UFP collected at an urban Los Angeles, California, site that was heavily affected by vehicular emissions; the exposure was carried out for 10 weeks in the presence or absence of D-4F, an apolipoprotein A-I mimetic peptide with antioxidant and anti-inflammation properties on a high-fat or normal chow diet. Results: Compared with FA, exposure to UFP significantly increased intestinal hydroxyeicosatetraenoic acids (HETEs), including 15-HETE, 12-HETE, 5-HETE, as well as hydroxyoctadecadienoic acids (HODEs), including 13-HODE and 9-HODE. Arachidonic acid (AA) and prostaglandin D2 (PGD2) as well as some of the lysophosphatidic acids (LPA) in the small intestine were also increased in response to UFP exposure. Administration of D-4F significantly reduced UFP-mediated increase in HETEs, HODEs, AA, PGD2, and LPA. Although exposure to UFP further led to shortened villus length accompanied by prominent macrophage and neutrophil infiltration into the intestinal villi, administration of D-4F mitigated macrophage infiltration. Conclusions: Exposure to UFP promotes lipid metabolism, villus shortening, and inflammatory responses in mouse small intestine, whereas administration of D-4F attenuated these effects. Our findings provide a basis to further assess the mechanisms underlying UFP-mediated lipid metabolism in the digestive system with clinical relevance to gut homeostasis and diseases. Citation: Li R, Navab K, Hough G, Daher N, Zhang M, Mittelstein D, Lee K, Pakbin P, Saffari A, Bhetraratana M, Sulaiman D, Beebe T, Wu L, Jen N, Wine E, Tseng CH, Araujo JA, Fogelman A, Sioutas C, Navab M, Hsiai TK. 2015. Effect of exposure to atmospheric ultrafine particles on production of free fatty acids and lipid metabolites in the mouse small intestine. Environ Health Perspect 123:34–41; http://dx.doi.org/10.1289/ehp.1307036 PMID:25170928

Resolving Peak Ground Displacements in Real-Time GNSS PPP Solutions

NASA Astrophysics Data System (ADS)

Hodgkinson, K. M.; Mencin, D.; Mattioli, G. S.; Sievers, C.; Fox, O.

2017-12-01

The goal of early earthquake warning (EEW) systems is to provide warning of impending ground shaking to the public, infrastructure managers, and emergency responders. Shaking intensity can be estimated using Ground Motion Prediction Equations (GMPEs), but only if site characteristics, hypocentral distance and event magnitude are known. In recent years work has been done analyzing the first few seconds of the seismic P wave to derive event location and magnitude. While initial rupture locations seem to be sufficiently constrained, it has been shown that P-wave magnitude estimates tend to saturate at M>7. Regions where major and great earthquakes occur may therefore be vulnerable to an underestimation of shaking intensity if only P waves magnitudes are used. Crowell et al., (2013) first demonstrated that Peak Ground Displacement (PGD) from long-period surface waves recorded by GNSS receivers could provide a source-scaling relation that does not saturate with event magnitude. GNSS PGD derived magnitudes could improve the accuracy of EEW GMPE calculations. If such a source-scaling method were to be implemented in EEW algorithms it is critical that the noise levels in real-time GNSS processed time-series are low enough to resolve long-period surface waves. UNAVCO currently operates 770 real-time GNSS sites, most of which are located along the North American-Pacific Plate Boundary. In this study, we present an analysis of noise levels observed in the GNSS Precise Point Positioning (PPP) solutions generated and distributed in real-time by UNAVCO for periods from seconds to hours. The analysis is performed using the 770 sites in the real-time network and data collected through July 2017. We compare noise levels determined from various monument types and receiver-antenna configurations. This analysis gives a robust estimation of noise levels in PPP solutions because the solutions analyzed are those that were generated in real-time and thus contain all the problems observed in routine network operations e.g., data outages, high latencies and data from research-quality to less ideal monumentation. Using these noise estimates we can identify which sites are best able to resolve the PGDs for earthquakes over a range of focal distances and those that may not using their current configurations.

Cyclooxygenase-2 Deficiency Leads to Intestinal Barrier Dysfunction and Increased Mortality During Polymicrobial Sepsis 1

PubMed Central

Fredenburgh, Laura E.; Velandia, Margarita M. Suarez; Ma, Jun; Olszak, Torsten; Cernadas, Manuela; Englert, Joshua A.; Chung, Su Wol; Liu, Xiaoli; Begay, Cynthia; Padera, Robert F.; Blumberg, Richard S.; Walsh, Stephen R.; Baron, Rebecca M.; Perrella, Mark A.

2011-01-01

Sepsis remains the leading cause of death in critically ill patients despite modern advances in critical care. Intestinal barrier dysfunction may lead to secondary bacterial translocation and the development of the multiple organ dysfunction syndrome during sepsis. Cyclooxygenase-2 (COX-2) is highly upregulated in the intestine during sepsis and we hypothesized that it may be critical in the maintenance of intestinal epithelial barrier function during peritonitis-induced polymicrobial sepsis. COX-2−/− and COX-2+/+ BALB/c mice underwent cecal ligation and puncture (CLP) or sham surgery. Mice chimeric for COX-2 were derived by bone marrow transplantation and underwent CLP. C2BBe1 cells, an intestinal epithelial cell line, were treated with the COX-2 inhibitor NS-398, PGD2, or vehicle and stimulated with cytokines. COX-2−/− mice developed exaggerated bacteremia and increased mortality compared with COX-2+/+ mice following CLP. Mice chimeric for COX-2 exhibited the recipient phenotype suggesting that epithelial COX-2 expression in the ileum attenuates bacteremia following CLP. Absence of COX-2 significantly increased epithelial permeability of the ileum and reduced expression of the tight junction proteins zonula occludens-1 (ZO-1), occludin, and claudin-1 in the ileum following CLP. Furthermore, PGD2 attenuated cytokine-induced hyperpermeability and ZO-1 downregulation in NS-398-treated C2BBe1 cells. Our findings reveal that absence of COX-2 is associated with enhanced intestinal epithelial permeability and leads to exaggerated bacterial translocation and increased mortality during peritonitis-induced sepsis. Taken together, our results suggest that epithelial expression of COX-2 in the ileum is a critical modulator of tight junction protein expression and intestinal barrier function during sepsis. PMID:21967897

Quercetin Is More Effective than Cromolyn in Blocking Human Mast Cell Cytokine Release and Inhibits Contact Dermatitis and Photosensitivity in Humans

PubMed Central

Asadi, Shahrzad; Sismanopoulos, Nikolaos; Butcher, Alan; Fu, Xueyan; Katsarou-Katsari, Alexandra; Antoniou, Christina; Theoharides, Theoharis C.

2012-01-01

Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell “stabilizer”, is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 µM) can effectively inhibit secretion of histamine and PGD2. Que and cromolyn also inhibit histamine, leukotrienes and PGD2 from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added together with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption. PMID:22470478

Postdoctoral education in dentistry: preparing dental practitioners to meet the oral health needs of America in the 21st century.

PubMed

Glassman, P; Meyerowitz, C

1999-08-01

There has been increasing interest in the organization and accreditation of Postdoctoral General Dentistry Programs (PGD). In addition, numerous national organizations have called for increases in the number of first postdoctoral year (PGY-1) positions and programs. At the same time there has been a movement to incorporate concepts of competency-based education into dental education programs in order to stress the outcomes of education rather then the process. These movements have coincided with an increased recognition that dental education will be affected by the changing demographics of our population, the emerging trends in health care delivery and financing, and the need for an increase in the number of primary care providers in dentistry, trained at an advanced level, who are capable of caring for an increasingly socially diverse and medically complex population in our country in the next century. This paper reviews the history of postdoctoral education programs in dentistry and medicine with a focus on PGD education, describes the changing health care environment in which future dental professionals will practice, and relates the dental postdoctoral experience to that in medicine. A strategy is presented for the dental profession to prepare dental practitioners with the competencies needed for the future and to create enough training opportunities to prepare these practitioners to care for the oral health needs of the nation. This proposal calls for a "National Consensus Development Conference on the Future of Postdoctoral Primary Care Education in Dentistry". This conference would define the strategies necessary to prepare dental practitioners with the competencies needed for the future and develop approaches to create enough training opportunities to prepare these practitioners to care for the oral health needs of the nation.

Quantitative analysis of eosinophil chemotaxis tracked using a novel optical device -- TAXIScan.

PubMed

Nitta, Nao; Tsuchiya, Tomoko; Yamauchi, Akira; Tamatani, Takuya; Kanegasaki, Shiro

2007-03-30

We have reported previously the development of an optically accessible, horizontal chemotaxis apparatus, in which migration of cells in the channel from a start line can be traced with time-lapse intervals using a CCD camera (JIM 282, 1-11, 2003). To obtain statistical data of migrating cells, we have developed quantitative methods to calculate various parameters in the process of chemotaxis, employing human eosinophil and CXCL12 as a model cell and a model chemoattractant, respectively. Median values of velocity and directionality of each cell within an experimental period could be calculated from the migratory pathway data obtained from time-lapse images and the data were expressed as Velocity-Directionality (VD) plot. This plot is useful for quantitatively analyzing multiple migrating cells exposed to a certain chemoattractant, and can distinguish chemotaxis from random migration. Moreover precise observation of cell migration revealed that each cell had a different lag period before starting chemotaxis, indicating variation in cell sensitivity to the chemoattractant. Thus lag time of each cell before migration, and time course of increment of the migrating cell ratio at the early stages could be calculated. We also graphed decrement of still moving cell ratio at the later stages by calculating the duration time of cell migration of each cell. These graphs could distinguish different motion patterns of chemotaxis of eosinophils, in response to a range of chemoattractants; PGD(2), fMLP, CCL3, CCL5 and CXCL12. Finally, we compared parameters of eosinophils from normal volunteers, allergy patients and asthma patients and found significant difference in response to PGD(2). The quantitative methods described here could be applicable to image data obtained with any combination of cells and chemoattractants and useful not only for basic studies of chemotaxis but also for diagnosis and for drug screening.

Prevalence and predictors of parental grief and depression after the death of a child from cancer.

PubMed

McCarthy, Maria C; Clarke, Naomi E; Ting, Cheng Lin; Conroy, Rowena; Anderson, Vicki A; Heath, John A

2010-11-01

To investigate patterns of grief and depression in a sample of parents whose child had died of cancer, and to examine factors related to burden of illness and end-of-life care as potential predictors of parental grief and depression outcomes. Fifty-eight parents completed standardized self-report questionnaires measuring prolonged grief disorder (Inventory of Complicated Grief-Revised [ICG-R]) and depression (Beck Depression Inventory-Second Edition [BDI-II]) and participated in structured interviews designed to elicit their perceptions of their child's end-of-life care and burden of illness. The majority of participants were mothers (84%) and the mean length of time since child death was 4.5 (standard deviation [SD] = 2.4) years (range, 1.0-9.8 years). Rates of prolonged grief disorder (PGD) were similar to those reported in other bereaved populations (10.3%); however, 41% of parents met diagnostic criteria for grief-related separation distress. Twenty-two percent of parents reported clinically significant depressive symptoms. Time since death and parental perception of the oncologist's care predicted parental grief symptoms but not depressive symptoms. Perceptions of the child's quality of life during the last month, preparedness for the child's death, and economic hardship also predicted grief and depression outcomes. A minority of parents met criteria for PGD and depression, however, almost half the sample was experiencing significant separation distress associated with persistent longing and yearning for their child. Time since death is a significant predictor of parental psychological distress. This study also highlights the importance of end-of-life factors in parents' long-term adjustment and the need for optimal palliative care to ensure the best possible outcomes for parents.

Evidence that histamine is the causative toxin of scombroid-fish poisoning.

PubMed

Morrow, J D; Margolies, G R; Rowland, J; Roberts, L J

1991-03-14

The highest morbidity worldwide from fish poisoning results from the ingestion of spoiled scombroid fish, such as tuna and mackerel, and its cause is not clear. Histamine could be responsible, because spoiled scombroid fish contain large quantities of histamine. Whether histamine is the causative toxin, however, has remained in question. To address this issue, we investigated whether histamine homeostasis is altered in poisoned people. The urinary excretion of histamine and its metabolite, N-methylhistamine, was measured in three persons who had scombroid-fish poisoning (scombrotoxism) after the ingestion of marlin. We measured 9 alpha, 11 beta-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid (PGD-M), the principal metabolite of prostaglandin D2, a mast-cell secretory product, to assess whether mast cells had been activated to release histamine. The fish contained high levels of histamine (842 to 2503 mumol per 100 g of tissue). Symptoms of scombrotoxism--flushing and headache--began 10 to 30 minutes after the ingestion of fish. In urine samples collected one to four hours after fish ingestion, the levels of histamine and N-methylhistamine were 9 to 20 times and 15 to 20 times the normal mean, respectively. During the subsequent 24 hours, the levels fell to 4 to 15 times and 4 to 11 times the normal values. Levels of both were normal 14 days later. PGD-M excretion was not increased at any time. Two persons treated with diphenhydramine had prompt amelioration of symptoms. Scombroid-fish poisoning is associated with urinary excretion of histamine in quantities far exceeding those required to produce toxicity. The histamine is most likely derived from the spoiled fish. These results identify histamine as the toxin responsible for scombroid-fish poisoning.

Number of blastocysts biopsied as a predictive indicator to obtain at least one normal/balanced embryo following preimplantation genetic diagnosis with single nucleotide polymorphism microarray in translocation cases.

PubMed

Wang, Yi-Zi; Ding, Chen-Hui; Wang, Jing; Zeng, Yan-Hong; Zhou, Wen; Li, Rong; Zhou, Can-Quan; Deng, Ming-Fen; Xu, Yan-Wen

2017-01-01

The aim of this study is to investigate the minimum number of blastocysts for biopsy to increase the likelihood of obtaining at least one normal/balanced embryo in preimplantation genetic diagnosis (PGD) for translocation carriers. This blinded retrospective study included 55 PGD cycles for Robertsonian translocation (RT) and 181 cycles for reciprocal translocation (rcp) to indicate when only one of the couples carried a translocation. Single-nucleotide polymorphism microarray after trophectoderm biopsy was performed. Reliable results were obtained for 355/379 (93.7 %) biopsied blastocysts in RT group and 986/1053 (93.6 %) in rcp group. Mean numbers of biopsied embryos per patient, normal/balanced embryos per patient, and mean normal/balanced embryo rate per patient were 7.4, 3.1, and 40.7 % in RT group and 8.0, 2.1, and 27.3 %, respectively, in rcp group. In a regression model, three factors significantly affected the number of genetically transferrable embryos: number of biopsied embryos (P = 0.001), basal FSH level (P = 0.040), and maternal age (P = 0.027). ROC analysis with a cutoff of 1.5 was calculated for the number of biopsied embryos required to obtain at least one normal/balanced embryo for RT carriers. For rcp carriers, the cutoff was 3.5. The clinical pregnancy rate per embryo transfer was 44.2 and 42.6 % in RT and rcp groups (P = 0.836). The minimum numbers of blastocysts to obtain at least one normal/balanced embryo for RT and rcp were 2 and 4 under the conditions of female age < 37 years with a basal FSH level < 11.4 IU/L.

Histopathological pattern in childhood glomerulonephritis.

PubMed

Moorani, Khemchand Netaram; Sherali, Afroze Ramzan

2010-12-01

To determine the histopathological pattern in childhood glomerulonephritis (CGN). This retrospective analysis of renal biopsies of 118 children with various clinical syndromes of CGN was carried out at the National Institute of Child Health (NICH) and The Kidney Center (TKC), Karachi, from July 2005 to December 2009. The age ranged from 6 months to 16 years. All biopsies were studied under light microscopy (LM) and immunoflourescence (IMF). Histopathological lesions (HPL) were classified as primary and secondary glomerular diseases. Demographic data, indications and HPL were retrieved and analyzed using descriptive statistics. Out of 118 patients, 62 (52.54%) were males and 56(47.45%) females. Mean age was 8.2 +/- 3.9 years. Major indications for biopsy were primary nephrotic syndrome (PNS 86, 72.88%). secondary GN (SGN, 17, 14.4%) and nephritic-nephrotic syndrome (NNS 13, 11%). Overall, primary glomerular diseases (PGD) accounted for 84.74% of all biopsies. Minimal change disease (MCD 38, 32.2%) and focal segmental glomerulosclerosis (FSGS 35, 29.66%) were the two most common lesions and accounted for 43% and 33.72% respectively in PNS. Other important lesions were membranous GN (MGN 10, 8.47%), membranoproliferative (MPGN 9, 7.16%), post-infective (PIGN 4, 3.38%) and IgM nephropathy (IgMN 3, 2.54%). Among secondary glomerular diseases (SGD), lupus nephritis (LN 11, 9.32%) was the most common lesion followed by Henoch-Schonlein nephritis (HSN) and haemolytic uraemic syndrome (HUS) each in 3 (2.52%). Overall, MCD and FSGS were the two most common HPL in PGD and both dominated in PNS. Lupus nephritis was the leading lesion in SGD. These histopathological pattern of CGN in our study is in conformity with the existing literature from Pakistan.

[Preimplantation genetic diagnosis of Duchenne muscular dystrophy by single cell triplex PCR].

PubMed

Wu, Yue-Li; Wu, Ling-Qian; Li, Yan-Ping; Liu, Dong-E; Zeng, Qiao; Zhu, Hai-Yan; Pan, Qian; Liang, De-Sheng; Hu, Hao; Long, Zhi-Gao; Li, Juan; Dai, He-Ping; Xia, Kun; Xia, Jia-Hui

2007-04-01

To detect two exons of Duchenne muscular dystrophy (DMD) gene and a gender discrimination locus amelogenin gene by single cell triplex PCR, and to evaluate the possibility of this technique for preimplantation genetic diagnosis (PGD) in DMD family with DMD deletion mutation. Single lymphocytes from a normal male, a normal female, two DMD patients (exon 8 and 47 deleted, respectively) and single blastomeres from the couples treated by the in vitro fertilization pre-embryo transfer (IVF-ET) and without family history of DMD were obtained. Exons 8 and 47 of DMD gene were amplified by a triplex PCR assay, the amelogenin gene on X and Y chromosomes were co-amplified to analyze the correlation between embryo gender and deletion status. In the normal single lymphocytes, the amplification rate of exons 8 and 47 of DMD and amelogenin gene were 93.8%, 93.8%, and 95.3% respectively. The false positive rate was 3.3%. In the exon 8 deleted DMD patient, the amplification rate of exon 47 of DMD and amelogenin gene was 95.8%, and the false positive rate was 3.3%. In the exon 47 deleted DMD patient, the amplification rate of exon 8 of DMD and amelogenin gene was 95.8%, and the false positive rate was 0. In the single blastomeres, the amplification rate of exons 8 and 47 of DMD and amelogenin gene was 82.5%, 80.0% and 77.5%, respectively, and the false positive rate was 0. The single cell triplex PCR protocol for the detection of DMD and amelogenin gene is highly sensitive, specific and reliable, and can be used for PGD in those DMD families with DMD deletion mutation.

Effects of orthopedic implants with a polycaprolactone polymer coating containing bone morphogenetic protein-2 on osseointegration in bones of sheep.

PubMed

Niehaus, Andrew J; Anderson, David E; Samii, Valerie F; Weisbrode, Steven E; Johnson, Jed K; Noon, Mike S; Tomasko, David L; Lannutti, John J

2009-11-01

To determine elution characteristics of bone morphogenetic protein (BMP)-2 from a polycaprolactone coating applied to orthopedic implants and determine effects of this coating on osseointegration. 6 sheep. An in vitro study was conducted to determine BMP-2 elution from polycaprolactone-coated implants. An in vivo study was conducted to determine the effects on osseointegration when the polycaprolactone with BMP-2 coating was applied to bone screws. Osseointegration was assessed via radiography, measurement of peak removal torque and bone mineral density, and histomorphometric analysis. Physiologic response was assessed by measuring serum bone-specific alkaline phosphatase activity and uptake of bone markers. Mean +/- SD elution on day 1 of the in vitro study was 263 +/- 152 pg/d, which then maintained a plateau at 59.8 +/- 29.1 pg/d. Mean peak removal torque for screws coated with polycalprolactone and BMP-2 (0.91 +/- 0.65 dN x m) and screws coated with polycaprolactone alone (0.97 +/- 1.30 dN.m) did not differ significantly from that for the control screws (2.34 +/- 1.62 dN x m). Mean bone mineral densities were 0.535 +/- 0.060 g/cm(2), 0.596 +/- 0.093 g/cm(2), and 0.524 +/- 0.142 g/cm(2) for the polycaprolactone-BMP-2-coated, polycaprolactone-coated, and control screws, respectively, and did not differ significantly among groups. Histologically, bone was in closer apposition to the implant with the control screws than with either of the coated screws. BMP-2 within the polycaprolactone coating did not stimulate osteogenesis. The polycaprolactone coating appeared to cause a barrier effect that prevented formation of new bone. A longer period or use of another carrier polymer may result in increased osseointegration.

Inhibition of hematopoietic prostaglandin D2 Synthase (H-PGDS) by an alkaloid extract from Combretum molle

PubMed Central

2014-01-01

Background Hematopoietic prostaglandin D2 synthase (H-PGDS, GST Sigma) is a member of the glutathione S-transferase super family of enzymes that catalyses the conjugation of electrophilic substances with reduced glutathione. The enzyme catalyses the conversion of PGH2 to PGD2 which mediates inflammatory responses. The inhibition of H-PGDS is of importance in alleviating damage to tissues due to unwarranted synthesis of PGD2. Combretum molle has been used in African ethno medicinal practices and has been shown to reduce fever and pain. The effect of C. molle alkaloid extract on H-PGDS was thus, investigated. Methods H-PGDS was expressed in Escherichia coli XL1-Blue cells and purified using nickel immobilized metal affinity chromatography. The effect of C. molle alkaloid extract on H-PGDS activity was determined with 1-chloro-2, 4-dinitrobenzene (CDNB) as substrate. The effect of C. molle alkaloid extract with time on H-PGDS was determined. The mechanism of inhibition was then investigated using CDNB and glutathione (GSH) as substrates. Results A specific activity of 24 μmol/mg/min was obtained after H-PGDS had been purified. The alkaloid extract exhibited a 70% inhibition on H-PGDS with an IC50 of 13.7 μg/ml. C. molle alkaloid extract showed an uncompetitive inhibition of H-PGDS with Ki = 41 μg/ml towards GSH, and non-competitive inhibition towards CDNB with Ki = 7.7 μg/ml and Ki′ = 9.2 μg/ml. Conclusion The data shows that C. molle alkaloid extract is a potent inhibitor of H-PGDS. This study thus supports the traditional use of the plant for inflammation. PMID:24996417

Inhibition of hematopoietic prostaglandin D2 synthase (H-PGDS) by an alkaloid extract from Combretum molle.

PubMed

Moyo, Rejoice; Chimponda, Theresa; Mukanganyama, Stanley

2014-07-05

Hematopoietic prostaglandin D2 synthase (H-PGDS, GST Sigma) is a member of the glutathione S-transferase super family of enzymes that catalyses the conjugation of electrophilic substances with reduced glutathione. The enzyme catalyses the conversion of PGH2 to PGD2 which mediates inflammatory responses. The inhibition of H-PGDS is of importance in alleviating damage to tissues due to unwarranted synthesis of PGD2. Combretum molle has been used in African ethno medicinal practices and has been shown to reduce fever and pain. The effect of C. molle alkaloid extract on H-PGDS was thus, investigated. H-PGDS was expressed in Escherichia coli XL1-Blue cells and purified using nickel immobilized metal affinity chromatography. The effect of C. molle alkaloid extract on H-PGDS activity was determined with 1-chloro-2, 4-dinitrobenzene (CDNB) as substrate. The effect of C. molle alkaloid extract with time on H-PGDS was determined. The mechanism of inhibition was then investigated using CDNB and glutathione (GSH) as substrates. A specific activity of 24 μmol/mg/min was obtained after H-PGDS had been purified. The alkaloid extract exhibited a 70% inhibition on H-PGDS with an IC50 of 13.7 μg/ml. C. molle alkaloid extract showed an uncompetitive inhibition of H-PGDS with Ki = 41 μg/ml towards GSH, and non-competitive inhibition towards CDNB with Ki = 7.7 μg/ml and Ki' = 9.2 μg/ml. The data shows that C. molle alkaloid extract is a potent inhibitor of H-PGDS. This study thus supports the traditional use of the plant for inflammation.

Impact of the Di(2-Ethylhexyl) Phthalate Administration on Trace Element and Mineral Levels in Relation of Kidney and Liver Damage in Rats.

PubMed

Aydemir, Duygu; Karabulut, Gözde; Şimşek, Gülsu; Gok, Muslum; Barlas, Nurhayat; Ulusu, Nuriye Nuray

2018-04-13

Di(2-ethylhexyl) phthalate (DEHP) is a widely used synthetic polymer in the industry. DEHP may induce reproductive and developmental toxicity, obesity, carcinogenesis and cause abnormal endocrine function in both human and wildlife. The aim of this study was to investigate trace element and mineral levels in relation of kidney and liver damage in DEHP-administered rats. Therefore, prepubertal male rats were dosed with 0, 100, 200, and 400 mg/kg/day of DEHP. At the end of the experiment, trace element and mineral levels, glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6-PGD), glutathione reductase (GR) and glutathione S-transferase (GST) enzyme activities were evaluated in the serum, liver, and kidney samples of rats. Furthermore, serum clinical biochemistry parameters, organ/body weight ratios and histological changes were investigated to evaluate impact of DEHP more detailed. Our data indicated that sodium (Na), calcium (Ca), potassium (K), lithium (Li), rubidium (Rb) and cesium (Cs) levels significantly decreased, however iron (Fe) and selenium (Se) concentrations significantly increased in DEHP-administered groups compared to the control in the serum samples. On the other hand, upon DEHP administration, selenium concentration, G6PD and GR activities were significantly elevated, however 6-PGD activity significantly decreased compared to the control group in the kidney samples. Decreased G6PD activity was the only significant change between anti-oxidant enzyme activities in the liver samples. Upon DEHP administration, aberrant serum biochemical parameters have arisen and abnormal histological changes were observed in the kidney and liver tissue. In conclusion, DEHP may induce liver and kidney damage, also result abnormalities in the trace element and mineral levels.

Magnesium Reduces Hepatic Lipid Accumulation in Yellow Catfish (Pelteobagrus fulvidraco) and Modulates Lipogenesis and Lipolysis via PPARA, JAK-STAT, and AMPK Pathways in Hepatocytes.

PubMed

Wei, Chuan-Chuan; Wu, Kun; Gao, Yan; Zhang, Li-Han; Li, Dan-Dan; Luo, Zhi

2017-06-01

Background: Magnesium influences hepatic lipid deposition in vertebrates, but the underlying mechanism is unknown. Objective: We used yellow catfish and their isolated hepatocytes to test the hypothesis that magnesium influences lipid deposition by modulating lipogenesis and lipolysis. Methods: Juvenile yellow catfish (mean ± SEM weight: 3.43 ± 0.02 g, 3 mo old, mixed sex) were fed a 0.14- (low), 0.87- (intermediate) or 2.11- (high) g Mg/kg diet for 56 d. Primary hepatocytes were incubated for 48 h in control or MgSO 4 -containing medium with or without 2-h pretreatment with an inhibitor (AG490, GW6471, or Compound C). Growth performance, cell viability, triglyceride (TG) concentrations, and expression of enzymes and genes involved in lipid metabolism were measured. Results: Compared with fish fed low magnesium, those fed intermediate or high magnesium had lower hepatic lipids (18%, 22%) and 6-phosphogluconate dehydrogenase (6PGD; 3.7%, 3.8%) and malic enzyme (ME; 35%, 48%) activities and greater mRNA levels of the lipolytic genes adipose triacylglyceride lipase ( atgl ; 82% and 1.7-fold) and peroxisome proliferator-activated receptor ( ppara ; 18% and 1.0-fold), respectively ( P < 0.05). Relative mRNA levels of AMP-activated protein kinase ( ampk ) a1 , ampka2 , ampkb1 , ampkb2 , ampkg1a , ampkg1b , Janus kinase (jak) 2a , jak2b, and signal transducers and activators of transcription ( stat ) 3 in fish fed high magnesium were higher (24% to 3.1-fold, P < 0.05) than in those fed low or intermediate magnesium. Compared with cells incubated with MgSO 4 alone, those incubated with MgSO 4 and pretreated with AG490, GW6471, or Compound C had greater TG concentrations (42%, 31%, or 56%), g6pd (98%, 59%, or 51%), 6pgd (68%, 73%, or 32%) mRNA expression, and activities of G6PD (35%, 45%, or 16%) and ME (1.5-fold, 1.3-fold, or 13%), and reduced upregulation (61%, 25%, or 45%) of the lipolytic gene, atgl ( P < 0.05). Conclusions: Magnesium reduced hepatic lipid accumulation in yellow catfish and the variation might be attributed to inhibited lipogenesis and increased lipolysis. PPARA, JAK-STAT, and AMPK pathways mediated the magnesium-induced changes in lipid deposition and metabolism. These results offer new insight into magnesium nutrition in vertebrates. © 2017 American Society for Nutrition.

The genetics of familial adenomatous polyposis (FAP) and MutYH-associated polyposis (MAP).

PubMed

Claes, Kathleen; Dahan, Karin; Tejpar, S; De Paepe, Anne; Bonduelle, Maryse; Abramowicz, Marc; Verellen, Christine; Franchimont, Denis; Van Cutsem, Eric; Kartheuser, Alex

2011-09-01

FAP is characterized by 100-1000s of adenomatous polyps in colon and rectum, and is in 70% of the patients associated with extracolonic manifestations. Attenuated FAP (AFAP) is a less severe form of FAP, marked by the presence of < 100 polyps and a later onset of colorectal cancer (CRC). (A)FAP is caused by autosomal dominantly inherited mutations in the APC (Adenomatous polyposis coli) gene, a tumour suppressor gene that controls beta-catenin turnover in the Wnt pathway. De novo occurrence is reported in 30-40% of the patients. Mutations are detected in 85% of classical FAP families, while only 20%-30% of AFAP cases will exhibit a germline APC mutation. MUTYH is the second (A)FAP-related gene and is involved with base-excision repair of DNA damaged by oxidative stress. MUTYH mutations are inherited in an autosomal recessive way and account for 10%-20% of classical FAP cases without an APC mutation and for 30% of AFAP cases. Genotype-phenotype correlations exist for mutations in the APC gene, however, contradictions in the literature caution against the sole use of the genotype for decisions regarding clinical management. Once the family's specific APC mutation is identified in the proband, predictive testing for first degree relatives is possible from the age of 10 to 12 years on. For AFAP, relatives are tested at age 18 and older. Opinions about the appropriate ages at which to initiate genetic testing may vary. Physicians must have a discussion about prenatal testing with patients in childbearing age. They may either opt for conventional prenatal diagnosis (amniocentesis or chorionic villous sampling) or for preimplantation genetic diagnosis (PGD).

Curine inhibits mast cell-dependent responses in mice.

PubMed

Ribeiro-Filho, Jaime; Leite, Fagner Carvalho; Costa, Hermann Ferreira; Calheiros, Andrea Surrage; Torres, Rafael Carvalho; de Azevedo, Carolina Trindade; Martins, Marco Aurélio; Dias, Celidarque da Silva; Bozza, Patrícia T; Piuvezam, Márcia Regina

2014-09-11

Curine is a bisbenzylisoquinoline alkaloid and the major constituent isolated from Chondrodendron platyphyllum, a plant that is used to treat inflammatory diseases in Brazilian folk medicine. This study investigates the effectiveness of curine on mast cell-dependent responses in mice. To induce mast cell-dependent responses, Swiss mice were subcutaneously sensitized with ovalbumin (OVA-12 μg/mouse) and Al(OH)3 in a 0.9% NaCl solution. Fifteen days later, the animals were challenged with OVA through different pathways. Alternatively, the animals were injected with compound 48/80 or histamine, and several parameters, including anaphylaxis, itching, edema and inflammatory mediator production, were analyzed. Promethazine, cromoglycate, and verapamil were used as control drugs, and all of the treatments were performed 1h before the challenges. Curine pre-treatment significantly inhibited the scratching behavior and the paw edema induced by either compound 48/80 or OVA, and this protective effect was comparable in magnitude with those associated with treatment with either cromoglycate or verapamil. In contrast, curine was a weak inhibitor of histamine-induced paw edema, which was completely inhibited by promethazine. Curine and verapamil significantly inhibited pleural protein extravasations and prostaglandin D2 (PGD2) and cysteinyl leukotrienes (CysLTs) production following allergen-induced pleurisy. Furthermore, like verapamil, curine inhibited the anaphylactic shock caused by either compound 48/80 or an allergen. In in vitro settings, these treatments also inhibited degranulation as well as PGD2 and CysLT production through IgE-dependent activation of the mast cell lineage RBL-2H3. Curine significantly inhibited immediate allergic reactions through mechanisms more related to mast cell stabilization and activation inhibition than interference with the pro-inflammatory effects of mast cell products. These findings are in line with the hypothesis that the alkaloid curine may be beneficial for the treatment of allergic disorders. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Time-dependent changes in the brain arachidonic acid cascade during cuprizone-induced demyelination and remyelination.

PubMed

Palumbo, S; Toscano, C D; Parente, L; Weigert, R; Bosetti, F

2011-07-01

Phospholipases A(2) (PLA(2)) are the enzymatic keys for the activation of the arachidonic acid (AA) cascade and the subsequent synthesis of pro-inflammatory prostanoids (prostaglandins and tromboxanes). Prostanoids play critical roles in the initiation and modulation of inflammation and their levels have been reported increased in several neurological and neurodegenerative disorders, including multiple sclerosis (MS). Here, we aimed to determine whether brain expression PLA(2) enzymes and the terminal prostagland in levels are changed during cuprizone-induced demyelination and in the subsequent remyelination phase. Mice were given the neurotoxicant cuprizone through the diet for six weeks to induce brain demyelination. Then, cuprizone was withdrawn and mice were returned to a normal diet for 6 weeks to allow spontaneous remyelination. We found that after 4-6 weeks of cuprizone, sPLA(2)(V) and cPLA(2), but not iPLA(2)(VI), gene expression was upregulated in the cortex, concomitant with an increase in the expression of astrocyte and microglia markers. Cyclooxygenase (COX)-2 gene expression was consistently upregulated during all the demyelination period, whereas COX-1 sporadically increased only at week 5 of cuprizone exposure. However, we found that at the protein level only sPLA(2)(V) and COX-1 were elevated during demyelination, with COX-1 selectively expressed by activated and infiltrated microglia/macrophages and astrocytes. Levels of PGE(2), PGD(2), PGI(2) and TXB(2) were also increased during demyelination. During remyelination, none of the PLA(2) isoforms was significantly changed, whereas COX-1 and -2 were sporadically upregulated only at the gene expression level. PGE(2), PGI(2) and PGD(2) levels returned to normal, whereas TXB(2) was still upregulated after 3 weeks of cuprizone withdrawal. Our study characterizes for the first time time-dependent changes in the AA metabolic pathway during cuprizone-induced demyelination and the subsequent remyelination and suggests that sPLA(2)(V) is the major isoform contributing to AA release. Published by Elsevier Ltd.

Exacerbating effects of PM2.5 in OVA-sensitized and challenged mice and the expression of TRPA1 and TRPV1 proteins in lungs.

PubMed

Liu, Hong; Fan, Xinsheng; Wang, Naiqian; Zhang, Yuyan; Yu, Jinghua

2017-10-01

To investigate the effects of particulate matter ≤ 2.5 microns (PM2.5) on asthma-related phenotypes and on lung expression of TRPA1 and TRPV1 proteins in a mouse model of asthma. Female BALB/c mice were utilized to establish 28- and 42-day asthma models. Mice were sensitized with ovalbumin (OVA) and challenged with OVA, OVA plus normal saline (NS), or OVA plus PM2.5 at two doses, 1.6 or 8.0 mg kg -1 . PM2.5 was instilled intratracheally without anesthesia. After the final OVA challenge was performed, 24 hours later, the changes in airway resistance (RI) and lung dynamic compliance (Cdyn) in response to acetylcholine chloride (ACH) were evaluated, and blood, bronchoalveolar lavage fluid (BALF) and lung tissue were taken at that time. The number of eosinophils in blood and various leukocytes in BALF were determined. Lung protein was extracted and probed for TRPA1 and TRPV1 expression. Interleukin (IL)-13, substance P (SP), prostaglandin D 2 (PGD 2 ) and nerve growth factor (NGF) in BALF were measured by enzyme-linked immunosorbent assay. PM2.5 treated mice showed significantly greater changes in the number of inflammatory cells in blood and BALF, in RI and Cdyn in response to ACH, and in lung histopathology, indicated by inflammatory cell infiltration, thickened bronchial smooth muscles and bronchial mucosa damage, compared to controls. In addition, higher expression of TRPA1 and TRPV1 in lung and IL-13, SP, PGD 2 and NGF in BALF were seen in mice exposed to PM2.5. All effects were most pronounced in mice in the 42-day model. PM2.5 exacerbates effects of asthma in this model, possibly by regulating TRPA1 and TRPV1 and the relevant neurokines.

New Insights on Taxonomy, Phylogeny and Population Genetics of Leishmania (Viannia) Parasites Based on Multilocus Sequence Analysis

PubMed Central

Boité, Mariana C.; Mauricio, Isabel L.; Miles, Michael A.; Cupolillo, Elisa

2012-01-01

The Leishmania genus comprises up to 35 species, some with status still under discussion. The multilocus sequence typing (MLST)—extensively used for bacteria—has been proposed for pathogenic trypanosomatids. For Leishmania, however, a detailed analysis and revision on the taxonomy is still required. We have partially sequenced four housekeeping genes—glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), mannose phosphate isomerase (MPI) and isocitrate dehydrogenase (ICD)—from 96 Leishmania (Viannia) strains and assessed their discriminatory typing capacity. The fragments had different degrees of diversity, and are thus suitable to be used in combination for intra- and inter-specific inferences. Species-specific single nucleotide polymorphisms were detected, but not for all species; ambiguous sites indicating heterozygosis were observed, as well as the putative homozygous donor. A large number of haplotypes were detected for each marker; for 6PGD a possible ancestral allele for L. (Viannia) was found. Maximum parsimony-based haplotype networks were built. Strains of different species, as identified by multilocus enzyme electrophoresis (MLEE), formed separated clusters in each network, with exceptions. NeighborNet of concatenated sequences confirmed species-specific clusters, suggesting recombination occurring in L. braziliensis and L. guyanensis. Phylogenetic analysis indicates L. lainsoni and L. naiffi as the most divergent species and does not support L. shawi as a distinct species, placing it in the L. guyanensis cluster. BURST analysis resulted in six clonal complexes (CC), corresponding to distinct species. The L. braziliensis strains evaluated correspond to one widely geographically distributed CC and another restricted to one endemic area. This study demonstrates the value of systematic multilocus sequence analysis (MLSA) for determining intra- and inter-species relationships and presents an approach to validate the species status of some entities. Furthermore, it contributes to the phylogeny of L. (Viannia) and might be helpful for epidemiological and population genetics analysis based on haplotype/diplotype determinations and inferences. PMID:23133690

[Establishment of a novel HLA genotyping method for preimplantation genetic diagnonis using multiple displacement amplification-polymerase chain reaction-sequencing based technique].

PubMed

Zhang, Yinfeng; Luo, Haining; Zhang, Yunshan

2015-12-01

To establish a novel HLA genotyping method for preimplantation genetic diagnonis (PGD) using multiple displacement amplification-polymerase chain reaction-sequencing based technique (MDA-PCR-SBT). Peripheral blood samples and 76 1PN, 2PN, 3PN discarded embryos from 9 couples were collected. The alleles of HLA-A, B, DR loci were detected from the MDA product with the PCR-SBT method. The HLA genotypes of the parental peripheral blood samples were analyzed with the same protocol. The genotypes of specific HLA region were evaluated for distinguishing the segregation of haplotypes among the family members, and primary HLA matching was performed between the embryos. The 76 embryos were subjected to MDA and 74 (97.4%) were successfully amplified. For the 34 embryos from the single blastomere group, the amplification rate was 94.1%, and for the 40 embryos in the two blastomeres group, the rate was 100%. The dropout rates for DQ allele and DR allele were 1.3% and 0, respectively. The positive rate for MDA in the single blastomere group was 100%, with the dropout rates for DQ allele and DR allele being 1.5% and 0, respectively. The positive rate of MDA for the two blastomere group was 100%, with the dropout rates for both DQ and DR alleles being 0. The recombination rate of fetal HLA was 20.2% (30/148). Due to the improper classification and abnormal fertilized embryos, the proportion of matched embryos HLA was 20.3% (15/74),which was lower than the theoretical value of 25%. PGD with HLA matching can facilitate creation of a HLA-identical donor (saviour child) for umbilical cord blood or bone marrow stem cells for its affected sibling with a genetic disease. Therefore, preimplantation HLA matching may provide a tool for couples desiring to conceive a potential donor progeny for transplantation for its sibling with a life-threatening disorder.

Time-dependent changes in the brain arachidonic acid cascade during cuprizone-induced demyelination and remyelination

PubMed Central

Palumbo, S.; Toscano, C.D.; Parente, L.; Weigert, R.; Bosetti, F.

2011-01-01

Phospholipases A2 (PLA2) are the enzymatic keys for the activation of the arachidonic acid (AA) cascade and the subsequent synthesis of proinflammatory prostanoids (prostaglandins and tromboxanes). Prostanoids play critical roles in the initiation and modulation of inflammation and their levels have been reported increased in several neurological and neurodegenerative disorders, including multiple sclerosis (MS). Here, we aimed to determine whether brain expression PLA2 enzymes and the terminal prostaglandin levels are changed during cuprizone-induced demyelination and in the subsequent remyelination phase. Mice were given the neurotoxicant cuprizone through the diet for six weeks to induce brain demyelination. Then, cuprizone was withdrawn and mice were returned to a normal diet for six weeks to allow spontaneous remyelination. We found that after 4–6 weeks of cuprizone, sPLA2(V) and cPLA2, but not iPLA2(VI), gene expression was upregulated in the cortex, concomitant with an increase in the expression of astrocyte and microglia markers. Cyclooxygenase (COX)-2 gene expression was consistently upregulated during all the demyelination period, whereas COX-1 sporadically increased only at week 5 of cuprizone exposure. However, we found that at the protein level only sPLA2(V) and COX-1 were elevated during demyelination, with COX-1 selectively expressed by activated and infiltrated microglia/macrophages and astrocytes. Levels of PGE2, PGD2, PGI2 and TXB2 were also increased during demyelination. During remyelination, none of the PLA2 isoforms was significantly changed, whereas COX-1 and -2 were sporadically upregulated only at the gene expression level. PGE2, PGI2, and PGD2 levels returned to normal, whereas TXB2 was still upregulated after 3 weeks of cuprizone withdrawal. Our study characterizes for the first time time-dependent changes in the AA metabolic pathway during cuprizone-induced demyelination and the subsequent remyelination and suggests that sPLA2(V) is the major isoform contributing to AA release. PMID:21530210

Dosimetric verification of small fields in the lung using lung-equivalent polymer gel and Monte Carlo simulation.

PubMed

Gharehaghaji, Nahideh; Dadgar, Habib Alah

2018-01-01

The main purpose of this study was evaluate a polymer-gel-dosimeter (PGD) for three-dimensional verification of dose distributions in the lung that is called lung-equivalent gel (LEG) and then to compare its result with Monte Carlo (MC) method. In the present study, to achieve a lung density for PGD, gel is beaten until foam is obtained, and then sodium dodecyl sulfate is added as a surfactant to increase the surface tension of the gel. The foam gel was irradiated with 1 cm × 1 cm field size in the 6 MV photon beams of ONCOR SIEMENS LINAC, along the central axis of the gel. The LEG was then scanned on a 1.5 Tesla magnetic resonance imaging scanner after irradiation using a multiple-spin echo sequence. Least-square fitting the pixel values from 32 consecutive images using a single exponential decay function derived the R2 relaxation rates. Moreover, 6 and 18 MV photon beams of ONCOR SIEMENS LINAC are simulated using MCNPX MC Code. The MC model is used to calculate the depth dose water and low-density water resembling the soft tissue and lung, respectively. Percentages of dose reduction in the lung region relative to homogeneous phantom for 6 MV photon beam were 44.6%, 39%, 13%, and 7% for 0.5 cm × 0.5 cm, 1 cm × 1 cm, 2 cm × 2 cm, and 3 cm × 3 cm fields, respectively. For 18 MV photon beam, the results were found to be 82%, 69%, 46%, and 25.8% for the same field sizes, respectively. Preliminary results show good agreement between depth dose measured with the LEG and the depth dose calculated using MCNP code. Our study showed that the dose reduction with small fields in the lung was very high. Thus, inaccurate prediction of absorbed dose inside the lung and also lung/soft-tissue interfaces with small photon beams may lead to critical consequences for treatment outcome.

Pre-implantation diagnosis of aneuploidy by polar body and blastomere FISH analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Munne, S.; Cohen, J.; Grifo, J.

1994-09-01

For preimplantation genetic diagnosis (PGD) of aneuploidy in human in-vitro fertilization (IVF), two blastomeres per embryo should be analyzed to minimize errors caused by FISH and mosaicism. But the biopsy of two cells from an 8-cell embryo can be detrimental. This can be substituted by initial FISH analysis of the first polar body (PB) and subsequent single blastomere analysis. Simultaneous FISH analysis of chromosomes X, Y, 18, 13/21 was used for first polar body aneuploidy analysis. Normal divalents appeared as single-dotted signals corresponding to their two chromatids. We found that pre-division of chromatids increased dramatically with time in culture. Allmore » but three pre-division events involved separation of chromatids within the PB or the egg, with a total of two chromatids in each. We concluded that PB aneuploidy analysis is safe when performed within 6 hours after egg retrieval. For our first clinical case we chose a 39 year-old female carrier of an X-linked disease already selected for FISH pre-implantation diagnosis. Eight polar bodies from 12 eggs were analyzed: six showed a normal X181321 complement of divalents; one had an extra chromatid for 13/21 (egg {number_sign}8); and one had a missing chromatid for 13/21 (egg {number_sign}10). After insemination, six fertilized eggs developed into embryos, including egg {number_sign}10 but not egg {number_sign}8. At day 3 of development, a single blastomere per embryo was analyzed by FISH. According to the blastomere analysis, one embryo was haploid, one tetraploid. The two normal female embryos were replaced and pregnancy and CFS results are pending. These results suggest that this technique can be successfully applied for PGD of major aneuploidies in IVF patients over 35. In addition, it indicates that studies on pre-division should be performed on eggs within six hours of retrieval.« less

A novel antipyretic action of 15-deoxy-Delta12,14-prostaglandin J2 in the rat brain.

PubMed

Mouihate, Abdeslam; Boissé, Lysa; Pittman, Quentin J

2004-02-11

Fever is an important part of the host defense response, yet fever can be detrimental if it is uncontrolled. We provide the first evidence that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), can attenuate the febrile response to lipopolysaccharide (LPS) in rats via an action on the brain. Furthermore, we show that PPARgamma is expressed in the hypothalamus, an important locus in the brain for fever generation. In addition, 15d-PGJ2 and its synthesizing enzyme (PGD2 synthase) were present in rat cerebrospinal fluid, and their levels were enhanced in response to systemic injection of LPS. The antipyretic effect of 15d-PGJ2 was associated with reduction in LPS-stimulated cyclooxygenase-2 expression in the hypothalamus but not in p44/p42 mitogen-activated protein kinase phosphorylation or in the expression of the PPARgamma. Thus it is likely that there is a parallel induction of an endogenous prostanoid pathway in the brain capable of limiting deleterious actions of the proinflammatory prostaglandin E2-dependent pathway.

Hearing the implant debate: therapy or cultural alienation?

PubMed

Baertschi, Bernard

2013-12-01

Cochlear implants are devices that allow deaf people to hear. Consequently, implanting them in children seems to be a very beneficent intervention. However, some deaf parents have opposed it in the name of the preservation of their culture. For them, deafness is a rich culture with its own language (signing), and implanting their children will prevent them from being members of their parents' culture. For the same reason, other deaf parents have asked for PGD (preimplantation genetic diagnoses) and embryo selection in order to have deaf children. Several arguments can be given in favour of the attitude and of the requests of deaf parents; nevertheless, I conclude that, ultimately, they cannot be morally supported because deafness is a true handicap in our civilization of information.

Indomethacin inhibits the effects of oestrogen in the anterior pituitary gland of the rat.

PubMed

Rosental, D G; Machiavelli, G A; Cherñavsky, A C; Speziale, N S; Burdman, J A

1989-06-01

Two inhibitors of prostaglandin synthesis, indomethacin and aspirin, blocked the increase of oestrogen-binding sites in the nuclear subcellular fraction, an increase which occurs after the administration of oestradiol. Consequently the biological effects of oestrogens in the anterior pituitary gland of the rat (prolactin synthesis, concentration of progesterone-binding sites and cell proliferation) are diminished. The anterior pituitary gland synthesized prostaglandin F2 alpha (PGF2 alpha), PGE2 and PGD2 from arachidonic acid. This synthesis was blocked when indomethacin was added to the culture media. Oestrogen increased the concentration of PGE2: an increase that was partially prevented by indomethacin. Prostaglandins may have an important role on the effects of oestrogen in the anterior pituitary gland of the rat.

Poly-γ-glutamic Acid Synthesis, Gene Regulation, Phylogenetic Relationships, and Role in Fermentation

PubMed Central

Hsueh, Yi-Huang; Huang, Kai-Yao; Kunene, Sikhumbuzo Charles; Lee, Tzong-Yi

2017-01-01

Poly-γ-glutamic acid (γ-PGA) is a biodegradable biopolymer produced by several bacteria, including Bacillus subtilis and other Bacillus species; it has good biocompatibility, is non-toxic, and has various potential biological applications in the food, pharmaceutical, cosmetic, and other industries. In this review, we have described the mechanisms of γ-PGA synthesis and gene regulation, its role in fermentation, and the phylogenetic relationships among various pgsBCAE, a biosynthesis gene cluster of γ-PGA, and pgdS, a degradation gene of γ-PGA. We also discuss potential applications of γ-PGA and highlight the established genetic recombinant bacterial strains that produce high levels of γ-PGA, which can be useful for large-scale γ-PGA production. PMID:29215550

Assisted procreation and its relationship to genetics and eugenics.

PubMed

Ricci, Mariella Lombardi

2009-01-01

The article below is intended to reflect on whether or not a eugenic tendency constitutes an intrinsic element of human fertilization in vitro. The author outlines ideas and circumstances which characterized the foundation and propagation of eugenics between the eighteenth and nineteenth centuries. A brief discussion follows on some of the standard procedures of in vitro fertilization, and in particular, those which manifest a trace or hint of eugenics--heterologous fertilization and sperm banking, preimplantation genetic diagnosis (PGD) and embryo selection--practices which, nonetheless, are used on a large scale and shed light on both the essence of procreative medicine and on the current cultural environment. The objective of the article is to explore whether it is possible to eliminate the eugenic connotations without foregoing the benefits of technical and scientific progress.

Sharing Patient-Generated Data in Clinical Practices: An Interview Study.

PubMed

Zhu, Haining; Colgan, Joanna; Reddy, Madhu; Choe, Eun Kyoung

2016-01-01

Patients are tracking and generating an increasingly large volume of personal health data outside the clinic due to an explosion of wearable sensing and mobile health (mHealth) apps. The potential usefulness of these data is enormous as they can provide good measures of everyday behavior and lifestyle. However, how we can fully leverage patient-generated data (PGD) and integrate them in clinical practice is less clear. In this interview study, we aim to understand how patients and clinicians currently share patient-generated data in clinical care practice. From the study, we identified technical, social, and organizational challenges in sharing and fully leveraging patient-generated data in clinical practices. Our findings can provide researchers potential avenues for enablers and barriers in sharing patient-generated data in clinical settings.

Microgeographic and temporal genetic variation in populations of the bluetongue virus vector Culicoides variipennis (Diptera: Ceratopogonidae).

PubMed

Tabachnick, W J

1992-05-01

Seven Colorado populations of the bluetongue virus vector Culicoides varipennis (Coquillett) were analyzed for genetic variation at 19-21 isozyme loci. Permanent populations, which overwinter as larvae, showed little temporal genetic change at 19 loci. PGD and MDH showed seasonal changes in gene frequencies, attributable to selection at two permanent populations. Two temporary populations showed low heterozygosity compared with permanent populations. Independent estimates of gene flow, calculated using FST and the private allele method, were Nm* = 2.15 and 6.95, respectively. Colorado C. variipennis permanent populations showed high levels of gene flow which prevented significant genetic differentiation due to genetic drift. Temporary populations showed significant gene frequency differences from nearby permanent populations due to the "founder effect" associated with chance colonization.

Multi-therapies in androgenetic alopecia: review and clinical experiences.

PubMed

Rossi, Alfredo; Anzalone, Alessia; Fortuna, Maria Caterina; Caro, Gemma; Garelli, Valentina; Pranteda, Giulia; Carlesimo, Marta

2016-11-01

Androgenetic alopecia (AGA) is a genetically determined progressive hair-loss condition which represents the most common cause of hair loss in men. The use of the medical term androgenetic alopecia reflects current knowledge about the important role of androgens and genetic factors in its etiology. In addition to androgen-dependent changes in the hair cycle, sustained microscopic follicular inflammation contributes to its onset. Furthermore, Prostaglandins have been demonstrated to have the ability in modulating hair follicle cycle; in particular, PGD2 inhibits hair growth while PGE2/F2a promote growth. Due to the progressive nature of AGA, the treatment should be started early and continued indefinitely, since the benefit will not be maintained upon ceasing therapy. To date, only two therapeutic agents have been approved by the Food and Drug Administration and European Medicines Agency for the treatment of AGA: topical minoxidil and oral finasteride. Considering the many pathogenetic mechanisms involved in AGA, various treatment options are available: topical and systemic drugs may be used and the choice depends on various factors including grading of AGA, patients' pathological conditions, practicability, costs and risks. So, the treatment for AGA should be based on personalized therapy and targeted at the different pathophysiological aspects of AGA. © 2016 Wiley Periodicals, Inc.

The low molecular weight fraction of human serum albumin upregulates COX2, prostaglandin E2, and prostaglandin D2 under inflammatory conditions in osteoarthritic knee synovial fibroblasts.

PubMed

Frederick, Elizabeth D; Hausburg, Melissa A; Thomas, Gregory W; Rael, Leonard T; Brody, Edward; Bar-Or, David

2016-12-01

The ability to decrease inflammation and promote healing is important in the intervention and management of a variety of disease states, including osteoarthritis of the knee (OAK). Even though cyclooxygenase 2 (COX2) has an established pro-inflammatory role, evidence suggests it is also critical to the resolution that occurs after the initial activation phase of the immune response. In this study, we investigated the effects of the low molecular weight fraction of 5% human serum albumin (LMWF-5A), an agent that has proven to decrease pain and improve function in OAK patients after intra-articular injection, on the expression of COX2 and its downstream products, prostaglandins (PGs). Fibroblast-like synoviocytes from the synovial membrane of OAK patients were treated with LMWF-5A or saline as a control with or without the addition of interleukin-1β (IL-1β) or tumor necrosis factor α (TNFα) to elicit an inflammatory response. Cells were harvested for RNA and protein at 2, 4, 8, 12, and 24 h, and media was collected at 24 h for analysis of secreted products. COX2 mRNA expression was determined by qPCR, and COX2 protein expression was determined by western blot analysis. Levels of prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2) in the media were quantified by competitive ELISA. In the presence of either IL-1β or TNFα, LMWF-5A increased the expression of both COX2 mRNA and protein, and this increase was significant compared to that observed with IL-1β- or TNFα-stimulated, saline-treated cells. Downstream of COX2, the levels of PGE2 were increased only in TNFα-stimulated, LMWF-5A-treated cells; however, in both IL-1β- and TNFα-stimulated cells, LMWF-5A increased the release of the anti-inflammatory prostaglandin PGD2. LMWF-5A appears to trigger increased anti-inflammatory PG signaling, and this may be a primary component of its therapeutic mode of action in the treatment of OAK.

The effect of a germline mutation in the APC gene on β-catenin in human embryonic stem cells.

PubMed

Yedid, Nofar; Kalma, Yael; Malcov, Mira; Amit, Ami; Kariv, Revital; Caspi, Michal; Rosin-Arbesfeld, Rina; Ben-Yosef, Dalit

2016-12-23

Most cases of colorectal cancer (CRC) are initiated by inactivation mutations in the APC gene, which is a negative regulator of the Wnt-β-catenin pathway. Patients with familial adenomatous polyposis (FAP) inherit a germline mutation in one APC allele, and loss of the second allele leads to the development of polyps that will turn malignant if not removed. It is not fully understood which molecular mechanisms are activated by APC loss and when the loss of the second APC allele occurs. Two FAP human embryonic stem cell (hESCs) lines were derived from APC mutated embryos following pre-implantation genetic diagnosis (PGD) for FAP. These FAP-hESCs were cultured in vitro and following extended culture: 1) β-catenin expression was analyzed by Western blot analysis; 2) Wnt-β-catenin/TCF-mediated transcription luciferase assay was performed; 3) cellular localization of β-catenin was evaluated by immunoflorecence confocal microscopy; and 4) DNA sequencing of the APC gene was performed. We have established a novel human in-vitro model for studying malignant transformation, using hESCs that carry a germline mutation in the APC gene following PGD for FAP. Extended culturing of FAP1 hESCs led to activation of the Wnt signaling pathway, as demonstrated by enhanced β-catenin/TCF-mediated activity. Additionally, β-catenin showed a distinct perinuclear distribution in most (91 %) of the FAP1 hESCs high passage colonies. DNA sequencing of the whole gene detected several polymorphisms in FAP1 hESCs, however, no somatic mutations were discovered in the APC gene. On the other hand, no changes in β-catenin were detected in the FAP2 hESCs, demonstrating the natural diversity of the human FAP population. Our results describe the establishment of novel hESC lines from FAP patients with a predisposition for cancer mutation. These cells can be maintained in culture for long periods of time and may serve as a platform for studying the initial molecular and cellular changes that occur during early stages of malignant transformation.

[Measurement of bronchoconstrictive eicosanoids in chronic obstructive pulmonary disease].

PubMed

Gross-Sondej, Iwona; Soja, Jerzy; Sładek, Krzysztof; Pulka, Grażyna; Skucha, Wojciech; Niżankowska-Mogilnicka, Ewa

2012-01-01

The aim of the study was the evaluation of the concentration of 9α11β prostaglandin F(2) - a stable metabolite of prostaglandin D(2) (PGD(2)) and leukotriene E(4) (LTE(4)) in stable and exacerbated COPD patients. 29 COPD patients aged 73 ± 8.34, mean FEV1 = 48.64 ± 15.75% of predictive value and 29 healthy controls aged 57.48 ± 10.86, mean FEV1 = 97.17 ± 13.81% of predictive value participated in this study. Samples of urine and blood were taken from COPD patients during exacerbation and in stable state of the disease; LTE(4) was determined in urine using commercial enzyme immunoassay (EIA) and 9α11β prostaglandin F(2) (9α11βPGF(2)) - stable metabolite of PGD(2) was evaluated in blood and urine using GC/MS. LTE(4) concentration in urine (677.15 vs. 436.4 pg/mg of creatinine; p = 0.035) and 9α11βPGF(2) in blood serum (5.35 vs. 3.07 pg/ml; p = 0.007) were significantly higher in exacerbated COPD patients than in control group. There was no difference in LTE(4) level in urine and 9α11βPGF2 in blood serum between exacerbated and stable COPD. The urinary 9α11βPGF(2) concentration did not differ between all studied groups. We found a positive correlation between smoking history and the urine LTE(4) level (r = 0.395; p = 0.002) as well as blood 9α11βPGF(2) concentration (r = 0.603; p = 0.001) in COPD patients. 9α11βPGF(2) and LTE(4) level in urine did not differ between the stable COPD group and the control group. We also did not find any difference between LTE4 level in urine and 9α11βPGF(2) in blood and urine between exacerbated and stable COPD. Finally, LTE(4) concentration in urine and 9α11βPGF(2) in blood occurred to be significantly higher in exacerbated COPD patients than in control group.

Single-Cell Whole-Genome Amplification and Sequencing: Methodology and Applications.

PubMed

Huang, Lei; Ma, Fei; Chapman, Alec; Lu, Sijia; Xie, Xiaoliang Sunney

2015-01-01

We present a survey of single-cell whole-genome amplification (WGA) methods, including degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR), multiple displacement amplification (MDA), and multiple annealing and looping-based amplification cycles (MALBAC). The key parameters to characterize the performance of these methods are defined, including genome coverage, uniformity, reproducibility, unmappable rates, chimera rates, allele dropout rates, false positive rates for calling single-nucleotide variations, and ability to call copy-number variations. Using these parameters, we compare five commercial WGA kits by performing deep sequencing of multiple single cells. We also discuss several major applications of single-cell genomics, including studies of whole-genome de novo mutation rates, the early evolution of cancer genomes, circulating tumor cells (CTCs), meiotic recombination of germ cells, preimplantation genetic diagnosis (PGD), and preimplantation genomic screening (PGS) for in vitro-fertilized embryos.

A LATIN-based model reduction approach for the simulation of cycling damage

NASA Astrophysics Data System (ADS)

Bhattacharyya, Mainak; Fau, Amelie; Nackenhorst, Udo; Néron, David; Ladevèze, Pierre

2017-11-01

The objective of this article is to introduce a new method including model order reduction for the life prediction of structures subjected to cycling damage. Contrary to classical incremental schemes for damage computation, a non-incremental technique, the LATIN method, is used herein as a solution framework. This approach allows to introduce a PGD model reduction technique which leads to a drastic reduction of the computational cost. The proposed framework is exemplified for structures subjected to cyclic loading, where damage is considered to be isotropic and micro-defect closure effects are taken into account. A difficulty herein for the use of the LATIN method comes from the state laws which can not be transformed into linear relations through an internal variable transformation. A specific treatment of this issue is introduced in this work.

The impact of eicosanoids on the crosstalk between innate and adaptive immunity: the key roles of dendritic cells.

PubMed

Harizi, H; Gualde, N

2005-06-01

The innate immune response is essentially the first line of defense against an invading pathogen. Through specialized receptors, known as pattern recognition receptors, especially Toll-like receptors, specialized cells of myeloid origin, including macrophages and dendritic cells (DCs) are able to phagocytose microorganisms and induce an innate inflammatory response. Although B and T lymphocytes recognize tissue antigens with high specificity, they are unable to initiate immune responses. The decision to activate an appropriate immune response is made by unique DC, the most professional antigen-presenting cells (APCs) which control the responses of several types of lymphocytes and play central role in the transition between innate and adaptive immunity. Increased secretion of inflammatory endogenous mediators such as cytokines and arachidonic acid-derived lipid mediators, also termed eicosanoids, can activate APC, particularly DC, which in turn induce an adaptive immune response. There is an increasing evidence that eicosanoids play an important role in connecting innate and adaptive immunity by acting on cells of both systems. Prostanoids, a major class of eicosanoids, have a great impact on inflammatory and immune responses. PGE(2) is one of the best known and most well-characterized prostanoids in terms of immunomodulation. Although cytokines are known as key regulators of immunity, eicosanoids, including PGE(2), PGD(2), LTB(4), and LTC(4), may also affect cells of immune system by modulating cytokine release, cell differentiation, survival, migration, antigen presentation, and apoptosis. By acting on various aspects of immune and inflammatory reactions, these lipid mediators emerge as key regulators of the crosstalk between innate and adaptive immunity.

Association of abnormal morphology and altered gene expression in human preimplantation embryos.

PubMed

Wells, Dagan; Bermúdez, Mercedes G; Steuerwald, Nury; Malter, Henry E; Thornhill, Alan R; Cohen, Jacques

2005-08-01

We set out to characterize the expression of nine genes in human preimplantation embryos and determine whether abnormal morphology is associated with altered gene activity. Reverse transcription and real-time polymerase chain reaction were used to quantify the expression of multiple genes in each embryo. The genes studied have various important cellular roles (e.g., cell cycle regulation, DNA repair, and apoptosis). Research laboratory working closely with a clinical IVF practice. Over 50 embryos were donated by infertile patients (various etiologies). Among these, all major stages of preimplantation development and a variety of common morphologic abnormalities were represented. None. Quantification of mRNA transcripts. We detected an association between certain forms of abnormal morphology and disturbances of gene activity. Cellular fragmentation was associated with altered expression of several genes, including TP53, suggesting that fragmenting blastomeres are suffering stress of a type monitored by p53, possibly as a consequence of suboptimal culture conditions. Appropriate gene expression is vital for the regulation of metabolic pathways and key developmental events. Our data indicates a possible causal relationship between changes in gene expression and the formation of clinically relevant abnormal embryo morphologies. We hypothesize that embryos with expression profiles characteristic of good morphology and appropriate for their developmental stage have the greatest potential for implantation. If confirmed, this could lead to a new generation of preimplantation genetic diagnosis (PGD) tests for assessing embryo viability and predicting implantation potential.

Hematopoietic prostaglandin D synthase (HPGDS): a high stability, Val187Ile isoenzyme common among African Americans and its relationship to risk for colorectal cancer

PubMed Central

Tippin, Brigette L.; Levine, A. Joan; Materi, Alicia M.; Song, Wen-Liang; Keku, Temitope O.; Goodman, Julie E.; Sansbury, Leah B.; Das, Sudipto; Dai, Aihua; Kwong, Alan M.; Lin, Amy M.; Lin, John M.; Park, Jae Man; Patterson, Ruth E.; Chlebowski, Rowan T.; Garavito, R. Michael; Inoue, Tsuyoshi; Cho, Wonhwa; Lawson, John A.; Kapoor, Shiv; Kolonel, Laurence N.; Marchand, Loïc Le; Haile, Robert W.; Sandler, Robert S.; Lin, Henry J.

2011-01-01

Intestinal tumors in ApcMin/+ mice are suppressed by over-production of HPGDS, which is a glutathione transferase that forms prostaglandin D2 (PGD2). We characterized naturally occurring HPGDS isoenzymes, to see if HPGDS variation is associated with human colorectal cancer risk. We used DNA heteroduplex analysis and sequencing to identify HPGDS variants among healthy individuals. HPGDS isoenzymes were produced in bacteria, and their catalytic activities were tested. To determine in vivo effects, we conducted pooled case-control analyses to assess whether there is an association of the isoenzyme with colorectal cancer. Roughly 8% of African Americans and 2% of Caucasians had a highly stable Val187lle isoenzyme (with isoleucine instead of valine at position 187). At 37 °C, the wild-type enzyme lost 15% of its activity in one hour, whereas the Val187Ile form remained >95% active. At 50 °C, the half life of native HPGDS was 9 minutes, compared to 42 minutes for Val187Ile. The odds ratio for colorectal cancer among African Americans with Val187Ile was 1.10 (95% CI, 0.75–1.62; 533 cases, 795 controls). Thus, the Val187Ile HPGDS isoenzyme common among African Americans is not associated with colorectal cancer risk. Other approaches will be needed to establish a role for HPGDS in occurrence of human intestinal tumors, as indicated by a mouse model. PMID:21821144

A visual analytics approach for pattern-recognition in patient-generated data.

PubMed

Feller, Daniel J; Burgermaster, Marissa; Levine, Matthew E; Smaldone, Arlene; Davidson, Patricia G; Albers, David J; Mamykina, Lena

2018-06-13

To develop and test a visual analytics tool to help clinicians identify systematic and clinically meaningful patterns in patient-generated data (PGD) while decreasing perceived information overload. Participatory design was used to develop Glucolyzer, an interactive tool featuring hierarchical clustering and a heatmap visualization to help registered dietitians (RDs) identify associative patterns between blood glucose levels and per-meal macronutrient composition for individuals with type 2 diabetes (T2DM). Ten RDs participated in a within-subjects experiment to compare Glucolyzer to a static logbook format. For each representation, participants had 25 minutes to examine 1 month of diabetes self-monitoring data captured by an individual with T2DM and identify clinically meaningful patterns. We compared the quality and accuracy of the observations generated using each representation. Participants generated 50% more observations when using Glucolyzer (98) than when using the logbook format (64) without any loss in accuracy (69% accuracy vs 62%, respectively, p = .17). Participants identified more observations that included ingredients other than carbohydrates using Glucolyzer (36% vs 16%, p = .027). Fewer RDs reported feelings of information overload using Glucolyzer compared to the logbook format. Study participants displayed variable acceptance of hierarchical clustering. Visual analytics have the potential to mitigate provider concerns about the volume of self-monitoring data. Glucolyzer helped dietitians identify meaningful patterns in self-monitoring data without incurring perceived information overload. Future studies should assess whether similar tools can support clinicians in personalizing behavioral interventions that improve patient outcomes.

Genetic structure of Quechua-speakers of the Central Andes and geographic patterns of gene frequencies in South Amerindian populations.

PubMed

Luiselli, D; Simoni, L; Tarazona-Santos, E; Pastor, S; Pettener, D

2000-09-01

A sample of 141 Quechua-speaking individuals of the population of Tayacaja, in the Peruvian Central Andes, was typed for the following 16 genetic systems: ABO, Rh, MNSs, P, Duffy, AcP1, EsD, GLOI, PGM1, AK, 6-PGD, Hp, Gc, Pi, C3, and Bf. The genetic structure of the population was analyzed in relation to the allele frequencies available for other South Amerindian populations, using a combination of multivariate and multivariable techniques. Spatial autocorrelation analysis was performed independently for 13 alleles to identify patterns of gene flow in South America as a whole and in more specific geographic regions. We found a longitudinal cline for the AcP1*a and EsD*1 alleles which we interpreted as the result of an ancient longitudinal expansion of a putative ancestral population of modern Amerindians. Monmonnier's algorithm, used to identify areas of sharp genetic discontinuity, suggested a clear east-west differentiation of native South American populations, which was confirmed by analysis of the distribution of genetic distances. We suggest that this pattern of genetic structures is the consequence of the independent peopling of western and eastern South America or to low levels of gene flow between these regions, related to different environmental and demographic histories. Copyright 2000 Wiley-Liss, Inc.

Searching for otherness: the view of a novel.

PubMed

Magalhães, Susana; Carvalho, Ana Sofia

2010-01-01

The ethical issues concerning the use of PGD (Preimplantation Genetic Diagnosis) to select embryos of a particular HLA (Human Leukocyte Antigen) type are numerous. They arise from the potentially conflicting interests between those of the pre-existing child, the subject of a treatment which may be curative, and those of the sibling to be created, who cannot give consent to the donation, together with the problem of the destruction of potentially healthy embryos. This essay focuses on the web of vulnerabilities affecting the parents, the sick child and the "saviour sibling," while addressing three areas: science, bioethics and literature. The novel My Sister's Keeper, by Jodi Picoult, provides the reader with an in-depth view of the conflicting interests and emotional problems that affect the Fitzgeralds, a family experiencing the pain of seeing one of their children dying while facing the tragic consequences of trying to save this child by having another offspring.

[Psychosexual aspects of intersex syndromes].

PubMed

Bosinski, H A G

2006-08-01

Disorders of somatosexual development that lead to ambiguous genitalia occur in one from 3,000-5,000 newborns. Parents and health care professionals are confronted with a number of crucial questions: to what sex should the child be assigned, what is the appropriate treatment in terms of hormonal and surgical interventions, when and how should these take place, and what impact do they have on the development of gender identity (GI), psychosexual well-being and fertility? This paper reviews the etiology, treatment and outcome in terms of GI and sexual health for the following syndromes: congenital adrenal hyperplasia (CAH), complete and partial androgen insensitivity (cAIS, pAIS), and pure and mixed gonadal dysgenesis (pGD, mGD). Emphasis is focussed on the current discussion involving the timing and extent of genital surgery. Finally, a procedure is introduced that covers the sexual-medical needs of patients, parents and health care professionals.

ANNIT - An Efficient Inversion Algorithm based on Prediction Principles

NASA Astrophysics Data System (ADS)

Růžek, B.; Kolář, P.

2009-04-01

Solution of inverse problems represents meaningful job in geophysics. The amount of data is continuously increasing, methods of modeling are being improved and the computer facilities are also advancing great technical progress. Therefore the development of new and efficient algorithms and computer codes for both forward and inverse modeling is still up to date. ANNIT is contributing to this stream since it is a tool for efficient solution of a set of non-linear equations. Typical geophysical problems are based on parametric approach. The system is characterized by a vector of parameters p, the response of the system is characterized by a vector of data d. The forward problem is usually represented by unique mapping F(p)=d. The inverse problem is much more complex and the inverse mapping p=G(d) is available in an analytical or closed form only exceptionally and generally it may not exist at all. Technically, both forward and inverse mapping F and G are sets of non-linear equations. ANNIT solves such situation as follows: (i) joint subspaces {pD, pM} of original data and model spaces D, M, resp. are searched for, within which the forward mapping F is sufficiently smooth that the inverse mapping G does exist, (ii) numerical approximation of G in subspaces {pD, pM} is found, (iii) candidate solution is predicted by using this numerical approximation. ANNIT is working in an iterative way in cycles. The subspaces {pD, pM} are searched for by generating suitable populations of individuals (models) covering data and model spaces. The approximation of the inverse mapping is made by using three methods: (a) linear regression, (b) Radial Basis Function Network technique, (c) linear prediction (also known as "Kriging"). The ANNIT algorithm has built in also an archive of already evaluated models. Archive models are re-used in a suitable way and thus the number of forward evaluations is minimized. ANNIT is now implemented both in MATLAB and SCILAB. Numerical tests show good performance of the algorithm. Both versions and documentation are available on Internet and anybody can download them. The goal of this presentation is to offer the algorithm and computer codes for anybody interested in the solution to inverse problems.

Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats

PubMed Central

2014-01-01

Background A thorough investigation of the neurobiology of HIV-induced neuronal dysfunction and its evolving phenotype in the setting of viral suppression has been limited by the lack of validated small animal models to probe the effects of concomitant low level expression of multiple HIV-1 products in disease-relevant cells in the CNS. Results We report the results of gene expression profiling of the hippocampus of HIV-1 Tg rats, a rodent model of HIV infection in which multiple HIV-1 proteins are expressed under the control of the viral LTR promoter in disease-relevant cells including microglia and astrocytes. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analysis. Gene expression changes observed are consistent with astrogliosis and microgliosis and include evidence of inflammation and cell proliferation. Among the genes with increased expression in HIV-1 Tg rats was the interferon stimulated gene 15 (ISG-15), which was previously shown to be increased in the cerebrospinal fluid (CSF) of HIV patients and to correlate with neuropsychological impairment and neuropathology, and prostaglandin D2 (PGD2) synthase (Ptgds), which has been associated with immune activation and the induction of astrogliosis and microgliosis. GSEA-based pathway analysis highlighted a broad dysregulation of genes involved in neuronal trophism and neurodegenerative disorders. Among the latter are genesets associated with Huntington’s disease, Parkinson’s disease, mitochondrial, peroxisome function, and synaptic trophism and plasticity, such as IGF, ErbB and netrin signaling and the PI3K signal transduction pathway, a mediator of neural plasticity and of a vast array of trophic signals. Additionally, gene expression analyses also show altered lipid metabolism and peroxisomes dysfunction. Supporting the functional significance of these gene expression alterations, HIV-1 Tg rats showed working memory impairments in spontaneous alternation behavior in the T-Maze, a paradigm sensitive to prefrontal cortex and hippocampal function. Conclusions Altogether, differentially regulated genes and pathway analysis identify specific pathways that can be targeted therapeutically to increase trophic support, e.g. IGF, ErbB and netrin signaling, and reduce neuroinflammation, e.g. PGD2 synthesis, which may be beneficial in the treatment of chronic forms of HIV-associated neurocognitive disorders in the setting of viral suppression. PMID:24980976

15-Deoxy-{delta}{sup 12,14}-prostaglandin J{sub 2} down-regulates CXCR4 on carcinoma cells through PPAR{gamma}- and NF{kappa}B-mediated pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richard, Cynthia Lee; Lowthers, Erica Lauren; Blay, Jonathan

2007-10-01

The chemokine receptor CXCR4 plays a key role in the metastasis of colorectal cancer and its growth at metastatic sites. Here, we have investigated the mechanisms by which CXCR4 on cancer cells might be regulated by eicosanoids present within the colorectal tumor microenvironment. We show that prostaglandins PGE{sub 2}, PGA{sub 2}, PGD{sub 2}, PGJ{sub 2} and 15dPGJ{sub 2} each down-regulates CXCR4 receptor expression on human colorectal carcinoma cells to differing degrees. The most potent of these were PGD{sub 2} and its metabolites PGJ{sub 2} and 15dPGJ{sub 2}. Down-regulation was most rapid with the end-product 15dPGJ{sub 2} and was accompanied bymore » a marked reduction in CXCR4 mRNA. 15dPGJ{sub 2} is known to be a ligand for the nuclear receptor PPAR{gamma}. Down-regulation of CXCR4 was also observed with the PPAR{gamma} agonist rosiglitazone, while 15dPGJ{sub 2}-induced CXCR4 down-regulation was substantially diminished by the PPAR{gamma} antagonists GW9662 and T0070907. These data support the involvement of PPAR{gamma}. However, the 15dPGJ{sub 2} analogue CAY10410, which can act on PPAR{gamma} but which lacks the intrinsic cyclopentenone structure found in 15dPGJ{sub 2}, down-regulated CXCR4 substantially less potently than 15dPGJ{sub 2}. The cyclopentenone grouping is known to inhibit the activity of NF{kappa}B. Consistent with an additional role for NF{kappa}B, we found that the cyclopentenone prostaglandin PGA{sub 2} and cyclopentenone itself could also down-regulate CXCR4. Immunolocalization studies showed that the cellular context was sufficient to trigger a focal nuclear pattern of NF{kappa}B p50 and that 15dPGJ{sub 2} interfered with this p50 nuclear localization. These data suggest that 15dPGJ{sub 2} can down-regulate CXCR4 on cancer cells through both PPAR{gamma} and NF{kappa}B. 15dPGJ{sub 2}, present within the tumor microenvironment, may act to down-regulate CXCR4 and impact upon the overall process of tumor expansion.« less

Species differences in the effects of prostanoids on MAP kinase phosphorylation, myosin light chain phosphorylation and contraction in bovine and cat iris sphincter smooth muscle.

PubMed

Kaddour-Djebbar, I; Ansari, H R; Akhtar, R A; Abdel-Latif, A A

2005-01-01

There is evidence from our own laboratory and that of others that EP-receptor ligands are strong contractile agonists in bovine iris sphincter and that FP-receptor agonists are strong contractile agonists in cat iris sphincter. Here, we have investigated the effects of prostaglandin (PG) receptor agonists of the FP-, EP-, TP- and DP-class on myosin light chain (MLC) phosphorylation, p42/p44 MAP kinase phosphorylation and contraction in the iris sphincter of bovine and cat. Using three signal transduction mechanism assays, namely MLC phosphorylation, MAP kinase phosphorylation and contraction, we demonstrated that in bovine iris sphincter the rank order of potency of the PG agonists in the contractile and MLC phosphorylation assays is as follows: E2>U46619>F2alpha>D2, and in cat F2alpha>D2>E2>U46619. In the MAP kinase assay, in bovine iris sphincter the rank order of potency is E2>F2alpha and in cat F2alpha>E2. These conclusions are supported by the following findings: (1) In the contractile assay, in the bovine sphincter the EC50s for PGF2alpha, PGE2, U46619 and PGD2 were found to be 1.4x10(-7), 5.0x10(-9), 9.0x10(-9) and 1.3x10(-6)M, respectively, and the corresponding values in the cat were 1.9x10(-8), 2.3x10(-7), 1.5x10(-6) and 6.9x10(-8)M, respectively. (2) In the MLC phophorylation assay, in the bovine sphincter PGF2alpha, PGE2, U46619 and PGD2 increased MLC phophorylation by 118%, 165%, 153% and 72%, respectively, and the corresponding values in cat were 175%, 99%, 90% and 95%, respectively. (3) In the MAP kinase assay, in the bovine iris sphincter PGF2alpha and PGE2, increased MAP kinase phosphorylation by 276% and 328%, respectively, and the corresponding values in cat were 308% and 245%, respectively. The data presented demonstrate pronounced species differences in the effects of the prostanoids on the MLC kinase signaling pathway in bovine and cat irides and furthermore confirm the existence of FP-receptors in that of the bovine.

African trypanosome infections of the nervous system: parasite entry and effects on sleep and synaptic functions.

PubMed

Kristensson, Krister; Nygård, Mikael; Bertini, Giuseppe; Bentivoglio, Marina

2010-06-01

The extracellular parasite Trypanosoma brucei causes human African trypanosomiasis (HAT), also known as sleeping sickness. Trypanosomes are transmitted by tsetse flies and HAT occurs in foci in sub-Saharan Africa. The disease, which is invariably lethal if untreated, evolves in a first hemo-lymphatic stage, progressing to a second meningo-encephalitic stage when the parasites cross the blood-brain barrier. At first, trypanosomes are restricted to circumventricular organs and choroid plexus in the brain outside the blood-brain barrier, and to dorsal root ganglia. Later, parasites cross the blood-brain barrier at post-capillary venules, through a multi-step process similar to that of lymphocytes. Accumulation of parasites in the brain is regulated by cytokines and chemokines. Trypanosomes can alter neuronal function and the most prominent manifestation is represented by sleep alterations. These are characterized, in HAT and experimental rodent infections, by disruption of the sleep-wake 24h cycle and internal sleep structure. Trypanosome infections alter also some, but not all, other endogenous biological rhythms. A number of neural pathways and molecules may be involved in such effects. Trypanosomes secrete prostaglandins including the somnogenic PGD2, and they interact with the host's immune system to cause release of pro-inflammatory cytokines. From the sites of early localization of parasites in the brain and meninges, such molecules could affect adjacent brain areas implicated in sleep-wakefulness regulation, including the suprachiasmatic nucleus and its downstream targets, to cause the changes characteristic of the disease. This raises challenging issues on the effects of cytokines on synaptic functions potentially involved in sleep-wakefulness alterations. (c) 2009 Elsevier Ltd. All rights reserved.

The D prostanoid receptor agonist BW245C [(4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid] inhibits fibroblast proliferation and bleomycin-induced lung fibrosis in mice.

PubMed

van den Brule, Sybille; Wallemme, Laurent; Uwambayinema, Francine; Huaux, François; Lison, Dominique

2010-11-01

Prostaglandin (PG) D(2) exerts contrasting activities in the inflamed lung via two receptors, the D prostanoid receptor (DP) and the chemoattractant receptor-homologous molecule expressed on T helper 2 lymphocytes. DP activation is known mainly to inhibit proinflammatory cell functions. We tested the effect of a DP-specific agonist, (4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid (BW245C), on pulmonary fibroblast functions in vitro and in a mouse model of lung fibrosis induced by bleomycin. DP mRNA expression was detected in cultured mouse lung primary fibroblasts and human fetal lung fibroblasts and found to be up- and down-regulated by interleukin-13 and transforming growth factor (TGF)-β, respectively. Although micromolar concentrations of BW245C and PGD(2) did not affect mouse fibroblast collagen synthesis or differentiation in myofibroblasts, they both inhibited fibroblast basal and TGF-β-induced proliferation in vitro. The repeated administration of BW245C (500 nmol/kg body weight instilled transorally in the lungs 2 days before and three times per week for 3 weeks) in bleomycin-treated mice significantly decreased both inflammatory cell recruitment and collagen accumulation in the lung (21 days). Our results indicate that BW245C can reduce lung fibrosis in part via its activity on fibroblast proliferation and suggest that DP activation should be considered as a new therapeutic target in fibroproliferative lung diseases.

The novel polysaccharide deacetylase homologue Pdi contributes to virulence of the aquatic pathogen Streptococcus iniae

PubMed Central

Milani, Carlo J. E.; Aziz, Ramy K.; Locke, Jeffrey B.; Dahesh, Samira; Nizet, Victor; Buchanan, John T.

2010-01-01

The aquatic zoonotic pathogen Streptococcus iniae represents a threat to the worldwide aquaculture industry and poses a risk to humans who handle raw fish. Because little is known about the mechanisms of S. iniae pathogenesis or virulence factors, we established a high-throughput system combining whole-genome pyrosequencing and transposon mutagenesis that allowed us to identify virulence proteins, including Pdi, the polysaccharide deacetylase of S. iniae, that we describe here. Using bioinformatics tools, we identified a highly conserved signature motif in Pdi that is also conserved in the peptidoglycan deacetylase PgdA protein family. A Δpdi mutant was attenuated for virulence in the hybrid striped bass model and for survival in whole fish blood. Moreover, Pdi was found to promote bacterial resistance to lysozyme killing and the ability to adhere to and invade epithelial cells. On the other hand, there was no difference in the autolytic potential, resistance to oxidative killing or resistance to cationic antimicrobial peptides between S. iniae wild-type and Δpdi. In conclusion, we have demonstrated that pdi is involved in S. iniae adherence and invasion, lysozyme resistance and survival in fish blood, and have shown that pdi plays a role in the pathogenesis of S. iniae. Identification of Pdi and other S. iniae virulence proteins is a necessary initial step towards the development of appropriate preventive and therapeutic measures against diseases and economic losses caused by this pathogen. PMID:19762441

Establishment of Homozygote Mutant Human Embryonic Stem Cells by Parthenogenesis.

PubMed

Epsztejn-Litman, Silvina; Cohen-Hadad, Yaara; Aharoni, Shira; Altarescu, Gheona; Renbaum, Paul; Levy-Lahad, Ephrat; Schonberger, Oshrat; Eldar-Geva, Talia; Zeligson, Sharon; Eiges, Rachel

2015-01-01

We report on the derivation of a diploid 46(XX) human embryonic stem cell (HESC) line that is homozygous for the common deletion associated with Spinal muscular atrophy type 1 (SMA) from a pathenogenetic embryo. By characterizing the methylation status of three different imprinted loci (MEST, SNRPN and H19), monitoring the expression of two parentally imprinted genes (SNRPN and H19) and carrying out genome-wide SNP analysis, we provide evidence that this cell line was established from the activation of a mutant oocyte by diploidization of the entire genome. Therefore, our SMA parthenogenetic HESC (pHESC) line provides a proof-of-principle for the establishment of diseased HESC lines without the need for gene manipulation. As mutant oocytes are easily obtained and readily available during preimplantation genetic diagnosis (PGD) cycles, this approach should provide a powerful tool for disease modelling and is especially advantageous since it can be used to induce large or complex mutations in HESCs, including gross DNA alterations and chromosomal rearrangements, which are otherwise hard to achieve.

Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37.

PubMed

Mastrangelo, F; Frydas, I; Ronconi, G; Kritas, S K; Tettamanti, L; Caraffa, Al; D Ovidio, C; Younes, A; Gallenga, C E; Conti, P

2018-01-01

It has been observed that acute stress causes the activation of TH1 cells, while TH2 cells regulate and act on chronic inflammation. Fibromyalgia (FM) is a chronic, idiopathic disorder which affects about twelve million people in the United States. FM is characterized by chronic widespread pain, fatigue, aching, joint stiffness, depression, cognitive dysfunction and non-restorative sleep. The mechanism of induction of muscle pain and inflammation is not yet clear. In FM there is an increase in reactivity of central neurons with increased sensitivity localized mainly in the CNS. Mast cells are involved in FM by releasing proinflammatory cytokines, chemokines, chemical mediators, and PGD2. TNF is a cytokine generated by MCs and its level is higher in FM. The inhibition of pro-inflammatory IL-1 family members and TNF by IL-37 in FM could have a therapeutic effect. Here, we report for the first time the relationship between MCs, inflammatory cytokines and the new anti-inflammatory cytokine IL-37 in FM.

Comparing the Reproductive Success of Yakima River Hatchery- and Wild-Origin Spring Chinook; Yakima/Klickitat Fisheries Project Monitoring and Evaluation, 2001-2002 Annual Report.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schroder, Steven L.; Knudsen, Curtis M.; Watson, Bruce D.

In 2001 hatchery- and wild-origin spring chinook were placed into an observation stream located at the Cle Elum Supplementation Research Facility to compare their reproductive success. Two groups containing both wild- and hatchery fish of both sexes were brought into the stream and allowed to spawn. Their longevity, spawning participation, and reproductive success were assessed. In addition, wild- and hatchery-origin precocious males were also introduced into one of the sections and allowed to spawn. We found that hatchery and wild males generally lived longer than females. In one group hatchery and wild females lived for similar periods of time whilemore » in the other wild females lived longer than hatchery fish. Wild females were also more successful at burying their eggs and the eggs they buried had higher survival rates. This result occurred in both groups of fish. Spawning participation in males was estimated by using two statistics referred to as percent gonad depletion (PGD) and percent testes retention (PRT). Both of these measures assumed that loss of testes weight in males would reflect their spawning participation and therefore could be used to estimate reproductive success. Hatchery and wild males had similar PGD and PRT values. One of these measures, PRT, was negatively associated with male reproductive success, confirming the idea that reduction in testes weight can be used as a surrogate measure of a male's ability to produce offspring Fry from the observation stream were collected throughout the emergence period that ran from January through May. Proportionate sub-samples of these fish were removed and microsatellite DNA was extracted from them. Pedigree analyses were performed to ascertain which adult fish had produced them. These analyses disclosed that wild males were more successful at producing progeny in one of the groups. No difference occurred in the other group. Precocial males and jacks fathered fewer progeny than did fish maturing at ages 4 and 5. In addition, male reproductive success was more than twice as variable as that seen in females. Some males apparently never spawned and others produced more than 7,000 offspring an amount that was more than double the quantity generated by the most successful female. Behavioral observations showed that a number of factors besides male origin influenced their reproductive success. One was relative body size; larger males tended to dominate smaller opponents and therefore had greater access to females. However, male dominance was not always related to relative size. The ability to attack and chase opponents was, however, positively related to reproductive success. We also discovered that the reproductive status of females and the social status of males were often reflected by their nuptial coloration. Territorial females typically had a single broad purple black stripe, light green or brown backs and white or gray ventral surfaces. Dominate males on the other hand, were generally a uniform dark brown or black color. The percentage of time that a male possessed a dark color pattern was positively linked to his reproductive success, as was the percentage of time he was observed courting or defending a female. The number of times a male was chased or attacked by a female also affected his reproductive success, in this situation the greater the frequency of such attacks the lower the reproductive success of the male. The pedigree analyses also disclosed that both hatchery and wild precocious males were able to fertilize eggs and produce offspring under natural spawning conditions. In conclusion we found differences in the reproductive competency of hatchery- and wild origin spring chinook. Wild females were better at depositing their eggs and having those eggs produce fry. In one study group wild males were more successful at producing offspring than hatchery males. Additional replications of such evaluations are being carried out to determine if the differences seen can be replicated. A repeat of the work done in 2001, for example, was performed in 2002 and additional studies will take place this coming year.« less

Finite Element Modelling of the Indo-Gangetic Basin to Study Site Amplification

NASA Astrophysics Data System (ADS)

Sivasubramonian, J.; Jaya, D.; Raghukanth, S. T. G.; Mai, P. M.

2017-12-01

We have developed a finite-element model of the 3D velocity structure of the Indo-Gangetic basin (IG basin) to quantify site amplifications due to seismic waves emanated from regional earthquakes. Estimating seismic wave amplifications is difficult in case of limited instrumentation, thus motivating us to propose a new simulation-based approach. The input required for the finite-element model include the spatial coordinates and the material properties (density, P-wave and S-wave velocities, Q factor) of the basin. Recent studies in the basin demarcate sediment layers of varying thickness, reaching down to a depth of 6 km and S-wave velocities ranging from 0.4-2.4 km/s (Srinivas et al., 2013). In the present study, our regional model has dimensions 900 x 900 x 80 km in x, y and z directions, discretized into 320 x 320 x 53 hexahedral elements. The top 6 km of the IG basin is divided into 8 different sediment layers with varying material properties. We use kinematic rupture models for the earthquake sources to simulate past as well as hypothetical future events. Two past earthquakes (Mw4.9, Delhi; Mw5.2, Chamoli) and two hypothetical earthquakes (Mw7.1; Mw8.5) are considered in our study. The rupture plane dimensions (L and W) and the slip distribution are estimated using the method of Mai and Beroza (2002). Based on focal-mechanism solutions and the depths of seismicity, we define the strike (580, 3090), the dip (650, 210), the rake (160, 770), and the depth of top edge of fault (5 km, 19 km) for the two large hypothetical earthquakes. Based on these parameters, the Centroid Moment Tensor (CMT) solution of the source is obtained. Ground motions are then simulated by solving the three-dimensional wave equation using the spectral element method (Komatitsch and Tromp, 1999). The key observations from our results are: 1) basin amplification factors for Peak Ground Velocity (PGV) are twice as high as Peak Ground Displacement (PGD) 2) PGV amplifications are as high as a factor of 6 for earthquakes occurring inside the basin, and a factor of 4 for Himalayan earthquakes (to the north of the study region) 3) The simulated shake maps of PGV and PGD show directivity. Based on the above observations, we conclude that it is important to include our model into low-frequency ground-motion estimation for seismic hazard analysis.

Application of the parametric proper generalized decomposition to the frequency-dependent calculation of the impedance of an AC line with rectangular conductors

NASA Astrophysics Data System (ADS)

Sancarlos-González, Abel; Pineda-Sanchez, Manuel; Puche-Panadero, Ruben; Sapena-Bano, Angel; Riera-Guasp, Martin; Martinez-Roman, Javier; Perez-Cruz, Juan; Roger-Folch, Jose

2017-12-01

AC lines of industrial busbar systems are usually built using conductors with rectangular cross sections, where each phase can have several parallel conductors to carry high currents. The current density in a rectangular conductor, under sinusoidal conditions, is not uniform. It depends on the frequency, on the conductor shape, and on the distance between conductors, due to the skin effect and to proximity effects. Contrary to circular conductors, there are not closed analytical formulas for obtaining the frequency-dependent impedance of conductors with rectangular cross-section. It is necessary to resort to numerical simulations to obtain the resistance and the inductance of the phases, one for each desired frequency and also for each distance between the phases' conductors. On the contrary, the use of the parametric proper generalized decomposition (PGD) allows to obtain the frequency-dependent impedance of an AC line for a wide range of frequencies and distances between the phases' conductors by solving a single simulation in a 4D domain (spatial coordinates x and y, the frequency and the separation between conductors). In this way, a general "virtual chart" solution is obtained, which contains the solution for any frequency and for any separation of the conductors, and stores it in a compact separated representations form, which can be easily embedded on a more general software for the design of electrical installations. The approach presented in this work for rectangular conductors can be easily extended to conductors with an arbitrary shape.

Familial Dysautonomia (FD) Human Embryonic Stem Cell Derived PNS Neurons Reveal that Synaptic Vesicular and Neuronal Transport Genes Are Directly or Indirectly Affected by IKBKAP Downregulation

PubMed Central

Kantor, Gal; Cheishvili, David; Even, Aviel; Birger, Anastasya; Turetsky, Tikva; Gil, Yaniv; Even-Ram, Sharona; Aizenman, Einat; Bashir, Nibal; Maayan, Channa; Razin, Aharon; Reubinoff, Benjamim E.; Weil, Miguel

2015-01-01

A splicing mutation in the IKBKAP gene causes Familial Dysautonomia (FD), affecting the IKAP protein expression levels and proper development and function of the peripheral nervous system (PNS). Here we found new molecular insights for the IKAP role and the impact of the FD mutation in the human PNS lineage by using a novel and unique human embryonic stem cell (hESC) line homozygous to the FD mutation originated by pre implantation genetic diagnosis (PGD) analysis. We found that IKBKAP downregulation during PNS differentiation affects normal migration in FD-hESC derived neural crest cells (NCC) while at later stages the PNS neurons show reduced intracellular colocalization between vesicular proteins and IKAP. Comparative wide transcriptome analysis of FD and WT hESC-derived neurons together with the analysis of human brains from FD and WT 12 weeks old embryos and experimental validation of the results confirmed that synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKBKAP downregulation in FD neurons. Moreover we show that kinetin (a drug that corrects IKBKAP alternative splicing) promotes the recovery of IKAP expression and these IKAP functional associated genes identified in the study. Altogether, these results support the view that IKAP might be a vesicular like protein that might be involved in neuronal transport in hESC derived PNS neurons. This function seems to be mostly affected in FD-hESC derived PNS neurons probably reflecting some PNS neuronal dysfunction observed in FD. PMID:26437462

[Performance of in vitro fertilization in Germany].

PubMed

van der Ven, Hans; Montag, Markus; van der Ven, Katrin

2002-07-01

In Germany the application of assisted reproductive techniques (ART) is regulated by federal legislation. Compared with the international situation the "German Embryo Protection Law" is very "restrictive" and various methods of ART are prohibited, e.g. oocyte/embryo donation, embryo cryopreservation and Preimplantation Genetic Diagnosis (PGD). Furthermore, in Germany only 1 to 3 fertilized oocytes may be cultured to embryo. All these embryos then have to be transferred into the uterus of a particular patient. Additional fertilized oocytes can only be cryopreserved in a pronuclear state. The success rate of ART has increased significantly over the past few years owing to the introduction of blastocyst cultures and the selection of 1 to 2 good quality blastocysts for embryo transfer. Furthermore, the transfer of only 1 to 2 blastocysts effectively reduces the risk of high rank multiple pregnancies. In Germany, however, the selection of only a few good quality blastocysts for transfer is prohibited by law. New laboratory techniques, e.g. pronuclear scoring and polar body biopsy screening for aneuploidy are in accordance with German law. The application of these methods provides a selection of "good quality oocytes" and seems to increase the overall success rate. Further studies are required, however. The success rate, quality and cost effectiveness of ART in Germany appears compromised when compared with many other countries. What is more, in contrast to the international situation research and development in ART in Germany has been decreasing constantly over the past few years, due to the inappropriate regulations of the German health care system and the insufficient support given to university-based centers.

Prostanoid receptor antagonists: development strategies and therapeutic applications

PubMed Central

Jones, RL; Giembycz, MA; Woodward, DF

2009-01-01

Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 …) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are ‘non-prostanoid’ (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage. PMID:19624532

An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK.

PubMed

Fisher, Andrew; Andreasson, Anders; Chrysos, Alexandros; Lally, Joanne; Mamasoula, Chrysovalanto; Exley, Catherine; Wilkinson, Jennifer; Qian, Jessica; Watson, Gillian; Lewington, Oli; Chadwick, Thomas; McColl, Elaine; Pearce, Mark; Mann, Kay; McMeekin, Nicola; Vale, Luke; Tsui, Steven; Yonan, Nizar; Simon, Andre; Marczin, Nandor; Mascaro, Jorge; Dark, John

2016-11-01

Many patients awaiting lung transplantation die before a donor organ becomes available. Ex vivo lung perfusion (EVLP) allows initially unusable donor lungs to be assessed and reconditioned for clinical use. The objective of the Donor Ex Vivo Lung Perfusion in UK lung transplantation study was to evaluate the clinical effectiveness and cost-effectiveness of EVLP in increasing UK lung transplant activity. A multicentre, unblinded, non-randomised, non-inferiority observational study to compare transplant outcomes between EVLP-assessed and standard donor lungs. Multicentre study involving all five UK officially designated NHS adult lung transplant centres. Patients aged ≥ 18 years with advanced lung disease accepted onto the lung transplant waiting list. The study intervention was EVLP assessment of donor lungs before determining suitability for transplantation. The primary outcome measure was survival during the first 12 months following lung transplantation. Secondary outcome measures were patient-centred outcomes that are influenced by the effectiveness of lung transplantation and that contribute to the health-care costs. Lungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34%) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan-Meier estimate of survival at 12 months was 0.67 [95% confidence interval (CI) 0.40 to 0.83] for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. The hazard ratio for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95% CI 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade 3 primary graft dysfunction (PGD) in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for extracorporeal membrane oxygenation (ECMO) support was higher in the EVLP arm (7/18, 38.8%) than in the standard arm (6/184, 3.2%). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants is approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that includes EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP can increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for lung transplantation. Study limitations include small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study. Overall, one-third of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experience a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limits the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation. Current Controlled Trials ISRCTN44922411. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 20, No. 85. See the NIHR Journals Library website for further project information.

SHARD - a SeisComP3 module for Structural Health Monitoring

NASA Astrophysics Data System (ADS)

Weber, B.; Becker, J.; Ellguth, E.; Henneberger, R.; Herrnkind, S.; Roessler, D.

2016-12-01

Monitoring building and structure response to strong earthquake ground shaking or human-induced vibrations in real-time forms the backbone of modern structural health monitoring (SHM). The continuous data transmission, processing and analysis reduces drastically the time decision makers need to plan for appropriate response to possible damages of high-priority buildings and structures. SHARD is a web browser based module using the SeisComp3 framework to monitor the structural health of buildings and other structures by calculating standard engineering seismology parameters and checking their exceedance in real-time. Thresholds can be defined, e.g. compliant with national building codes (IBC2000, DIN4149 or EC8), for PGA/PGV/PGD, response spectra and drift ratios. In case thresholds are exceeded automatic or operator driven reports are generated and send to the decision makers. SHARD also determines waveform quality in terms of data delay and variance to report sensor status. SHARD is the perfect tool for civil protection to monitor simultaneously multiple city-wide critical infrastructure as hospitals, schools, governmental buildings and structures as bridges, dams and power substations.

Simulating squeeze flows in multiaxial laminates using an improved TIF model

NASA Astrophysics Data System (ADS)

Ibañez, R.; Abisset-Chavanne, Emmanuelle; Chinesta, Francisco

2017-10-01

Thermoplastic composites are widely considered in structural parts. In this paper attention is paid to squeeze flow of continuous fiber laminates. In the case of unidirectional prepregs, the ply constitutive equation is modeled as a transversally isotropic fluid, that must satisfy both the fiber inextensibility as well as the fluid incompressibility. When laminate is squeezed the flow kinematics exhibits a complex dependency along the laminate thickness requiring a detailed velocity description through the thickness. In a former work the solution making use of an in-plane-out-of-plane separated representation within the PGD - Poper Generalized Decomposition - framework was successfully accomplished when both kinematic constraints (inextensibility and in-compressibility) were introduced using a penalty formulation for circumventing the LBB constraints. However, such a formulation makes difficult the calculation on fiber tractions and compression forces, the last required in rheological characterizations. In this paper the former penalty formulation is substituted by a mixed formulation that makes use of two Lagrange multipliers, while addressing the LBB stability conditions within the separated representation framework, questions never until now addressed.

Reproduction opportunists in the new global sex trade: PGD and non-medical sex selection.

PubMed

Whittaker, Andrea M

2011-11-01

Regulatory differences between countries are an important driver of the cross-border trade in assisted reproduction as people move to seek services unavailable in their home countries. The development of a lucrative global trade in non-medical sex selection needs to be considered in ethical debates over its availability. I suggest that depictions of non-medical sex selection as a means of 'family balancing' or supportive of reproductive autonomy serve to distance the technologies rhetorically from the gender stereotyping inherent in their use and the commodification upon which they depend. They construct new social categories such as the 'unbalanced' family, the pathologization of 'gender disappointment' and a limited and highly individualized definition of reproductive freedom that permits medical interventions on healthy bodies. Orientalism pervades ethical debate depicting non-medical sex selection in the West as more acceptable to practices in 'Asia'. A case study of the interconnections between Australia and Thailand highlights the global economy sustaining the practice. Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Proper Generalized Decomposition (PGD) for the numerical simulation of polycrystalline aggregates under cyclic loading

NASA Astrophysics Data System (ADS)

Nasri, Mohamed Aziz; Robert, Camille; Ammar, Amine; El Arem, Saber; Morel, Franck

2018-02-01

The numerical modelling of the behaviour of materials at the microstructural scale has been greatly developed over the last two decades. Unfortunately, conventional resolution methods cannot simulate polycrystalline aggregates beyond tens of loading cycles, and they do not remain quantitative due to the plasticity behaviour. This work presents the development of a numerical solver for the resolution of the Finite Element modelling of polycrystalline aggregates subjected to cyclic mechanical loading. The method is based on two concepts. The first one consists in maintaining a constant stiffness matrix. The second uses a time/space model reduction method. In order to analyse the applicability and the performance of the use of a space-time separated representation, the simulations are carried out on a three-dimensional polycrystalline aggregate under cyclic loading. Different numbers of elements per grain and two time increments per cycle are investigated. The results show a significant CPU time saving while maintaining good precision. Moreover, increasing the number of elements and the number of time increments per cycle, the model reduction method is faster than the standard solver.

Explicit parametric solutions of lattice structures with proper generalized decomposition (PGD) - Applications to the design of 3D-printed architectured materials

NASA Astrophysics Data System (ADS)

Sibileau, Alberto; Auricchio, Ferdinando; Morganti, Simone; Díez, Pedro

2018-01-01

Architectured materials (or metamaterials) are constituted by a unit-cell with a complex structural design repeated periodically forming a bulk material with emergent mechanical properties. One may obtain specific macro-scale (or bulk) properties in the resulting architectured material by properly designing the unit-cell. Typically, this is stated as an optimal design problem in which the parameters describing the shape and mechanical properties of the unit-cell are selected in order to produce the desired bulk characteristics. This is especially pertinent due to the ease manufacturing of these complex structures with 3D printers. The proper generalized decomposition provides explicit parametic solutions of parametric PDEs. Here, the same ideas are used to obtain parametric solutions of the algebraic equations arising from lattice structural models. Once the explicit parametric solution is available, the optimal design problem is a simple post-process. The same strategy is applied in the numerical illustrations, first to a unit-cell (and then homogenized with periodicity conditions), and in a second phase to the complete structure of a lattice material specimen.

Research to Operations: From Point Positions, Earthquake and Tsunami Modeling to GNSS-augmented Tsunami Early Warning

NASA Astrophysics Data System (ADS)

Stough, T.; Green, D. S.

2017-12-01

This collaborative research to operations demonstration brings together the data and algorithms from NASA research, technology, and applications-funded projects to deliver relevant data streams, algorithms, predictive models, and visualization tools to the NOAA National Tsunami Warning Center (NTWC) and Pacific Tsunami Warning Center (PTWC). Using real-time GNSS data and models in an operational environment, we will test and evaluate an augmented capability for tsunami early warning. Each of three research groups collect data from a selected network of real-time GNSS stations, exchange data consisting of independently processed 1 Hz station displacements, and merge the output into a single, more accurate and reliable set. The resulting merged data stream is delivered from three redundant locations to the TWCs with a latency of 5-10 seconds. Data from a number of seismogeodetic stations with collocated GPS and accelerometer instruments are processed for displacements and seismic velocities and also delivered. Algorithms for locating and determining the magnitude of earthquakes as well as algorithms that compute the source function of a potential tsunami using this new data stream are included in the demonstration. The delivered data, algorithms, models and tools are hosted on NOAA-operated machines at both warning centers, and, once tested, the results will be evaluated for utility in improving the speed and accuracy of tsunami warnings. This collaboration has the potential to dramatically improve the speed and accuracy of the TWCs local tsunami information over the current seismometer-only based methods. In our first year of this work, we have established and deployed an architecture for data movement and algorithm installation at the TWC's. We are addressing data quality issues and porting algorithms into the TWCs operating environment. Our initial module deliveries will focus on estimating moment magnitude (Mw) from Peak Ground Displacement (PGD), within 2-3 minutes of the event, and coseismic displacements converging to static offsets. We will also develop visualizations of module outputs tailored to the operational environment. In the context of this work, we will also discuss this research to operations approach and other opportunities within the NASA Applied Science Disaster Program.

Comparative chronology of Archean HT/UHT crustal metamorphism

NASA Astrophysics Data System (ADS)

Caddick, Mark; Dragovic, Besim; Guevara, Victor

2017-04-01

Attainment of high crustal heat fluxes and consequent partial melting is critical to the stabilization of continental roots. Understanding the processes and timescales behind partial melting of continental crust in the Archean is thus paramount for understanding Archean tectonic modes and how stable cratons formed. High-temperature (HT) to ultrahigh-temperature (UHT) metamorphic rocks can record evidence for dynamic processes that result in advective heat fluxes and a substantial deviation from normal crustal geothermal gradients. Examination of the pressure-temperature conditions and timescales of HT/UHT metamorphism is thus essential to understanding the tectonic processes behind extreme crust heat fluxes and the formation of stable cratonic crust. Here, utilizing both traditional and nontraditional petrologic and geochronologic techniques, we compare the pressure-temperature-time paths of two Neoarchean terranes: the eastern Beartooth Mountains of the Wyoming Craton and the Pikwitonei Granulite Domain of the Superior Province. The Beartooth Mountains of Montana, USA, expose Archean rocks of the Wyoming Craton that are dominated by an ˜2.8 Ga calc-alkaline granitoid batholith known as the Long Lake Magmatic Complex (LLMC). The LLMC contains widespread, up to km-scale metasedimentary roof pendants, with ID-TIMS Sm-Nd garnet geochronology and laser ablation split stream (LASS) monazite geochronology suggesting that metamorphism occurred almost 100 Ma after entrainment by the LLMC [1]. Phase equilibria modeling and Zr-in-rutile thermometry constrain peak pressures and temperatures of ˜6-7 kbar and ˜780-800˚ C. Major element diffusion modeling of garnet suggest that granulite-facies temperatures were only maintained for a short duration, < 2 Ma. In contrast, the Pikwitonei Granulite Domain consists of >150,000 km2 of high-grade metamorphic rocks situated in the NW Superior Province. Phase equilibria modeling and trace element thermometry constrain peak temperatures in the southernmost part of the PGD to ˜760˚ C, while across the vast central and western parts of the PGD, peak temperatures range from 900-1000°C. LASS monazite and zircon ages, combined with ID-TIMS zircon and Sm-Nd garnet ages range from ˜2720 Ma to ˜2600 Ma, and combined with the thermometry, suggest that temperatures of >700˚ C were maintained region-wide for over 100 Ma, and that this was punctuated by thermal perturbations exceeding 900-950˚ C and occurring over substantially shorter timescales. The depths, temperatures and timescales inferred here suggest that although these regions were experiencing metamorphism within ˜100 Ma of each other, the primary driver for this metamorphism was different in each case. Timescale of metamorphism might be the most important constrained parameter here, highlighting the benefit of high resolution isotopic and geospeedometry approaches. [1] Dragovic et al., 2016. Precamb. Res., 283, 24-49. [2] Guevara et al., 2016. AGU abstracts with programs.

Enterococcus faecalis Constitutes an Unusual Bacterial Model in Lysozyme Resistance▿

PubMed Central

Hébert, Laurent; Courtin, Pascal; Torelli, Riccardo; Sanguinetti, Maurizio; Chapot-Chartier, Marie-Pierre; Auffray, Yanick; Benachour, Abdellah

2007-01-01

Lysozyme is an important and widespread compound of the host constitutive defense system, and it is assumed that Enterococcus faecalis is one of the few bacteria that are almost completely lysozyme resistant. On the basis of the sequence analysis of the whole genome of E. faecalis V583 strain, we identified two genes that are potentially involved in lysozyme resistance, EF_0783 and EF_1843. Protein products of these two genes share significant homology with Staphylococcus aureus peptidoglycan O-acetyltransferase (OatA) and Streptococcus pneumoniae N-acetylglucosamine deacetylase (PgdA), respectively. In order to determine whether EF_0783 and EF_1843 are involved in lysozyme resistance, we constructed their corresponding mutants and a double mutant. The ΔEF_0783 mutant and ΔEF_0783 ΔEF_1843 double mutant were shown to be more sensitive to lysozyme than the parental E. faecalis JH2-2 strain and ΔEF_1843 mutant were. However, compared to other bacteria, such as Listeria monocytogenes or S. pneumoniae, the tolerance of ΔEF_0783 and ΔEF_0783 ΔEF_1843 mutants towards lysozyme remains very high. Peptidoglycan structure analysis showed that EF_0783 modifies the peptidoglycan by O acetylation of N-acetyl muramic acid, while the EF_1843 deletion has no obvious effect on peptidoglycan structure under the same conditions. Moreover, the EF_0783 and EF_1843 deletions seem to significantly affect the ability of E. faecalis to survive within murine macrophages. In all, while EF_0783 is currently involved in the lysozyme resistance of E. faecalis, peptidoglycan O acetylation and de-N-acetylation are not the main mechanisms conferring high levels of lysozyme resistance to E. faecalis. PMID:17785473

Chromosome fragility at FRAXA in human cleavage stage embryos at risk for fragile X syndrome.

PubMed

Verdyck, Pieter; Berckmoes, Veerle; De Vos, Anick; Verpoest, Willem; Liebaers, Inge; Bonduelle, Maryse; De Rycke, Martine

2015-10-01

Fragile X syndrome (FXS), the most common inherited intellectual disability syndrome, is caused by expansion and hypermethylation of the CGG repeat in the 5' UTR of the FMR1 gene. This expanded repeat, also known as the rare fragile site FRAXA, causes X chromosome fragility in cultured cells from patients but only when induced by perturbing pyrimidine synthesis. We performed preimplantation genetic diagnosis (PGD) on 595 blastomeres biopsied from 442 cleavage stage embryos at risk for FXS using short tandem repeat (STR) markers. In six blastomeres, from five embryos an incomplete haplotype was observed with loss of all alleles telomeric to the CGG repeat. In all five embryos, the incomplete haplotype corresponded to the haplotype carrying the CGG repeat expansion. Subsequent analysis of additional blastomeres from three embryos by array comparative genomic hybridization (aCGH) confirmed the presence of a terminal deletion with a breakpoint close to the CGG repeat in two blastomeres from one embryo. A blastomere from another embryo showed the complementary duplication. We conclude that a CGG repeat expansion at FRAXA causes X chromosome fragility in early human IVF embryos at risk for FXS. © 2015 Wiley Periodicals, Inc.

Earthquake Intensity and Strong Motion Analysis Within SEISCOMP3

NASA Astrophysics Data System (ADS)

Becker, J.; Weber, B.; Ghasemi, H.; Cummins, P. R.; Murjaya, J.; Rudyanto, A.; Rößler, D.

2017-12-01

Measuring and predicting ground motion parameters including seismic intensities for earthquakes is crucial and subject to recent research in engineering seismology.gempa has developed the new SIGMA module for Seismic Intensity and Ground Motion Analysis. The module is based on the SeisComP3 framework extending it in the field of seismic hazard assessment and engineering seismology. SIGMA may work with or independently of SeisComP3 by supporting FDSN Web services for importing earthquake or station information and waveforms. It provides a user-friendly and modern graphical interface for semi-automatic and interactive strong motion data processing. SIGMA provides intensity and (P)SA maps based on GMPE's or recorded data. It calculates the most common strong motion parameters, e.g. PGA/PGV/PGD, Arias intensity and duration, Tp, Tm, CAV, SED and Fourier-, power- and response spectra. GMPE's are configurable. Supporting C++ and Python plug-ins, standard and customized GMPE's including the OpenQuake Hazard Library can be easily integrated and compared. Originally tailored to specifications by Geoscience Australia and BMKG (Indonesia) SIGMA has become a popular tool among SeisComP3 users concerned with seismic hazard and strong motion seismology.

Personality Traits and Cortical Activity Affect Gambling Behavior in Parkinson's Disease.

PubMed

Balconi, Michela; Siri, Chiara; Meucci, Nicoletta; Pezzoli, Gianni; Angioletti, Laura

2018-03-26

Pathological gambling (PG) in Parkinson's disease (PD) manifests as a persistent and uncontrollable gambling behavior, characterized by dysfunctional decision-making and emotional impairment related to high-risk decisions. The aim of this study was to explore the relationship between personality traits and prefrontal cortex activity in PD patients with or without PG. Thus, hemodynamic cortical activity measured by functional near-infrared spectroscopy (fNIRS) and Iowa Gambling Task (IGT) performance were recorded in forty-six PD patients, divided into three groups according to their gambling status: PD patients with active gambling behavior (PDG); PD patients who remitted from PG (PDNG); and a control group (CG) composed by patients with PD only. Results indicates that gambling behavior in PD patients is strongly predictive of dysfunctional cognitive strategy; affecting anomalous cortical response with a left hemispheric unbalance in dorsal areas; and it is related to more reward sensitivity than impulsivity personality components. PDG patients differed from PDNG and CG from both behavioral and brain response to decision-making. Overall, these effects confirm a pathological condition related to cognitive and emotional aspects which makes the patients with PGD victims of their dysfunctional behavior.

How physician electronic health record screen sharing affects patient and doctor non-verbal communication in primary care.

PubMed

Asan, Onur; Young, Henry N; Chewning, Betty; Montague, Enid

2015-03-01

Use of electronic health records (EHRs) in primary-care exam rooms changes the dynamics of patient-physician interaction. This study examines and compares doctor-patient non-verbal communication (eye-gaze patterns) during primary care encounters for three different screen/information sharing groups: (1) active information sharing, (2) passive information sharing, and (3) technology withdrawal. Researchers video recorded 100 primary-care visits and coded the direction and duration of doctor and patient gaze. Descriptive statistics compared the length of gaze patterns as a percentage of visit length. Lag sequential analysis determined whether physician eye-gaze influenced patient eye gaze, and vice versa, and examined variations across groups. Significant differences were found in duration of gaze across groups. Lag sequential analysis found significant associations between several gaze patterns. Some, such as DGP-PGD ("doctor gaze patient" followed by "patient gaze doctor") were significant for all groups. Others, such DGT-PGU ("doctor gaze technology" followed by "patient gaze unknown") were unique to one group. Some technology use styles (active information sharing) seem to create more patient engagement, while others (passive information sharing) lead to patient disengagement. Doctors can engage patients in communication by using EHRs in the visits. EHR training and design should facilitate this. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Law, bioethics and practice in France: forging a new legislative pact.

PubMed

Berthiau, Denis

2013-02-01

In France, bioethics norms have emerged in close interaction with medical practices. The first bioethics laws were adopted in 1994, with provisions for updates in 2004 and most recently, in 2011. As in other countries, bioethics laws indirectly refer to certain fundamental values. The purpose of this paper is threefold. First, I shall briefly describe the construction of the French bioethics laws and the values they are meant to protect. Secondly, I will show that the practice of clinical ethics, as reported in a few studies on ART, living organ donation and PGD, challenge the role attributed to doctors as "gatekeepers" of those fundamental values. Thirdly, I will suggest that the quality of medical practices would improve if the law focused on strengthening the tacit pact between doctors and patients, rather than putting doctors in charge of enforcing societal values. Doctors, for their part, would limit their role to what they can do best: provide sufficient patient support and safe care. Against those who argue that we should dispense with bioethics laws altogether, I hold that the laws are useful in order to limit the development of abusive practices. However, a new legislative approach should be adopted which would a positive presumption in favor of patients' requests.

1,2-Hydroxypyridonates as Contrast Agents for Magnetic ResonanceImaging: TREN-1,2-HOPO

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jocher, Christoph J.; Moore, Evan G.; Xu, Jide

2007-05-08

1,2-Hydroxypyridinones (1,2-HOPO) form very stable lanthanide complexes that may be useful as contrast agents for Magnetic Resonance Imaging (MRI). X-ray diffraction of single crystals established that the solid state structures of the Eu(III) and the previously reported [Inorg. Chem. 2004, 43, 5452] Gd(III) complex are identical. The recently discovered sensitizing properties of 1,2-HOPO chelates for Eu(III) luminescence allow direct measurement of the number if water molecules in the metal complex. Fluorescence measurements of the Eu(III) complex corroborate that in solution two water molecules coordinate the lanthanide (q = 2) as proposed from the analysis of NMRD profiles. In addition, fluorescencemore » measurements have verified the anion binding interactions of lanthanide TREN-1,2-HOPO complexes in solution, studied by relaxivity, revealing only very weak oxalate binding (K{sub A} = 82.7 {+-} 6.5 M{sup -1}). Solution thermodynamic studies of the metal complex and free ligand have been carried out using potentiometry, spectrophotometry and fluorescence spectroscopy. The metal ion selectivity of TREN-1,2-HOPO supports the feasibility of using 1,2-HOPO ligands for selective lanthanide binding [pGd = 19.3 (2); pZn = 15.2 (2), pCa = 8.8 (3)].« less

Where does New Zealand stand on permitting research on human embryos?

PubMed

Jones, D Gareth

2014-08-01

In many respects New Zealand has responded to the assisted reproductive technologies (ARTs) as positively as many comparable societies, such as Australia and the UK. Consequently, in vitro fertilisation (IVF) and pre-implantation genetic diagnosis (PGD) are widely available, as is non-commercial surrogacy utilising IVF. These developments have been made possible by the Human Assisted Reproductive Technology (HART) Act 2004, overseen by its two committees, the Advisory Committee on Assisted Reproductive Technology (ACART) and the Ethics Committee (ECART). However, New Zealand stands apart from many of these other societies by the lack of permission for scientists to conduct research using human embryos. There is no doubt this reflects strongly held viewpoints on the part of some that embryos should be protected and not exploited. Legitimate as this stance is, the resulting situation is problematic when IVF is already designated as an established procedure. This is because the development of IVF involved embryo research, and continuing improvements in procedures depend upon ongoing embryo research. While prohibition of research on human embryos gives the impression of protecting embryos, it fails to do this and also fails to enhance the health and wellbeing of children born using IVF. This situation will not be rectified until research is allowed on human embryos.

Military and VA general dentistry training: a national resource.

PubMed

Atchison, Kathryn A; Bachand, William; Buchanan, C Richard; Lefever, Karen H; Lin, Sylvia; Engelhardt, Rita

2002-06-01

In 1999, HRSA contracted with the UCLA School of Dentistry to evaluate the postgraduate general dentistry (PDG) training programs. The purpose of this article is to compare the program characteristics of the PGD training programs sponsored by the Armed Services (military) and VA. Surveys mailed to sixty-six VA and forty-two military program directors in fall 2000 sought information regarding the infrastructure of the program, the program emphasis, resident preparation prior to entering the program, and a description of patients served and types of services provided. Of the eighty-one returned surveys (75 percent response rate), thirty were received from military program directors and fifty-one were received from VA program directors. AEGDs reported treating a higher proportion of children patients and GPRs more medically intensive, disadvantaged and HIV/AIDS patients. Over half of the directors reported increases in curriculum emphasis in implantology. The program directors reported a high level of inadequate preparation among incoming dental residents. Having a higher ratio of residents to total number of faculty predicted inadequate preparation (p=.022) although the model was weak. Although HRSA doesn't financially support federally sponsored programs, their goal of improved dental training to care for medically compromised individuals is facilitated through these programs, thus making military and VA general dentistry programs a national resource.

Phylogenetic relationships of the tribe Toxotrypanini (Diptera: Tephritidae) based on molecular characters.

PubMed

Mengual, Ximo; Kerr, Peter; Norrbom, Allen L; Barr, Norman B; Lewis, Matthew L; Stapelfeldt, Anna M; Scheffer, Sonja J; Woods, Patrick; Islam, Md-Sajedul; Korytkowski, Cheslavo A; Uramoto, Keiko; Rodriguez, Erick J; Sutton, Bruce D; Nolazco, Norma; Steck, Gary J; Gaimari, Stephen

2017-08-01

Current hypotheses of relationship among the species of the fruit fly genera Anastrepha and Toxotrypana are tested using sequence data from six DNA regions: the mitochondrial regions 16S, CAD, and COI, and the nuclear regions EF1a, PER, and PGD. DNA sequences were obtained from 146 species of Anastrepha, representing 19 of the 21 species groups as well as five of the six clades of the robusta group, and four species of Toxotrypana in addition to species of Hexachaeta, Pseudophorellia, Alujamyia, and 13 other tephritid genera used as outgroups. The results indicate that Hexachaeta is more closely related to the Molynocoelia group than to Toxotrypana and Anastrepha, and it is removed from the tribe Toxotrypanini. The group Anastrepha+Toxotrypana and the genus Toxotrypana are strongly supported as monophyletic, consistent with previous studies, but Toxotrypana arises within Anastrepha, confirming that Anastrepha as currently defined is paraphyletic. The placement of Toxotrypana within Anastrepha is clearly defined for the first time with high support, as the sister group to the cryptostrepha clade of the robusta group of Anastrepha. Within Anastrepha, the daciformis, dentata, leptozona, raveni, and striata species groups are highly supported clades. The serpentina group is recognized with lower support, and the fraterculus and pseudoparallela groups are supported with minor alterations. The robusta group is resolved as polyphyletic, but four of the six species clades within it are recovered monophyletic (one clade is not represented and another is represented by one species). The punctata and panamensis groups are resolved together in a clade. At least some species of the mucronota group are related, however this group requires further study. The benjamini, grandis, and spatulata groups appear to be polyphyletic. Relationships among the species groups are generally poorly resolved, with the following exceptions: (1) the lineage including Toxotrypana, the cryptostrepha clade, and the tripunctata group; (2) the sister group relationship of the daciformis+dentata groups; (3) a clade comprising the punctata and panamensis groups; and (4) the large clade comprising the pseudoparallela+spatulata+ramosa+grandis+serpentina+striata+fraterculus groups. Copyright © 2017 Elsevier Inc. All rights reserved.

Dietary antioxidants and the biochemical response to oxidant inhalation. II. Influence of dietary selenium on the biochemical effects of ozone exposure in mouse lung

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elsayed, N.M.; Hacker, A.D.; Kuehn, K.

The influence of dietary selenium (Se) on the pulmonary biochemical response to ozone (O/sub 3/) exposure was examined. For 11 weeks, weanling female strain A/St mice were fed a test diet containing Se either at 0 ppm (-Se) or 1 ppm (+Se). Each diet contained 55 ppm vitamin E (vit E). Mice from each dietary group were exposed to 0.8 +/- 0.05 ppm (1568 +/- 98 micrograms/m3) O/sub 3/ continuously for 5 days. After O/sub 3/ exposure, they were killed along with a matched number of unexposed controls, and their lungs were analyzed for various biochemical parameters. The Se contentsmore » of lung tissue and whole blood were determined, and the levels were seven- to eightfold higher in +Se mice than in -Se mice, reflecting the Se intake of the animals. In unexposed control mice, Se deficiency caused a decline in glutathione peroxidase (GP) activity relative to +Se group. After O/sub 3/ exposure, the GP activity in the -Se group was associated with a lack of stimulation of glutathione reductase (GR) activity and the pentose phosphate cycle (PPC) as assessed by measuring glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) activities. In contrast, the +Se group after O/sub 3/ exposure exhibited increases in all four enzyme activities. Other parameters, e.g., lung weight, total lung protein, DNA and nonprotein sulfhydryl contents, and O/sub 2/ consumption, were not affected by dietary Se in the presence or absence of O/sub 3/ exposure. The data indicate that dietary Se alters the GP activity, which in turn influences the GR and PPC activities in the lung evidently through a reduced demand for NADPH. The level of vit E in the lung was found to be twofold higher in the -Se group than in the +Se group, suggesting a compensatory relationship between Se and vit E in the lung. With O3 exposure, both Se and vit E contents further increased in the lungs of each dietary group.« less

Modulation of human dermal microvascular endothelial cells by Sarcoptes scabiei in combination with proinflammatory cytokines, histamine, and lipid-derived biologic mediators

PubMed Central

Elder, B. Laurel; Arlian, Larry G.; Morgan, Marjorie S.

2009-01-01

The ectoparasitic mite, Sarcoptes scabiei, produces molecules that depress initiation of host inflammatory and immune responses. Some of these down-regulate expression of adhesion molecules or secretion of chemokines or cytokines on and by cultured dermal endothelial cells (HMVEC-D). This study was undertaken to determine if the response of HMVEC-D to scabies is altered in the presence of various proinflammatory cytokines (tumor necrosis factor α and interleukins 1α, 1β and 6), histamine, and lipid-derived mediators (prostaglandins D2 and E2, leukotriene B4, platelet activation factor) that likely occur in scabietic lesions in vivo. Scabies extract down-regulated the TNFα-induced expression of VCAM-1 by HMVEC-D and this down-regulation still occurred in the presence of the other proinflammatory cytokines, histamine or the lipid-derived mediators. Scabies inhibited the IL-1α and IL-1β-induced secretion of IL-6, while a combination of scabies and histamine or LTB4 reduced the TNFα-induced secretion of IL-6. Scabies extract inhibited secretion of IL-8. Histamine, PGD2, PGE2, LTB4, PAF, and IL-6 alone had no effect on this inhibition, but the scabies-induced inhibition of IL-8 secretion was reduced in a dose-dependent fashion in the presence of IL-1α and IL-1β. PMID:19523846

High activity antioxidant enzymes protect flying-fox haemoglobin against damage: an evolutionary adaptation for flight?

PubMed

Reinke, N B; O'Brien, G M

2006-11-01

Flying-foxes are better able to defend haemoglobin against autoxidation than non-volant mammals such as sheep. When challenged with the common physiological oxidant, hydrogen peroxide, haemolysates of flying-fox red blood cells (RBC) were far less susceptible to methaemoglobin formation than sheep. Challenge with 1-acetyl-2-phenylhydrazine (APH) caused only half as much methaemoglobin formation in flying-fox as in ovine haemolysates. When intact cells were challenged with phenazine methosulfate (PMS), flying-fox RBC partially reversed the oxidant damage, and reduced methaemoglobin from 40 to 20% over 2 h incubation, while ovine methaemoglobin remained at 40%. This reflected flying-fox cells' capacity to replenish GSH fast enough that it did not deplete beyond 50%, while ovine RBC GSH was depleted to around 20%. The greater capacity of flying-foxes to defend haemoglobin against oxidant damage may be explained in part by antioxidant enzymes catalase, superoxide dismutase and cytochrome-b ( 5 ) reductase having two- to four-fold higher activity than in sheep (P < 0.001). Further, their capacity to limit GSH depletion to 50% and reduce methaemoglobin (in the presence of glucose), despite ongoing exposure to PMS may result from having ten-fold higher activity of G6PD and 6PGD than sheep (P < 0.001), indicating the presence of a very efficient pentose phosphate pathway in flying-foxes.

COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells.

PubMed

Ramer, Robert; Heinemann, Katharina; Merkord, Jutta; Rohde, Helga; Salamon, Achim; Linnebacher, Michael; Hinz, Burkhard

2013-01-01

The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-γ in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD(2) and 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-γ in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2-dependent PGs.

Prenatal diagnosis as a tool and support for eugenics: myth or reality in contemporary French society?

PubMed

Gaille, Marie; Viot, Géraldine

2013-02-01

Today, French public debate and bioethics research reflect an ongoing controversy about eugenics. The field of reproductive medicine is often targeted as pre-implantation genetic diagnosis (PGD), prenatal diagnosis, and prenatal detection are accused of drifting towards eugenics or being driven by eugenics considerations. This article aims at understanding why the charge against eugenics came at the forefront of the ethical debate. Above all, it aims at showing that the charge against prenatal diagnosis is groundless. The point of view presented in this article has been elaborated jointly by a geneticist and a philosopher. Besides a survey of the medical, bioethical, philosophical and social sciences literature on the topic, the methodology is founded on a joint analysis of geneticist's various consults. Evidence from office visits demonstrated that prenatal diagnosis leads to case-by-case decisions. As we have suggested, this conclusion does not mean that prenatal diagnosis is devoid of ethical issues, and we have identified at least two. The first is related to the evaluation of a decision to abort. The second line of ethical questions arises from the fact that the claim for "normality" hardly hides normative and ambiguous views about disability. As a conclusion, ethical dilemmas keep being noticeable in the field of reproductive medicine and genetic counselling, but an enquiry about eugenic tendencies probably does not allow us to understand them in the proper way.

Strong motion simulation by the composite source modeling: A case study of 1679 M8.0 Sanhe-Pinggu earthquake

NASA Astrophysics Data System (ADS)

Liu, Bo-Yan; Shi, Bao-Ping; Zhang, Jian

2007-05-01

In this study, a composite source model has been used to calculate the realistic strong ground motions in Beijing area, caused by 1679 M S8.0 earthquake in Sanhe-Pinggu. The results could provide us the useful physical parameters for the future seismic hazard analysis in this area. Considering the regional geological/geophysical background, we simulated the scenario earthquake with an associated ground motions in the area ranging from 39.3°N to 41.1°N in latitude and from 115.35°E to 117.55°E in longitude. Some of the key factors which could influence the characteristics of strong ground motion have been discussed, and the resultant peak ground acceleration (PGA) distribution and the peak ground velocity (PGV) distribution around Beijing area also have been made as well. A comparison of the simulated result with the results derived from the attenuation relation has been made, and a sufficient discussion about the advantages and disadvantages of composite source model also has been given in this study. The numerical results, such as the PGA, PGV, peak ground displacement (PGD), and the three-component time-histories developed for Beijing area, have a potential application in earthquake engineering field and building code design, especially for the evaluation of critical constructions, government decision making and the seismic hazard assessment by financial/insurance companies.