1,721,133 research outputs found
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Prevalence of Heavy Prenatal Alcohol Exposure in Uganda via Analysis of Fatty Acid Ethyl Esters in Meconium
Get PDFFetal alcohol spectrum disorder (FASD) manifests as a continuum of permanent birth defects and neurodevelopmental impairments that originate from maternal alcohol use during pregnancy. The number of recognized FASD cases in parts of Sub-Saharan Africa is growing, which is a cause for concern. Prenatal alcohol exposure was examined via regional hospital population-based collection of meconium, and analysis of the fatty acid ethyl esters (FAEEs) contained within. Meconium samples were collected from five hundred ten neonates over a two-month period at Mbarara Regional Referral Hospital. Each meconium sample was accompanied by a maternal questionnaire. The prevalence of prenatal alcohol exposure using the maternal questionnaire was 16.1% (81 of 510). The overall prevalence of prenatal alcohol exposure via FAEE-meconium analysis in this population was 1.6% (8 of 510). This is the first population-based study of an entire local neonatal population examining fetal alcohol exposure via meconium-FAEE analysis conducted in Uganda.M.Sc
Discontinuation Patterns of Substances of Abuse in Pregnancy in a Cohort of Women Seeking Addiction and Parenting Support: A Mixed Methods Study
No full textBackground: Substance use during pregnancy is a major public health concern, stemming from potential physical and psychosocial harms to both the mother and child.
Objective: It was my aim to characterize substance use patterns throughout pregnancy and explore the reasons that women attribute to these patterns of use.
Methods: A mixed methods approach was used to investigate a group of women that attend(ed) Breaking the Cycle (BTC). BTC is a â one-stopâ comprehensive service available to pregnant or parenting women who have substance use issues.
Results: Through a chart review (N=470), I found that the greatest number of women used tobacco and cannabis for the duration of pregnancy (N=231 and N=101, respectively), while the proportion of women continuing opioid use was comparably high (61.8%). The results from the two focus groups highlighted the importance of self-efficacy and quality relationships for women who are trying to make positive changes to their substance use during pregnancy.M.Sc
PREGNANCY, NEONATAL AND DISEASE OUTCOMES IN WOMEN WITH RELAPSING REMITTING MULTIPLE SCLEROSIS
Get PDFObjective
To compare pregnancy, neonatal and disease outcomes in women with Relapsing Remitting Multiple Sclerosis (RRMS) exposed to different therapeutic agents— natalizumab (Tysabri®) and Vitamin D.
Methods
Data from German and Canadian Multiple Sclerosis (MS) pregnancy registries was compared to evaluate neonatal and pregnancy outcomes in natalizumab exposed and unexposed groups. A healthy control group of pregnant women unexposed to teratogens was also utilized; primary outcome of interest was birth defects and miscarriage rates. For the Vitamin D study we first compared postpartum disease outcomes using Kaplan Meier and Cox Regression in a German (GER) cohort not supplementing with Vitamin D to a Canadian (CAN) cohort with Vitamin D supplementation in pregnancy; primary outcome of interest was time to disease resurgence in the postpartum period. We then evaluated neonatal outcomes in Canadians with high dose Vitamin D (>4000IU/day) in pregnancy to ones with lower intake. Primary outcome of interest was birth weight.
Results
There were no significant differences in birth defects or other adverse neonatal outcomes between the 101 natalizumab exposed, 78 disease matched, and 97 healthy controls. The rates of miscarriage were higher in both MS groups in comparison to the healthy controls. In the Vitamin D study, significantly more GERs used Disease Modifying Drugs (DMDs) in pregnancy and postpartum compared to CANs. There was no difference in disease resurgence between the two cohorts. Neonatal outcomes including birth weight did not differ significantly in the 29 women that exceeded 4000IU/day in pregnancy, compared to women that took lower doses.
Conclusion
Gestational exposure to either therapy, natalizumab or Vitamin D, is not associated with adverse outcomes. Larger studies are needed to investigate the longer duration of therapy with natalizumab and higher doses of Vitamin D >4000IU/day in pregnancy.Ph.D
Nuclear Factor (Erythroid 2-like) Factor 2 (Nrf2) as Cellular Protector in Bile Acid and Retinoid Toxicities
No full textExposure to toxic bile acids (BA) and retinoic acids (RA) is implicated in toxicities related to excessive oxidative stress. This thesis examined roles and mechanisms of the oxidative stress-responsive nuclear factor (erythroid 2-like) factor 2 (Nrf2) in adaptive cell defense against BA and RA toxicities. Using liver cells and mouse models, many antioxidant proteins known to be Nrf2 target genes, particularly the rate-limiting enzyme for glutathione (GSH) biosynthesis, i.e., glutamate-cysteine ligase subunits (GCLM/GCLC), were induced by BA [lithocholic acid (LCA)] or RA (all-trans, 9-cis and 13-cis) treatment. Evidence for increased Nrf2 transactivation by LCA and all-trans-RA was exemplified in HepG2 by: (1) reduced constitutive and inducible expression of GCLM/GCLC upon Nrf2 silencing via small-interfering RNA; (2) increased inducible expression of GCLM/GCLC genes by Nrf2 overexpression, but overexpression of dominant-negative Nrf2 decreased it; (3) increased nuclear accumulation of Nrf2 as signature event of receptor activation; (4) enhanced Nrf2-dependent antioxidant-response-element (ARE) reporter activity as indicative of increased Nrf2 transactivation; and (5) increased Nrf2 occupancy to AREs of GCLM and GCLC. Additionally, in BA-treated HepG2 cells, we observed concomitant increases of many ATP-binding cassette (ABC) transporters (MRPs 1-5, MDR1 and BCRP) in parallel with increased cellular efflux. Nrf2 silencing in HepG2 cells decreased constitutive and inducible expression of MRP2, MRP3 and ABCG2. However, Nrf2-silenced mouse hepatoma cells, Hepa1c1c7, and Nrf2-/- mice had decreased constitutive and/or inducible expression of Mrps 1-4, suggesting species differences in Nrf2-dependent regulation of hepatic ABC transporters. Protection by Nrf2 against BA and RA toxicities was confirmed by observations that Nrf2 silencing increased cell susceptibility to BA- and RA-induced cell death. Moreover, Nrf2-/- mice suffered more severe liver injury than the wildtype. Increased GSH and efflux activity following increased GCLM/GCLC and ABC transporters, respectively, can mitigate LCA toxicity. Activation of MEK1-ERK1/2 MAPK was shown to primarily mediate Nrf2 transactivation and LCA-induced expression of antioxidant proteins and Nrf2-dependent and -independent ABC transporters. In conclusion, Nrf2 activation by BA and RA led to coordinated induction of antioxidant and ABC proteins, thereby counteracting resultant oxidative cytotoxicity. The potential of targeting Nrf2 in management of BA and RA toxicities merits further investigation.Ph
Hypertonicity Regulation of Cytochrome P450 CYP3A
Get PDFCytochrome P450 3A isozymes (CYP3A) metabolize approximately 50% of therapeutic drugs. It has recently been discovered that human CYP3A mRNA levels can be induced by hypertonicity; a physiological state not previously linked to its regulation. The osmosensitive transcription factor, Nuclear Factor of Activated T-Cells 5 (NFAT5), regulates multiple genes that restore osmolyte homeostasis and promote cell protection during osmotic stress.
In silico examinations and in vitro experiments using reporters, knockdown and binding assays in the human intestinal cell line C2bbe1 have revealed an active tonicity-responsive enhancer (TonE) within CYP3A7 intron (+5417/+5427 from CYP3A7 transcriptional start site) that is responsible for NFAT5 binding and NFAT5-dependent regulation of CYP3A isoforms. In addition, hypertonicity-mediated CYP3A induction is also observed in both hepatic and intestinal cell lines.
Effects of tonicity changes on in vivo CYP3A expression and function were examined in a humanized CYP3A transgenic mouse with similar tissue expression in humans. More specifically, intervention with prolonged dehydration involving alternating between 24-hour cycles of water-deprivation and water ad lib for 1 week (cyclic water-deprivation; four 24-hour water-deprivation and three 24-hour water ad lib periods), increased expression of NFAT5 target genes Slc6a12 in the liver and kidney (2.5 ± 0.6-fold over water ad lib, n = 14, p = 0.04; and 3.1 ± 0.6-fold, n = 10, p = 0.02, respectively), Akr1b3 in the liver, and Slc5a3 in the kidney. Immunofluorescent microscopy revealed an increase of nuclear-distributed mouse NFAT5 in cyclic water-deprived animals, consistent with NFAT5 activation. Most importantly, CYP3A4 mRNA levels were noted to be elevated in the liver and kidney (11.8 ± 4.8-fold over water ad lib, n = 14, p = 0.04 and 2.2 ± 0.4-fold, n = 9, p = 0.02, respectively), with concurrent CYP3A protein and activity increase. Localized hypertonic environment in the gut was simulated by providing animals with a week-long high-salt diet. The effects of high-salt diet in the gut were similar to those of cyclic water-deprivation in the liver and kidney; where NFAT5 showed nuclear distribution and NFAT5 target gene expression (Slc6a12; 20.5 ± 6.7-fold over a week-long low-salt diet, n = 8, p = 0.02 and Slc6a6; 3.2 ± 0.7-fold, n = 10, p < 0.01, in the duodenum). Furthermore, an increase of CYP3A4 mRNA was observed (2.6 ± 0.5-fold over a week-long low-salt diet, n = 14, p = 0.03), with a corresponding rise in protein expression and activity levels.
In summary, increased expression of in vitro and in vivo human CYP3A was achieved using a hypertonic stimulus; concurrent NFAT5 activation and NFAT5 target gene expression were observed. These results suggested a possible binding of activated NFAT5 to CYP3A TonE situated within the intronic region of CYP3A7. It could be further concluded that NFAT5 may be responsible for the hypertonic induction of human CYP3A.Ph
Nuclear Factor (Erythroid 2-like) Factor 2 (Nrf2) as Cellular Protector in Bile Acid and Retinoid Toxicities
Get PDFExposure to toxic bile acids (BA) and retinoic acids (RA) is implicated in toxicities related to excessive oxidative stress. This thesis examined roles and mechanisms of the oxidative stress-responsive nuclear factor (erythroid 2-like) factor 2 (Nrf2) in adaptive cell defense against BA and RA toxicities. Using liver cells and mouse models, many antioxidant proteins known to be Nrf2 target genes, particularly the rate-limiting enzyme for glutathione (GSH) biosynthesis, i.e., glutamate-cysteine ligase subunits (GCLM/GCLC), were induced by BA [lithocholic acid (LCA)] or RA (all-trans, 9-cis and 13-cis) treatment. Evidence for increased Nrf2 transactivation by LCA and all-trans-RA was exemplified in HepG2 by: (1) reduced constitutive and inducible expression of GCLM/GCLC upon Nrf2 silencing via small-interfering RNA; (2) increased inducible expression of GCLM/GCLC genes by Nrf2 overexpression, but overexpression of dominant-negative Nrf2 decreased it; (3) increased nuclear accumulation of Nrf2 as signature event of receptor activation; (4) enhanced Nrf2-dependent antioxidant-response-element (ARE) reporter activity as indicative of increased Nrf2 transactivation; and (5) increased Nrf2 occupancy to AREs of GCLM and GCLC. Additionally, in BA-treated HepG2 cells, we observed concomitant increases of many ATP-binding cassette (ABC) transporters (MRPs 1-5, MDR1 and BCRP) in parallel with increased cellular efflux. Nrf2 silencing in HepG2 cells decreased constitutive and inducible expression of MRP2, MRP3 and ABCG2. However, Nrf2-silenced mouse hepatoma cells, Hepa1c1c7, and Nrf2-/- mice had decreased constitutive and/or inducible expression of Mrps 1-4, suggesting species differences in Nrf2-dependent regulation of hepatic ABC transporters. Protection by Nrf2 against BA and RA toxicities was confirmed by observations that Nrf2 silencing increased cell susceptibility to BA- and RA-induced cell death. Moreover, Nrf2-/- mice suffered more severe liver injury than the wildtype. Increased GSH and efflux activity following increased GCLM/GCLC and ABC transporters, respectively, can mitigate LCA toxicity. Activation of MEK1-ERK1/2 MAPK was shown to primarily mediate Nrf2 transactivation and LCA-induced expression of antioxidant proteins and Nrf2-dependent and -independent ABC transporters. In conclusion, Nrf2 activation by BA and RA led to coordinated induction of antioxidant and ABC proteins, thereby counteracting resultant oxidative cytotoxicity. The potential of targeting Nrf2 in management of BA and RA toxicities merits further investigation.Ph
Regulating Lactation: Defining Key Players in the Lactogenic Process for the Development of an In Vitro Model of Drug Transfer into Breast Milk
Get PDFThe study of xenobiotic transfer into breast milk remains an unresolved and difficult task, as clinical trials involving the administration of drugs to breastfeeding mothers to measure milk levels mostly remain unethical and unsafe. Although prediction of drug excretion into milk using physiologically based pharmacokinetic (PBPK) modeling coupled with in vitro-in vivo extrapolation is becoming an important alternative, in vitro experimental approaches remain to be fully developed. This thesis attempted to enrich the knowledge required for the development of in vitro approaches and PBPK models of lactation in 4 domains: the identification of gene expression profiles of the lactating mammary gland; the elucidation of the role of ELF5 in ABCG2 expression; the 3D visualization of milk and vascular compartments of the lactating mammary gland and development of a microfluidic mammary gland-on-chip as an experimental platform in vitro; and the exploration of methotrexate mammary gland transport. First, a gene expression profile in the lactating mouse mammary gland was identified through GEO2R analysis of published microarray data, which was then used to examine hormone responses of the CIT3 mammary epithelial (MEC) line. Second, ELF5, an identified lactogenic marker, was found to be a transcription factor for ABCG2 expression, a transporter marker of the lactating mammary gland, upon prolactin stimulation in vitro. Third, the 3D imaging of the milk and vascular compartments of the lactating mouse mammary gland by 2-photon microscopy revealed dimensional characteristics of milk compartments interspersed by attenuated epithelia and a network of microvasculature. Further, a microfluidic chip was developed as an in vitro platform of the mammary gland, composed of poly(methylmethacrylate) pieces with channels accommodating media flow on either side of a porous membrane. Lastly, in order to gain mechanistic insight into the influx of methotrexate into MECs as a potential target pathway for riboflavin-associated reduction of methotrexate excretion into milk, folate receptor alpha (FRα) was tested for its capacity to mediate methotrexate influx into FRα-overexpressing HEK293 cells. A known methotrexate receptor highly upregulated in the lactating mammary gland, data reveal FRα to be a mediator of methotrexate influx into MECs, however riboflavin interference of methotrexate uptake was not detected.Ph.D
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