Controlled human exposures to diesel exhaust: a human epigenome-wide experiment of target bronchial epithelial cells.

Diesel exhaust (DE) is a major contributor to ambient air pollution around the world. It is a known human carcinogen that targets the respiratory system and increases risk for many diseases, but there is limited research on the effects of DE exposure on the epigenome of human bronchial epithelial cells. Understanding the epigenetic impact of this environmental pollutant can elucidate biological mechanisms involved in the pathogenesis of harmful DE-related health effects. To estimate the causal effect of short-term DE exposure on the bronchial epithelial epigenome, we conducted a controlled single-blinded randomized crossover human experiment of exposure to DE and used bronchoscopy and Illumina 450K arrays for data collection and analysis, respectively. Of the 13 participants, 11 (85%) were male and 2 (15%) were female, and 12 (92%) were White and one (8%) was Hispanic; the mean age was 26 years (SD = 3.8 years). Eighty CpGs were differentially methylated, achieving the minimum possible exact P-value of P = 2.44 × 10-4 (i.e. 2/213). In regional analyses, we found two differentially methylated regions (DMRs) annotated to the chromosome 5 open reading frame 63 genes (C5orf63; 7-CpGs) and unc-45 myosin chaperone A gene (UNC45A; 5-CpGs). Both DMRs showed increased DNA methylation after DE exposure. The average causal effects for the DMRs ranged from 1.5% to 6.0% increases in DNA methylation at individual CpGs. In conclusion, we found that short-term DE alters DNA methylation of genes in target bronchial epithelial cells, demonstrating epigenetic level effects of exposure that could be implicated in pulmonary pathologies.

An educational intervention on HPV knowledge and comfortability discussing vaccination among oral health care professionals of the American Indian and Alaskan Native population.

This study aimed to evaluate the effectiveness of an educational intervention at improving Oral Health Professionals (OHP's) knowledge of HPV and comfortability to discuss vaccination with their American Indian and Alaskan Native patients. OHP's attended an educational lecture covering HPV vaccination. Participants completed four validated questionnaires that encompassed a sociodemographic survey, a pre-lecture questionnaire (pre-Q), a post-lecture questionnaire (post-Q), and a follow-up questionnaire (follow-Q). The McNemar test was used to assess the significance of marginal probabilities in the responses between the pre-Q and post-Q and the Chi-square test to assess responses between the post-Q and follow-Q. A total of 122 OHP's completed the sociodemographic survey, pre-Q, and post-Q. Among these, 29 OHP's completed the eight-week follow-Q. The majority of all the participants were White/Caucasian (41%), 31 to 60 years of age (72%), females (64%), and held a graduate/professional degree (52%). Analysis of the pre-Q responses showed that only 6.8% of OHP's discuss the connection between HPV and oropharyngeal cancer with patients and a lack of information on the topic was the major barrier reported. After the educational intervention (post-Q), 86.5% of OHP's reported they were more likely to recommend the HPV vaccine and 69.8% felt more comfortable administering it. Comparison between the pre-Q and the post-Q showed a significant improvement in overall HPV knowledge. Similarly, a comparison between the post-Q and the follow-Q showed retained knowledge overtime. Our study suggests that the educational intervention was effective at improving OHP's knowledge of HPV and enhancing their comfortability and preparedness to discuss the vaccination with their patients.

T-shaped Peptide Amphiphiles Self Assemble into Nanofiber Networks.

BACKGROUND: Conventional nanofiber forming peptide amphiphiles comprise a beta sheet forming, short peptide sequence with an alkyl chain attached at one terminus. We report the selfassembly of a peptide amphiphile possessing a mid-chain located alkyl substituent (a T-shaped peptide amphiphile) into nanofiber networks. METHOD: Peptide synthesis was carried out using standard 9-fluorenylmethoxycarbonyl solid phase peptide synthesis protocols, followed by covalent attachment of the alkyl chains to yield target peptide amphiphiles. Self-assembly was then studied using electron microscopy and coarse-grained molecular dynamics simulations. RESULTS: T-shaped peptide amphiphiles self-assembled into nanofibers just like linear peptide amphiphiles, but then unlike linear peptide amphiphiles, T-shaped peptide amphiphiles formed inter-fiber associations and ultimately nanofiber networks. CONCLUSION: Changing the position of the alkyl chain in a peptide amphiphile from the terminal end of the peptide to the middle part of the peptide, to form a T-shaped peptide amphiphile, does not disrupt the molecular interactions required for the self-assembly of the peptide amphiphiles into nanofibers.

Is the flexible GnRH antagonist protocol better suited for fresh eSET cycles?

OBJECTIVE: This study was performed to evaluate the efficacy of the flexible GnRH antagonist protocol in comparison with the long GnRH agonist protocol in elective single embryo transfer (eSET) practice. It was conducted in a publicly funded in vitro fertilization program. METHODS: We performed a prospective cohort analysis of data from a private infertility clinic from August 2010 to August 2011. Three hundred fourteen women with normal ovarian reserve and undergoing fresh eSET cycles were included. Sixty-four women underwent follicular stimulation using a flexible GnRH antagonist protocol, and 250 underwent stimulation with a standard long mid-luteal GnRH agonist protocol. RESULTS: Implantation rates (35.9% in the GnRH antagonist group and 29.6% in the GnRH agonist group, P = 0.5) and ongoing pregnancy rates (32.8% in the GnRH antagonist group and 28.8% in the GnRH agonist group, P = 0.5) were equivalent in both groups. The duration of stimulation (9.8 ± 2 days vs. 10.7 ± 1.8 days, P < 0.001) and total FSH dose required (2044 vs. 2775 IU, P < 0.001) were lower in the GnRH antagonist group than in the GnRH agonist group. The number of mature oocytes (6.0 vs. 10.0, P < 0. 001) and number of embryos (5.0 vs. 7.0, P < 0.001) were also lower in GnRH antagonist group. However, the number of embryos cryopreserved was similar in both groups (median 2.0, P = 0.3). CONCLUSION: In women undergoing in vitro fertilization, the flexible GnRH antagonist protocol yields implantation and ongoing pregnancy rates that are similar to the long GnRH agonist protocol, and requires lower doses of gonadotropins and a shorter duration of treatment. The flexible GnRH antagonist protocol appears to be the protocol of choice for an eSET IVF program.

Objectif : La présente étude visait à évaluer l'efficacité d'un protocole flexible ayant recours à des antagonistes de la GnRH, par comparaison avec celle d'un protocole long ayant recours à des agonistes de la GnRH, relativement au transfert sélectif d'un seul embryon (TsSE). L'étude a été menée dans le cadre d'un programme de fécondation in vitro financé par l'État. Méthodes : Nous avons effectué une analyse de cohorte prospective au moyen de données issues d'une clinique de fertilité privée, pour ce qui est de la période d'août 2010 à août 2011. Trois cent quatorze femmes présentant une réserve ovarienne normale et se soumettant à des cycles de TsSE frais ont été admises à l'étude. Un protocole flexible ayant recours à des antagonistes de la GnRH a été utilisé chez 64 femmes, aux fins de la stimulation folliculaire, tandis qu'un protocole long en phase lutéale standard ayant recours à des agonistes de la GnRH a été utilisé chez 250 autres femmes. Résultats : Les taux d'implantation (35,9 % au sein du groupe « antagonistes de la GnRH ¼ et 29,6 % au sein du groupe « agonistes de la GnRH ¼, P = 0,5) et les taux de grossesse en cours (32,8 % au sein du groupe « antagonistes de la GnRH ¼ et 28,8 % au sein du groupe « agonistes de la GnRH ¼, P = 0,5) étaient équivalents dans les deux groupes. La durée de la stimulation (9,8 jours ± 2 jours vs 10,7 jours ± 1,8 jour, P < 0,001) et la dose totale de FSH requise (2 044 vs 2 775 UI, P < 0,001) étaient moins élevées au sein du groupe « antagonistes de la GnRH ¼, par comparaison avec le groupe « agonistes de la GnRH ¼. Le nombre d'ovocytes matures (6,0 vs 10,0, P < 0,001) et le nombre d'embryons (5,0 vs 7,0, P < 0,001) étaient également moins élevés au sein du groupe « antagonistes de la GnRH ¼. Cependant, le nombre d'embryons cryoconservés était similaire dans les deux groupes (médiane : 2,0, P = 0,3). Conclusion : Chez les femmes qui font appel à la fécondation in vitro, le protocole flexible ayant recours à des antagonistes de la GnRH donne des taux d'implantation et de grossesse en cours similaires à ceux que permet le protocole long standard ayant recours à des agonistes de la GnRH, tout en nécessitant des doses plus faibles de gonadotropines et un traitement de plus courte durée. Le protocole flexible ayant recours à des antagonistes de la GnRH semble être le protocole à privilégier dans le cadre d'un programme de FIV utilisant le TsSE.

Rescue in vitro fertilization using a GnRH antagonist in hyper-responders from gonadotropin intrauterine insemination (IUI) cycles.

OBJECTIVE: To evaluate the outcomes in the conversion of high-response gonadotropin intrauterine insemination (IUI) cycles to "rescue" in vitro fertilization (IVF) using a Gonadotropin-Releasing Hormone (GnRH) antagonist, with regards to implantation rates, pregnancy rates, cost, and ovarian hyperstimulation syndrome (OHSS) as compared to matched, hyper-responder, IVF controls. METHODS: This prospective cohort study was conducted between January 2007 and December 2009 at our institution. In order to decrease high-order multiple pregnancy, minimize the incidence of OHSS, and avoid cycle cancellation, high-response stimulated-IUI patients opted to convert to "rescue" IVF using the GnRH antagonist cetrorelix acetate. We then compared their clinical outcomes with matched patients from high-response IVF cycles of the standard long mid-luteal GnRH agonist protocol (14 or more collected oocytes). Only cases of conventional IVF without intra-cytoplasmic sperm injection (ICSI) were included in the control group. RESULTS: Out of 184 patients undergoing stimulated-IUI cycles with gonadotropins, 87 patients developed a hyper-response, and 20 opted to convert to "rescue" IVF. These patients were compared with 157 matched, hyper responder IVF controls from our registry. The implantation rate was 25.6 % in the "rescue" IVF group and 20.7 % in the control IVF group (p < 0.0047). The ongoing clinical pregnancy rate per embryo transfer was 45.0 % and 33.6 % in the "rescue" IVF and the control IVF groups, respectively (p < 0.0001). The mean duration of stimulation was comparable between cohorts (10.0 vs.10.4 days, p = 0.6324). The mean dose of gonadotropin used per cycle was higher in the control group, 2664 international units (IU) of follicle stimulation hormone (FSH) compared to 1450 IU of FSH in the "rescue" IVF group (p < 0.0001). The incidence of severe OHSS is also higher in the control group, 5.1 % versus no cases in the "rescue" IVF group (p < 0.0001). CONCLUSION: Our study demonstrates that conversion of high-response gonadotropin-IUI cycles to "rescue" IVF using a GnRH antagonist is a cost-effective strategy that produces better results than regular IVF with relatively minimal morbidity, and shorter duration to achieve pregnancy. Implantation and ongoing clinical pregnancy rates tend to be higher than those from hyper-responder regular IVF patients.

Postmenopausal hormone therapy increases retinal blood flow and protects the retinal nerve fiber layer.

PURPOSE: To investigate whether postmenopausal hormone therapy (HT) increases retinal and ONH blood flow (BF) and protects ONH topography and the function of retinal ganglion cells in postmenopausal women (PMW). The effect of estradiol (E(2)) treatment on retinal tissue perfusion was also investigated in ovariectomized rats, an animal model for menopause. METHODS: Sixty-four healthy PMW were recruited, 29 of whom never used HT ( HT) and 35 of whom had used HT (+HT) continuously since the onset of menopause. Blood flow of the inferotemporal retinal artery (ITRA), peripapillary retina, and ONH rim were measured in one eye. The ONH stereometric parameters and the pattern electroretinogram (PERG) were also measured. In ovariectomized rats, the retinal tissue perfusion was assessed using the BF tracer N-isopropyl-p-[(14)C]-iodoamphetamine ([(14)C]-IMP) in rats treated with either E(2) (n = 7) or placebo (n = 5). RESULTS: Compared with the HT group, the +HT group presented significantly greater BF of the ITRA (P = 0.006), greater rim volume for the entire ONH region (P = 0.032), and greater rim volume (P = 0.042), height variation contour (P = 0.011), mean thickness (P = 0.033), and cross-sectional area (P = 0.020) of the retinal nerve fiber layer for the inferotemporal region of the ONH when adjusted for age, ocular perfusion pressure, and age at menarche. In ovariectomized rats, E(2) treatment significantly increased retinal perfusion in a range of 22% to 45%. CONCLUSIONS: These findings indicate that estrogens and HT increase retinal blood flow and protect the retinal nerve fiber layer.

Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome.

OBJECTIVE: To determine which first-line medication is more effective in polycystic ovary syndrome (PCOS) patients for ovulation induction and pregnancy achievement and to verify whether any patient characteristic is associated with a better response to therapy. DESIGN: Observational comparative study. SETTING: Fertility clinic. PATIENT(S): One hundred fifty-four infertile women with oligomenorrhea and hyperandrogenism. INTERVENTION(S): Group 1 (56 patients) received clomiphene citrate (CC) 50 mg from days 5-9 of the cycle. Group 2 (57 patients) received 500 mg of metformin 3 times a day. Group 3 (41 patients) received both medications. MAIN OUTCOME MEASURE(S): Ovulation and pregnancy. RESULT(S): Patients receiving metformin alone had an increased ovulation rate compared with those receiving CC alone (75.4% vs. 50%). Patients on metformin had similar ovulation rates compared with those in the combination group (75.4% vs. 63.4%). Pregnancy rates were equivalent in the 3 groups. Response to metformin was independent of body weight and dose. Finally, nonsmoking predicted better ovulatory response overall as well as lower fasting glucose for CC and lower androgens for metformin. CONCLUSION(S): Metformin is better for ovulation induction than CC alone and equivalent for pregnancy achievement. We suggest that metformin can be used first for ovulation induction in patients with PCOS regardless of their weight and insulin levels because of its efficacy and known safety profile.