Examination of exogenous estrogenic chemical exposure and altered fetal nutrition in the CD-1 mouse fetus

Title from PDF of title page (University of Missouri--Columbia, viewed on September 15, 2010).The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file.Dissertation advisor: Dr. Frederick vom Saal.Vita.Ph. D. University of Missouri--Columbia 2009.My dissertation examines two issues related to disruption of fetal growth: exposure to exogenous estrogenic chemicals and altered nutrition. My first set of studies was aimed at manipulating isoflavones in feed on serum estradiol levels in pregnant female CD-1 mice and their fetuses. Results were that fetal serum estradiol concentrations were elevated due to the absence of either isoflavones or soy protein in feed. Also, I show a difference in response to low doses of natural estrogens compared to manmade estrogens. I also show that isoflavones gave a nonmonotonic dose-response curve in that low levels of isoflavones elevated fetal estradiol levels and higher doses decreased fetal estradiol levels. The data show that the feed groups that had earlier onset of puberty in females were the same feed groups with higher estradiol during fetal life. These finding show that isoflavones have the potential to disrupt the fetal endocrine system. My last study involved examining placental transport in a crowded uterine horn. In the model used here, uterine crowding causes differential blood flow to fetuses. The fetuses with decreased blood flow relative to their siblings show decreased growth. I show here that the placenta does influence amino acid transport and that a reduced fetal growth is related to a reduced placental transport of nutrients. The importance of the crowded uterine model for the study of the effects of fetal nutrition on fetal growth is that this model incidence of IUGR in developed countries.Includes bibliographical reference

Rat Race: Insider Advice on Landing Judicial Clerkships

For many, the judicial clerkship application process is, to quote Sir Winston Churchill, a “riddle wrapped in a mystery inside an enigma.” It is a frenzied “Pamplona-like” atmosphere that begins on Labor Day +1 and continues unabated for several weeks. The initial week is the make or break point in the application review process because it is then that the judge starts to read each application and makes a “yes” or “no” evaluation. If his vote is a “no,” then no further action is taken. If it is a “yes,” the application passes to the law clerks, who then begin their evaluation. Our experience reviewing these applications has led us to the unanimous conclusion that many applicants select their list of judges and put together their packets with little or no thought of strategy as to how to get their applications past this initial phase and into the “yes” pile. We would like to guide the judicial clerkship applicant through the application process by discussing how our chambers conducts the interview and selection process. Specifically, we hope to dispel rumors of what goes on behind the curtain, and ultimately shed some light on how a clerkship applicant could improve his or her chances of receiving an offer. Although this article reflects the viewpoint of only one chambers, our collective experience is broad. Judge Ruggero J. Aldisert has been receiving law clerk applications, interviewing candidates and selecting clerks since 1961. From the standpoint of sheer experience in the law clerk selection process, Judge Aldisert must be near the top of the list of current federal appellate judges. His two present law clerks, Ryan Kirkpatrick and James Stevens, each wear two battle stars for action in the application process. Kirkpatrick and Stevens earned their first star in 2004 when they survived the initial post-Labor Day “running of the bulls,” a term which appropriately describes the federal judiciary’s present hiring plan. The two clerks earned their second star a year later when they closely examined each of the 200 applicants in the 2005 “stampede” and ultimately helped to select the two best candidates to go on to future honors. The authors are fully aware that there is a vast amount of literature discussing the clerkship application process. Most of the literature is couched in somber academic tomes, one of which was serious enough to require 334 footnotes. Our treatment of the subject is far less scholarly. We will not be discussing the role of game theory or the use of the “medical-matching model” in law clerk selection. Our purpose is simply to provide an insider’s perspective into the clerkship application process and, in doing so, defend the following theses: Unless you are the Editor-in-Chief of your school’s main law review or one of the top five or ten students in your class, you need to set yourself apart from the competition. Your road to success is through the face-to-face interview with the Judge. In making this point, we depart from the truism in the decision-making process that writing a good brief is more important than oral argument. In your written applications you may have sterling academic records, stunning extracurricular activities, and superb references, but whether you get the job offer depends on how you perform at the personal interview

Benefits of soy-based feeds for fetal estrogen levels and obesity in adulthood

Abstract only availableWe examined the effect of maternal exposure to naturally occurring estrogenic chemicals in diets on circulating levels of estradiol in mouse fetuses. An animal's specific response to estrogen can vary according to the time of exposure. The time when the fetus is sensitive to permanent “programming” effects of estrogen is called a “critical period” in development of organ systems. An important factor in the regulation of estrogen in the fetus is the composition of the mother's diet. Our hypothesis was that if a diet that was fed to pregnant mice during the fetal critical period contained estrogenic chemicals, these chemicals would “estrogenize” the fetus. In contrast to this prediction, a casein-based diet with virtually no estrogenic chemicals led to significantly higher levels of endogenous estradiol relative to a soy-based diet with very high levels of estrogenic chemicals. In a follow-up experiment we compared a soy-based diet containing estrogenic chemicals with a soy-based diet from which these estrogenic chemicals were extracted. The complete soy diet resulted in estrodiol levels of 60 pg/ml in fetal serum, while the extracted soy diet dramatically increased serum estradiol by over 50%. This finding shows that the naturally occurring estrogens in soy (phytoestrogens) fed to pregnant mice reduce endogenous estradiol levels in the fetuses. This is important since elevated levels of estradiol during fetal life "program" certain characteristics into the animal later on in adulthood. One of these characteristics is obesity. Obesity is associated with Type II diabetes, and the mice with elevated fetal estradiol levels show evidence of impaired glucose tolerance in later adulthood. These effects are relevant since obesity and diabetes are abnormalities in humans that are increasing.Life Sciences Undergraduate Research Opportunity Progra

Crosstalk between osteoblasts and endothelial cells co-cultured on a polycaprolactone-starch scaffold and the in vitro development of vascularization

The reconstruction of bone defects based on cell-seeded constructs requires a functional microvasculature that meets the metabolic demands of the engineered tissue. Therefore, strategies that augment neovascularization need to be identified. We propose an in vitro strategy consisting of the simultaneous culture of osteoblasts and endothelial cells on a starch-based scaffold for the formation of pre-vascular structures, with the final aim of accelerating the establishment of a vascular bed in the implanted construct. Human dermal microvascular endothelial cells (HDMECs) were co-cultured with human osteoblasts (hOBs) on a 3D starch-based scaffold and after 21 days of culture HDMEC aligned and organized into microcapillary-like structures. These vascular-like structures evolved from a cord-like configuration to a more complex branched morphology, had a lumen and stained in the perivascular region for type IV collagen. Genetic profiling of 84 osteogenesis-related genes was performed on coculture vs. monoculture. Osteoblasts in co-culture showed a significant up-regulation of type I collagen and immunohistochemistry revealed that the scaffold was filled with a dense matrix stained for type I collagen. In direct contact with HDMEC hOBs secreted higher amounts of VEGF in relation to monoculture and the highest peak in the release profile correlated with the formation of microcapillary-like structures. The heterotypic communication between the two cell types was also assured by direct cell– cell contact as shown by the expression of the gap junction connexin 43. In summary, by making use of heterotypic cellular crosstalk this co-culture system is a strategy to form vascular-like structures in vitro on a 3D scaffold.M.I. Santos would like to acknowledge the Portuguese Foundation for Science and Technology (FCT) for her PhD scholarship (SFRH/BD/13428/2003). This work was partially supported by FCT through funds from POCTI and/or FEDER programs and by the European Union funded STREP Project HIPPOCRATES (NMP3-CT-2003-505758). This work was carried out under the scope of the European NOE EXPERTISSUES (NMP3-CT-2004-500283)

Computational and Spectroscopic Investigations of the Molecular Scale Structure and Dynamics of Geologically Important Fluids and Mineral-Fluid Interfaces

Research supported by this grant focuses on molecular scale understanding of central issues related to the structure and dynamics of geochemically important fluids, fluid-mineral interfaces, and confined fluids using computational modeling and experimental methods. Molecular scale knowledge about fluid structure and dynamics, how these are affected by mineral surfaces and molecular-scale (nano-) confinement, and how water molecules and dissolved species interact with surfaces is essential to understanding the fundamental chemistry of a wide range of low-temperature geochemical processes, including sorption and geochemical transport. Our principal efforts are devoted to continued development of relevant computational approaches, application of these approaches to important geochemical questions, relevant NMR and other experimental studies, and application of computational modeling methods to understanding the experimental results. The combination of computational modeling and experimental approaches is proving highly effective in addressing otherwise intractable problems. In 2006-2007 we have significantly advanced in new, highly promising research directions along with completion of on-going projects and final publication of work completed in previous years. New computational directions are focusing on modeling proton exchange reactions in aqueous solutions using ab initio molecular dynamics (AIMD), metadynamics (MTD), and empirical valence bond (EVB) approaches. Proton exchange is critical to understanding the structure, dynamics, and reactivity at mineral-water interfaces and for oxy-ions in solution, but has traditionally been difficult to model with molecular dynamics (MD). Our ultimate objective is to develop this capability, because MD is much less computationally demanding than quantum-chemical approaches. We have also extended our previous MD simulations of metal binding to natural organic matter (NOM) to a much longer time scale (up to 10 ns) for significantly larger systems. These calculations have allowed us, for the first time, to study the effects of metal cations with different charges and charge density on the NOM aggregation in aqueous solutions. Other computational work has looked at the longer-time-scale dynamical behavior of aqueous species at mineral-water interfaces investigated simultaneously by NMR spectroscopy. Our experimental NMR studies have focused on understanding the structure and dynamics of water and dissolved species at mineral-water interfaces and in two-dimensional nano-confinement within clay interlayers. Combined NMR and MD study of H2O, Na+, and Cl- interactions with the surface of quartz has direct implications regarding interpretation of sum frequency vibrational spectroscopic experiments for this phase and will be an important reference for future studies. We also used NMR to examine the behavior of K+ and H2O in the interlayer and at the surfaces of the clay minerals hectorite and illite-rich illite-smectite. This the first time K+ dynamics has been characterized spectroscopically in geochemical systems. Preliminary experiments were also performed to evaluate the potential of 75As NMR as a probe of arsenic geochemical behavior. The 75As NMR study used advanced signal enhancement methods, introduced a new data acquisition approach to minimize the time investment in ultra-wide-line NMR experiments, and provides the first evidence of a strong relationship between the chemical shift and structural parameters for this experimentally challenging nucleus. We have also initiated a series of inelastic and quasi-elastic neutron scattering measurements of water dynamics in the interlayers of clays and layered double hydroxides. The objective of these experiments is to probe the correlations of water molecular motions in confined spaces over the scale of times and distances most directly comparable to our MD simulations and on a time scale different than that probed by NMR. This work is being done in collaboration with Drs. C.-K. Loong, N. de Souza, and A.I. Kolesnikov at the Intense Pulsed Neutron Source facility of the Argonne National Lab, and Dr. A. Faraone at the NIST Center for Neutron Research. A manuscript reporting the first results of these experiments, which are highly complimentary to our previous NMR, X-ray, and infra-red results for these phases, is currently in preparation. In total, in 2006-2007 our work has resulted in the publication of 14 peer-reviewed research papers. We also devoted considerable effort to making our work known to a wide range of researchers, as indicated by the 24 contributed abstracts and 14 invited presentations

J-Band Infrared Spectroscopy of a Sample of Brown Dwarfs Using Nirspec on Keck II

Near-infrared spectroscopic observations of a sample of very cool, low-mass objects are presented with higher spectral resolution than in any previous studies. Six of the objects are L-dwarfs, ranging in spectral class from L2 to L8/9, and the seventh is a methane or T-dwarf. These new observations were obtained during commissioning of NIRSPEC, the first high-resolution near-infrared cryogenic spectrograph for the Keck II 10-meter telescope on Mauna Kea, Hawaii. Spectra with a resolving power of R=2500 from 1.135 to 1.360 microns (approximately J-band) are presented for each source. At this resolution, a rich spectral structure is revealed, much of which is due to blending of unresolved molecular transitions. Strong lines due to neutral potassium (K I), and bands due to iron hydride (FeH) and steam (H2O) change significantly throughout the L sequence. Iron hydride disappears between L5 and L8, the steam bands deepen and the K I lines gradually become weaker but wider due to pressure broadening. An unidentified feature occurs at 1.22 microns which has a temperature dependence like FeH but has no counterpart in the available FeH opacity data. Because these objects are 3-6 magnitudes brighter in the near-infrared compared to the I-band, spectral classification is efficient. One of the objects studied (2MASSW J1523+3014) is the coolest L-dwarf discovered so far by the 2-Micron All-Sky Survey (2MASS), but its spectrum is still significantly different from the methane-dominated objects such as Gl229B or SDSS 1624+0029.Comment: New paper, Latex format, 2 figures, accepted to ApJ Letter

Right ventricular dysfunction after resuscitation predicts poor outcomes in cardiac arrest patients independent of left ventricular function.

OBJECTIVE: Determination of clinical outcomes following resuscitation from cardiac arrest remains elusive in the immediate post-arrest period. Echocardiographic assessment shortly after resuscitation has largely focused on left ventricular (LV) function. We aimed to determine whether post-arrest right ventricular (RV) dysfunction predicts worse survival and poor neurologic outcome in cardiac arrest patients, independent of LV dysfunction. METHODS: A single-center, retrospective cohort study at a tertiary care university hospital participating in the Penn Alliance for Therapeutic Hypothermia (PATH) Registry between 2000 and 2012. PATIENTS: 291 in- and out-of-hospital adult cardiac arrest patients at the University of Pennsylvania who had return of spontaneous circulation (ROSC) and post-arrest echocardiograms. MEASUREMENTS AND MAIN RESULTS: Of the 291 patients, 57% were male, with a mean age of 59 ± 16 years. 179 (63%) patients had LV dysfunction, 173 (59%) had RV dysfunction, and 124 (44%) had biventricular dysfunction on the initial post-arrest echocardiogram. Independent of LV function, RV dysfunction was predictive of worse survival (mild or moderate: OR 0.51, CI 0.26-0.99, p CONCLUSIONS: Echocardiographic findings of post-arrest RV dysfunction were equally prevalent as LV dysfunction. RV dysfunction was significantly predictive of worse outcomes in post-arrest patients after accounting for LV dysfunction. Post-arrest RV dysfunction may be useful for risk stratification and management in this high-mortality population

Geological constraints on the mechanisms of slow earthquakes

The recognition of slow earthquakes in geodetic and seismological data has transformed the understanding of how plate motions are accommodated at major plate boundaries. Slow earthquakes, which slip more slowly than regular earthquakes but faster than plate motion velocities, occur in a range of tectonic and metamorphic settings. They exhibit spatiotemporal associations with large seismic events that indicate a causal relation between modes of slip at different slip rates. Defining the physical controls on slow earthquakes is, therefore, critical for understanding fault and shear zone mechanics. In this Review, we synthesize geological observations of a suite of ancient structures that were active in tectonic settings comparable to where slow earthquakes are observed today. At inferred slow earthquake regions, a range of grain-scale deformation mechanisms accommodated slip at low effective stresses. Material heterogeneity and the geometric complexity of structures that formed at different inferred strain rates are common to faults and shear zones in multiple tectonic environments, and might represent key limiting factors of slow earthquake slip rates. Further geological work is needed to resolve how the spectrum of slow earthquake slip rates can arise from different grain-scale deformation mechanisms and whether there is one universal rate-limiting mechanism that defines slow earthquake slip