Panel Discussion: Judges\u27 Perspectives on Law Clerk Hiring, Utilization, and Influence

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“Digital James Dickey” Developing an App for the iPad based on a poem by James Dickey (grade level 11 & 12)

The purpose of our project was to create an app for the ipad based on a nature poem by James Dickey that could be used by a high school teacher in a classroom. The app includes a poem, video readings by the poet, perspectives (comment and literary criticisms) by a number of experts, biography, a gallery of photos, and a resources page. In fall of 2013 we will test the app in the high school classroo

The Th1:Th2 Dichotomy of Pregnancy and Preterm Labour

Pregnancy is a unique immunological state in which a balance of immune tolerance and suppression is needed to protect the fetus without compromising the mother. It has long been established that a bias from the T helper 1 cytokine profile towards the T helper 2 profile contributes towards successful pregnancy maintenance. The majority of publications that report on aberrant Th1:Th2 balance focus on early pregnancy loss and preeclampsia. Over the last few decades, there has been an increased awareness of the role of infection and inflammation in preterm labour, and the search for new biomarkers to predict preterm labour continues. In this paper, we explore the evidence for an aberrant Th1:Th2 profile associated with preterm labour. We also consider the potential for its use in screening women at high risk of preterm labour and for prophylactic therapeutic measures for the prevention of preterm labour and associated neonatal adverse outcomes

A Prospective Longitudinal Assessment of Medical Records for Diagnostic Substitution among Subjects Diagnosed with a Pervasive Developmental Disorder in the United States

Background: Previously, investigators suggested that diagnostic substitution from other diagnoses, e.g., mental retardation (MR) and/or cerebral palsy (CP) to pervasive developmental disorder (PDD) is a driving factor behind increases in PDD. This study evaluated potential diagnostic substitution among subjects diagnosed with PDD vs MR or CP by examining birth characteristic overlap.Methods: SAS® and StatsDirect software examined medical records for subjects within the Vaccine Safety Datalink (VSD) database who were Health Maintenance Organization (HMO)-enrolled from birth until diagnosed with an International Classification of Disease, 9th revision (ICD-9) outcome of PDD (299.xx, n=84), CP (343.xx, n=300), or MR (317.xx, 318.xx, or 319.xx, n=51).Results: Subjects with PDD had significantly (p<0.01) increased: male/female ratio (PDD=5.5 vs CP=1.5 or MR=1.3), mean age of initial diagnosis in years (PDD=3.13 vs CP=1.09 or MR=1.62), mean gestational age in weeks at birth (PDD=38.73 vs CP=36.20 or MR=34.84), mean birth weight in grams (PDD=3,368 vs CP=2,767 or MR=2,406), and mean Appearance-Pulse-Grimace-Activity-Respiration (APGAR) scores at 1 minute (PDD=7.82 vs CP=6.37 or MR=6.76) and 5 minutes (PDD=8.77 vs CP=7.92 or MR=8.04), as compared to subjects diagnosed with CP or MR.Conclusion: This study suggests diagnostic substitution cannot fully explain increased PDD prevalence during the 1990s within the United States

Changes in the Th1 : Th2 Cytokine Bias in Pregnancy and the Effects of the Anti-Inflammatory Cyclopentenone Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2

Pregnancy is a complex immunological state in which a bias towards T helper 2 (Th2) protects the fetus. Evidence suggests that proinflammatory cytokines increase the risk of poor neonatal outcome, independently of the direct effect of preterm labour. The anti-inflammatory prostaglandin 15-deoxy-Δ12,14-Prostaglandin J2 (15dPGJ2) inhibits nuclear factor Kappa B (NF-κB) in amniocytes and myocytes in vitro and is a ligand for the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptor. Here we examine the Th1:Th2 cytokine bias in pregnancy and whether 15dPGJ2 could be used to inhibit the production of the proinflammatory cytokines through inhibition of NF-κB while simultaneously promoting Th2 interleukin 4 (IL-4) synthesis via CRTH2 in T helper cells. Peripheral blood mononuclear cells (PBMCs) from women at 28 weeks, term pre-labour, term labour as well as non-pregnant female controls were cultured with 15dPGJ2 or vehicle control and stimulated with phorbol myristyl acetate (PMA)/ionomycin. The percentage of CD4+ cells producing interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) in response to PMA/ionomycin was significantly reduced in pregnancy. 15dPGJ2 reduced IFN-γ and TNF-α production in stimulated T helper cells, but did not alter IL-4 production in CRTH2+ve cells. 15dPGJ2 also reduced phospho-p65 in stimulated PBMCs. In summary, 15dPGJ2 suppresses the Th1 response of PBMCs during pregnancy and active labour whilst maintaining the Th2 response suggesting a therapeutic benefit in reducing neonatal morbidity in inflammation-induced PTL

Excisional treatment in women with cervical adenocarcinoma in situ (AIS): a prospective randomised controlled noninferiority trial to compare AIS persistence/recurrence after loop electrosurgical excision procedure with cold knife cone biopsy: protocol for a pilot study

Introduction: Adenocarcinoma in situ (AIS) of the uterine cervix is the precursor to invasive endocervical adenocarcinoma. An excisional biopsy such as a cold knife cone biopsy (CKC) should be performed to exclude invasive adenocarcinoma. Loop electrosurgical excision procedure (LEEP) is an alternative modality to CKC but is controversial in AIS. There is a perception that there is a greater likelihood of incomplete excision of AIS with LEEP because the depth of excised tissue tends to be smaller and the tissue margins may show thermal artefact which can interfere with pathology assessment. In the USA, guidelines recommend that any treatment modality can be used to excise AIS, provided that the specimen remains intact with interpretable margins. However, there are no high-quality studies comparing LEEP with CKC and well-designed prospective studies are needed. If such a study were to show that LEEP was non-inferior to CKC for the outcomes of post-treatment persistence, recurrence and adenocarcinoma, LEEP could be recommended as an appropriate treatment option for AIS in selected patients. This would benefit women because, unlike CKC, LEEP does not require general anaesthesia and may be associated with reduced morbidity. Methods and analysis: The proposed exploratory study is a parallel group trial with an allocation ratio of 2:1 in favour of the intervention (LEEP: CKC). Participants are women aged ≥18 to ≤45 years diagnosed with AIS on cervical screening and/or colposcopically directed biopsy in Australia and New Zealand, who are to receive excisional treatment in a tertiary level centre. Ethics and dissemination: Ethical approval for the study has been granted by the St John of God Healthcare Human Research Ethics Committee (reference number #1137)

A longitudinal cohort study of the relationship between Thimerosal-containing hepatitis B vaccination and specific delays in development in the United States: Assessment of attributable risk and lifetime care costs

AbstractEpidemiological evidence suggests a link between mercury (Hg) exposure from Thimerosal-containing vaccines and specific delays in development. A hypothesis-testing longitudinal cohort study (n=49,835) using medical records in the Vaccine Safety Datalink (VSD) was undertaken to evaluate the relationship between exposure to Hg from Thimerosal-containing hepatitis B vaccines (T-HBVs) administered at specific intervals in the first 6months of life and specific delays in development [International Classification of Disease, 9th revision (ICD-9): 315.xx] among children born between 1991 and 1994 and continuously enrolled from birth for at least 5.81years. Infants receiving increased Hg doses from T-HBVs administered within the first month, the first 2months, and the first 6months of life were significantly more likely to be diagnosed with specific delays in development than infants receiving no Hg doses from T-HBVs. During the decade in which T-HBVs were routinely recommended and administered to US infants (1991–2001), an estimated 0.5–1million additional US children were diagnosed with specific delays in development as a consequence of 25μg or 37.5μg organic Hg from T-HBVs administered within the first 6months of life. The resulting lifetime costs to the United States may exceed $1 trillion

Discovery of a Brown Dwarf Companion to Gliese 570ABC: A 2MASS T Dwarf Significantly Cooler than Gliese 229B

We report the discovery of a widely separated (258\farcs3\pm0\farcs4) T dwarf companion to the Gl 570ABC system. This new component, Gl 570D, was initially identified from the Two Micron All Sky Survey (2MASS). Its near-infrared spectrum shows the 1.6 and 2.2 \micron CH$_4$ absorption bands characteristic of T dwarfs, while its common proper motion with the Gl 570ABC system confirms companionship. Gl 570D (M$_J$ = 16.47$\pm$0.07) is nearly a full magnitude dimmer than the only other known T dwarf companion, Gl 229B, and estimates of L = (2.8$\pm$0.3)x10$^{-6}$ L_{\sun} and T$_{eff}$ = 750$\pm$50 K make it significantly cooler and less luminous than any other known brown dwarf companion. Using evolutionary models by Burrows et al. and an adopted age of 2-10 Gyr, we derive a mass estimate of 50$\pm$20 M$_{Jup}$ for this object.Comment: 13 pages, 2 figures, 2 tables, accepted by ApJ

Transmembrane Inhibitor of RICTOR/mTORC2 in Hematopoietic Progenitors

Summary Central to cellular proliferative, survival, and metabolic responses is the serine/threonine kinase mTOR, which is activated in many human cancers. mTOR is present in distinct complexes that are either modulated by AKT (mTORC1) or are upstream and regulatory of it (mTORC2). Governance of mTORC2 activity is poorly understood. Here, we report a transmembrane molecule in hematopoietic progenitor cells that physically interacts with and inhibits RICTOR, an essential component of mTORC2. Upstream of mTORC2 (UT2) negatively regulates mTORC2 enzymatic activity, reducing AKTS473, PKCα, and NDRG1 phosphorylation and increasing FOXO transcriptional activity in an mTORC2-dependent manner. Modulating UT2 levels altered animal survival in a T cell acute lymphoid leukemia (T-ALL) model that is known to be mTORC2 sensitive. These studies identify an inhibitory component upstream of mTORC2 in hematopoietic cells that can reduce mortality from NOTCH-induced T-ALL. A transmembrane inhibitor of mTORC2 may provide an attractive target to affect this critical cell regulatory pathway

Binding kinetics of ligands acting at GPCRs

The influence of drug-receptor binding kinetics has often been overlooked during the development of new therapeutics that target G protein-coupled receptors (GPCRs). Over the last decade there has been a growing understanding that an in-depth knowledge of binding kinetics at GPCRs is required to successfully target this class of proteins. Ligand binding to a GPCR is often not a simple single step process with ligand freely diffusing in solution. This review will discuss the experiments and equations that are commonly used to measure binding kinetics and how factors such as allosteric regulation, rebinding and ligand interaction with the plasma membrane may influence these measurements. We will then consider the molecular characteristics of a ligand and if these can be linked to association and dissociation rates