When should acute nonvenereal conjunctivitis be treated with topical antibiotics?

Children with suspected or culture-proven acute nonvenereal bacterial conjunctivitis should be treated with topical antibiotics, which hastens clinical and microbiological remission and may prevent potentially serious morbidity. In light of recent evidence regarding the self-limiting nature of conjunctivitis in adults and the development of antibiotic resistance, a "wait-and-see"� approach with careful follow-up may be reasonable for adults, but this approach has not been evaluated. (Grade of recommendation: C, based on extrapolation from systematic reviews of specialty clinic trials and cohort studies.

Darpp-32 and Its Truncated Variant t-Darpp Have Antagonistic Effects on Breast Cancer Cell Growth and Herceptin Resistance

BACKGROUND: Herceptin (trastuzumab) is a humanized monoclonal antibody that is approved for the treatment of metastatic breast cancer patients whose tumors overexpress Her2 (erbB2/neu). Up to 70% of Her2-positive breast cancers demonstrate a response to Herceptin-based therapies, but resistance almost inevitably arises within a year of the initial response. To help understand the mechanism of Herceptin resistance, we isolated clonal variants of Her2-positive BT474 human breast cancer cells (BT/Her(R)) that are highly resistant to Herceptin. These cell lines exhibit sustained PI3K/Akt signaling as an essential component of Herceptin-resistant proliferation. Several genes in the protein kinase A (PKA) signaling network have altered expression in BT/Her(R) cells, including PPP1R1B, which encodes a 32 kDa protein known as Darpp-32 and its amino-terminal truncated variant, t-Darpp. The purpose of the current work was to determine the role of Darpp-32 and t-Darpp in Herceptin resistance. METHODOLOGY AND RESULTS: We determined expression of Darpp-32 and t-Darpp in BT/Her(R) cells selected for resistance to Herceptin. Subsequently, cDNAs encoding the two isoforms of Darpp-32 were transfected, separately and together, into Her2-positive SK-Br-3 breast cancer cells. Transfected cells were tested for resistance to Herceptin and Herceptin-mediated dephosphorylation of Akt. DNA binding activity by the cAMP response element binding protein (CREB) was also measured. We found that BT/Her(R) cells overexpressed t-Darpp but not Darpp-32. Moreover, t-Darpp overexpression in SK-Br-3 cells was sufficient for conferring resistance to Herceptin and Herceptin-mediated dephosphorylation of Akt. Darpp-32 co-expression reversed t-Darpp's effects on Herceptin resistance and Akt phosphorylation. t-Darpp overexpression led to increased CREB binding activity, which was also reversible by Darpp-32. CONCLUSIONS: t-Darpp and Darpp-32 appear to have antagonistic effects on Herceptin resistance. We present a unified model by which these effects might be mediated via the PKA regulatory network

A ruptured ectopic pregnancy in a patient with an intrauterine device: A case report.

Intrauterine devices (IUDs) are used worldwide. The 2 types that are used are the levonorgestrel IUD and a copper containing IUD. This is a case study of a 30-year-old female with a levonorgestrel IUD who was diagnosed with a ruptured ectopic pregnancy in the emergency department (ED). Point-of-care urine pregnancy test and point-of-care ultrasound (POCUS) were vital in making this diagnosis and should be utilized in patients assigned female at birth who present with abdominal pain

Abnormal Glycosylation of Procathepsin L Due to N-terminal Point Mutations Correlates with Failure to Sort to Lysosomes

A single point mutation in the lysosomal proenzyme receptor-inhibiting sequence near the N terminus of mouse procathepsin L can result in glycosylation of a normally cryptic site near its C terminus. When alanine replaced His36, Arg38, or Tyr40, the nascent chain of the mutant protein cotranslationally acquired a high mannose oligosaccharide chain at Asn268. In contrast, when alanine replaced Ser34, Arg37, or Leu39, this second carbohydrate chain was not added. This alternating pattern of abnormal glycosylation suggested that propeptide residues 36-40 normally assume an extended conformation having the side chains of residues 36, 38, and 40 facing in the same direction. When tyrosine conservatively replaced His36 or lysine replaced Arg38, Asn268 was not glycosylated. But the procathepsin L mutant having phenylalanine in place of Tyr40 was glycosylated at Asn268, which indicates that the hydrogen bond between the hydroxyl group of Tyr40 and the carboxylate group of Asp82 is necessary for normal folding of the nascent proenzyme chain. Mutation of the adjacent alpha2p (ERININ) helix of the propeptide or addition of a C-terminal epitope tag sequence to procathepsin L also induced misfolding of the proenzyme, as indicated by addition of the second oligosaccharide chain. In contrast, the propeptide mutation KAKK99-102AAAA had no effect on carbohydrate modification even though it reduced the positive charge of the proenzyme. Misfolded mutant mouse procathepsin L was not efficiently targeted to lysosomes on expression in human HeLa cells, even though it acquired phosphate on mannose residues. The majority of the mutant protein was secreted after undergoing modification with complex sugars. Similarly, epitope-tagged mouse procathepsin L was not targeted to lysosomes in homologous mouse cells but was efficiently secreted. Since production of mature endogenous protease was not reduced in cells expressing the tagged protein, the tagged protein did not compete with endogenous procathepsin L for targeting to lysosomes

Teaching the Newly Essential Knowledge, Skills, and Values in a Changing World

This chapter of Building on Best Practices: Transforming Legal Education in a Changing World has contributions from many authors: Section A, Professional Identity Formation, includes: Teaching Knowledge, Skills, and Values of Professional Identity Formation, by Larry O. Natt Gantt, II & Benjamin V. Madison III, Integrating Professionalism into Doctrinally-Focused Courses, by Paula Schaefer, Learning Professional Responsibility, by Clark D. Cunningham, and Teaching Leadership, by Deborah L. Rhode. Section B, Pro Bono as a Professional Value, is by Cynthia F. Adcock, Eden E. Harrington, Elizabeth Kane, Susan Schechter, David S. Udell & Eliza Vorenberg. Section C, The Relational Skills of the Law, includes: Teaching Relational Skills: The Evidence, by Susan Daicoff, and Cultivating Students\u27 Relational Skills, by Susan L. Brooks. Section D, Teamwork, is by Linda Morton & Janet Weinstein. Section E, Intercultural Effectiveness, is by Mary A. Lynch with Robin Boyle, Rhonda Magee & Antoinette Sedillo López. Section F, Social Justice Across the Curriculum, is by Susan Bryant. Section G, Problem-Solving and Conflict Resolution, includes: Teaching Students to Be Healers: The Comprehensive Law Movement, by Susan Daicoff, Teaching Alternative Dispute Resolution, by Andrea Kupfer Schneider, and Integrating Alternative Dispute Resolution and Problem-Solving Across the Curriculum, by Jill Gross & John Lande Section H, Interprofessional Education, is by Lisa Radtke Bliss, Sylvia B. Caley, Patty Roberts, Emily F. Suski & Robert Pettignano. Section I, Technology in the Profession, is by Conrad Johnson. Section J, Business and Financial Literacy, is by Dwight Drake. Chapter 1 is available at: http://ssrn.com/abstract=2637100 Chapter 2 is available at: http://ssrn.com/abstract=2637068 Chapter 3 is available at: http://ssrn.com/abstract=2637102 Chapter 4 is available at: http://ssrn.com/abstract=2637490 Chapter 5 is available at: http://ssrn.com/abstract=2637495 Chapter 7 is available at: http://ssrn.com/abstract=2637541 Chapter 8 is available at: http://ssrn.com/abstract=2637544 The content of this SSRN posting is material that was published in the book Building on Best Practices: Transforming Legal Education in a Changing World, Maranville, et al., Lexis Nexis 2015. The content has been posted on SSRN with the express permission of Lexis Nexis and of Carolina Academic Press, publisher of the book as of January 1, 2016

Exoplanet Catalogues

One of the most exciting developments in the field of exoplanets has been the progression from 'stamp-collecting' to demography, from discovery to characterisation, from exoplanets to comparative exoplanetology. There is an exhilaration when a prediction is confirmed, a trend is observed, or a new population appears. This transition has been driven by the rise in the sheer number of known exoplanets, which has been rising exponentially for two decades (Mamajek 2016). However, the careful collection, scrutiny and organisation of these exoplanets is necessary for drawing robust, scientific conclusions that are sensitive to the biases and caveats that have gone into their discovery. The purpose of this chapter is to discuss and demonstrate important considerations to keep in mind when examining or constructing a catalogue of exoplanets. First, we introduce the value of exoplanetary catalogues. There are a handful of large, online databases that aggregate the available exoplanet literature and render it digestible and navigable - an ever more complex task with the growing number and diversity of exoplanet discoveries. We compare and contrast three of the most up-to-date general catalogues, including the data and tools that are available. We then describe exoplanet catalogues that were constructed to address specific science questions or exoplanet discovery space. Although we do not attempt to list or summarise all the published lists of exoplanets in the literature in this chapter, we explore the case study of the NASA Kepler mission planet catalogues in some detail. Finally, we lay out some of the best practices to adopt when constructing or utilising an exoplanet catalogue.Comment: 14 pages, 6 figures. Invited review chapter, to appear in "Handbook of Exoplanets", edited by H.J. Deeg and J.A. Belmonte, section editor N. Batalh

Neighborhood and Family Environment of Expectant Mothers May Influence Prenatal Programming of Adult Cancer Risk: Discussion and an Illustrative DNA Methylation Example

Childhood stressors including physical abuse predict adult cancer risk. Prior research portrays this finding as indirect through coping behaviors including adult smoking or through increased toxic exposures during childhood. Little is known about potential direct causal mechanisms between early-life stressors and adult cancer. Because prenatal conditions can affect gene expression by altering DNA methylation with implications for adult health, we hypothesize that maternal stress may program methylation of cancer-linked genes during gametogenesis

Maternal-to-fetal allopurinol transfer and xanthine oxidase suppression in the late gestation pregnant rat.

Fetal brain hypoxic injury remains a concern in high-risk delivery. There is significant clinical interest in agents that may diminish neuronal damage during birth asphyxia, such as in allopurinol, an inhibitor of the prooxidant enzyme xanthine oxidase. Here, we established in a rodent model the capacity of allopurinol to be taken up by the mother, cross the placenta, rise to therapeutic levels, and suppress xanthine oxidase activity in the fetus. On day 20 of pregnancy, Wistar dams were given 30 or 100 mg kg(-1) allopurinol orally. Maternal and fetal plasma allopurinol and oxypurinol concentrations were measured, and xanthine oxidase activity in the placenta and maternal and fetal tissues determined. There were significant strong positive correlations between maternal and fetal plasma allopurinol (r = 0.97, P < 0.05) and oxypurinol (r = 0.88, P < 0.05) levels. Under baseline conditions, maternal heart (2.18 ± 0.62 mU mg(-1)), maternal liver (0.29 ± 0.08 mU mg(-1)), placenta (1.36 ± 0.42 mU mg(-1)), fetal heart (1.64 ± 0.59 mU mg(-1)), and fetal liver (0.14 ± 0.08 mU mg(-1)) samples all showed significant xanthine oxidase activity. This activity was suppressed in all tissues 2 h after allopurinol administration and remained suppressed 24 h later (P < 0.05), despite allopurinol and oxypurinol levels returning toward baseline. The data establish a mammalian model of xanthine oxidase inhibition in the mother, placenta, and fetus, allowing investigation of the role of xanthine oxidase-derived reactive oxygen species in the maternal, placental, and fetal physiology during healthy and complicated pregnancy

Large-Scale Transport into the Arctic: The Roles of the Midlatitude Jet and the Hadley Cell

Transport from the Northern Hemisphere (NH) midlatitudes to the Arctic plays a crucial role in determining the abundance of trace gases and aerosols that are important to Arctic climate via impacts on radiation and chemistry. Here we examine this transport using an idealized tracer with a fixed lifetime and predominantly midlatitude land-based sources in models participating in the Chemistry Climate Model Initiative (CCMI). We show that there is a 25%-45% difference in the Arctic concentrations of this tracer among the models. This spread is correlated with the spread in the location of the Pacific jet, as well as the spread in the location of the Hadley Cell (HC) edge, which varies consistently with jet latitude. Our results suggest that it is likely that the HC-related zonal-mean meridional transport rather than the jet-related eddy mixing is the major contributor to the inter-model spread in the transport of land-based tracers into the Arctic. Specifically, in models with a more northern jet, the HC generally extends further north and the tracer source region is mostly covered by surface southward flow associated with the lower branch of the HC, resulting in less efficient transport poleward to the Arctic. During boreal summer, there are poleward biases in jet location in free-running models, and these models likely underestimate the rate of transport into the Arctic. Models using specified dynamics do not have biases in the jet location, but do have biases in the surface meridional flow, which may result in differences in transport into the Arctic. In addition to the land-based tracer, the midlatitude-to-Arctic transport is further examined by another idealized tracer with zonally uniform sources. With equal sources from both land and ocean, the inter-model spread of this zonally uniform tracer is more related to variations in parameterized convection over oceans rather than variations in HC extent, particularly during boreal winter. This suggests that transport of land-based and oceanic tracers or aerosols towards the Arctic differs in pathways and therefore their corresponding inter-model variabilities result from different physical processes

On the Stratospheric Chemistry of Midlatitude Wildfire Smoke

Massive Australian wildfires lofted smoke directly into the stratosphere in the austral summer of 2019/20. The smoke led to increases in optical extinction throughout the midlatitudes of the southern hemisphere that rivalled substantial volcanic perturbations. Previous studies have assumed that the smoke became coated with sulfuric acid and water and would deplete the ozone layer through heterogeneous chemistry on those surfaces, as is routinely observed following volcanic enhancements of the stratospheric sulfate layer. Here, observations of extinction and reactive nitrogen species from multiple independent satellites that sampled the smoke region are compared to one another and to model calculations. The data display a strong decrease in reactive nitrogen concentrations with increased aerosol extinction in the stratosphere, which is a known fingerprint for key heterogeneous chemistry on sulfate/H2O particles (specifically the hydrolysis of N2O5 to form HNO3). This chemical shift affects not only reactive nitrogen but also chlorine and reactive hydrogen species and is expected to cause midlatitude ozone layer depletion. Comparison of the model ozone to observations suggests that N2O5 hydrolysis contributed to reduced ozone, but additional chemical and/or dynamical processes are also important. These findings suggest that if wildfire smoke injection into the stratosphere increases sufficiently in frequency and magnitude as the world warms due to climate change, ozone recovery under the Montreal Protocol could be impeded, at least sporadically. Modeled austral midlatitude total ozone loss was about 1% in March 2020, which is significant compared to expected ozone recovery of about 1% per decade