Resolution of Historically Discordant Ames Test Negative / Rodent Carcinogenicity Positive N-nitrosamines using a Sensitive, OECD-aligned Design.

The in vitro Bacterial Reverse Mutation (Ames) Test is crucial for evaluating the mutagenicity of pharmaceutical impurities. For N-nitrosamines (NAs) historical data indicated that for certain members of this chemical class the outcomes of the Ames Test did not correlate with their associated rodent carcinogenicity outcomes. This has resulted in negative outcomes in an OECD aligned Ames Test alone (standard or enhanced) no longer being considered sufficient by regulatory authorities to assess potential carcinogenic risk of NAs if present as impurities in drug products.

Sleep Apnea Prediction Using Deep Learning.

Obstructive sleep apnea (OSA) is a sleep disorder that causes partial or complete cessation of breathing during an individual's sleep. Various methods have been proposed to automatically detect OSA events, but little work has focused on predicting such events in advance, which is useful for the development of devices that regulate breathing during a patient's sleep. We propose four methods for sleep apnea prediction based on convolutional and long short-term memory neural networks (1D-CNN, ConvLSTM, 1D-CNN-LSTM and 2D-CNN-LSTM), which use raw data from three respiratory signals (nasal flow, abdominal and thoracic) sampled at 32 Hz, without any human-engineered features.

Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery.

Efficient drug discovery is based on a concerted effort in optimizing bioactivity and compound properties such as lipophilicity, and is guided by efficiency metrics that reflect both aspects. While conformation-activity relationships and ligand conformational control are known strategies to improve bioactivity, the use of conformer-specific lipophilicities (logp) is much less explored. Here we show how conformer-specific logp values can be obtained from knowledge of the macroscopic logP value, and of the equilibrium constants between the individual species in water and in octanol.

Managing a rare complication of HELLP syndrome in Australia: Spontaneous liver haematoma in pregnancy.

Spontaneous subcapsular haematoma of the liver is a rare but life-threatening complication of pregnancy. Prevention of maternal and fetal death requires early identification and specialised management. We report three cases of spontaneous liver haematoma in pregnancy from our institution between 2011 and 2018.

Experiments with a prototype titanium hot cavity surface ionization source intended for electromagnetic separation of radioactive samarium and other lanthanide elements.

This paper reports experimental results of a prototype titanium surface ionization source. For the first time, a lanthanide ion beam has been produced with a surface ionizer composed completely of titanium metal. Titanium does not readily activate with neutron irradiation.

Systematic Investigation of Lipophilicity Modulation by Aliphatic Fluorination Motifs.

Optimization of compound lipophilicity is a key aspect of drug discovery. The aim of this work was to compare the lipophilicity modulations induced by 16 distinct known and novel fluoroalkyl motifs on three parent models. Fifty fluorinated compounds, with 28 novel experimental aliphatic log values, are involved in discussing various lipophilicity trends.

Characterization of the neutron flux during production of F at a medical cyclotron and evaluation of the incidental neutron spectrum for neutron damage studies.

The fast neutron spectrum was measured in an irradiation position adjacent to two F (fluorine-18) production targets at a medical cyclotron. The neutron spectrum was modeled using MCNP6 and experimentally determined using activation foils. A three-group neutron spectrum was determined using an over-determined least squares fitting method.

A New Straightforward Method for Lipophilicity (logP) Measurement using 19F NMR Spectroscopy.

Fluorination has become an effective tool to optimize physicochemical properties of bioactive compounds. One of the applications of fluorine introduction is to modulate the lipophilicity of the compound. In our group, we are interested in the study of the impact of fluorination on lipophilicity of aliphatic fluorohydrins and fluorinated carbohydrates.

Reducing the Lipophilicity of Perfluoroalkyl Groups by CF-F/CF-Me or CF/CH Exchange.

Fluorination is commonly employed to optimize bioactivity and pharmaco-kinetic properties of drug candidates. Aliphatic fluorination often reduces the lipophilicity (log P), but polyfluoroalkylation typically increases lipophilicity. Hence, identification of polyfluorinated motifs that nonetheless lead to similar or even reduced lipophilicities is of interest to expand the arsenal of medicinal chemistry tools in tackling properties such as compound metabolic stability or off-target selectivity.

Use of intravenous iron polymaltose in the management of iron deficiency in pregnancy: A retrospective cohort study.

Background: Intravenous iron polymaltose (IPM) is commonly utilised in pregnancy when oral treatment is not tolerated or where rapid replenishment of iron stores is required, but data on use in pregnancy is scarce.

Aim: To examine the use, safety and efficacy of intravenous IPM in pregnancy.

Methods: Retrospective cohort study of pregnant women administered intravenous IPM between January 2014 and January 2016 at a Tertiary teaching hospital in Adelaide, Australia.

Approaches for optimising intravenous iron dosing in pregnancy: a retrospective cohort study.

Background: Intravenous iron is commonly utilised in pregnancy when treatment with oral is not tolerated or where rapid replenishment of iron stores is required.

Aims: To examine the relationship between doses of intravenous iron administered during pregnancy according to different maternal bodyweight measures and subsequent treatment response.

Methods: Retrospective cohort study of pregnant women with confirmed iron deficiency anaemia who received intravenous iron polymaltose at a tertiary teaching hospital in Australia from 1 January 2014 to 31 January 2016.

Dual origins of functionally distinct O-LM interneurons revealed by differential 5-HT(3A)R expression.

Forebrain circuits rely upon a relatively small but remarkably diverse population of GABAergic interneurons to bind and entrain large principal cell assemblies for network synchronization and rhythmogenesis. Despite the high degree of heterogeneity across cortical interneurons, members of a given subtype typically exhibit homogeneous developmental origins, neuromodulatory response profiles, morphological characteristics, neurochemical signatures and electrical features. Here we report a surprising divergence among hippocampal oriens-lacunosum moleculare (O-LM) projecting interneurons that have hitherto been considered a homogeneous cell population.

Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity.

Disrupted excitatory synapse maturation in GABAergic interneurons may promote neuropsychiatric disorders such as schizophrenia. However, establishing developmental programs for nascent synapses in GABAergic cells is confounded by their sparsity, heterogeneity and late acquisition of subtype-defining characteristics. We investigated synaptic development in mouse interneurons targeting cells by lineage from medial ganglionic eminence (MGE) or caudal ganglionic eminence (CGE) progenitors.

A blueprint for the spatiotemporal origins of mouse hippocampal interneuron diversity.

Although vastly outnumbered, inhibitory interneurons critically pace and synchronize excitatory principal cell populations to coordinate cortical information processing. Precision in this control relies upon a remarkable diversity of interneurons primarily determined during embryogenesis by genetic restriction of neuronal potential at the progenitor stage. Like their neocortical counterparts, hippocampal interneurons arise from medial and caudal ganglionic eminence (MGE and CGE) precursors.

Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial.

Background: Results of previous studies support the hypothesis that implantable haemodynamic monitoring systems might reduce rates of hospitalisation in patients with heart failure. We undertook a single-blind trial to assess this approach.

Methods: Patients with New York Heart Association (NYHA) class III heart failure, irrespective of the left ventricular ejection fraction, and a previous hospital admission for heart failure were enrolled in 64 centres in the USA.

Common origins of hippocampal Ivy and nitric oxide synthase expressing neurogliaform cells.

GABAergic interneurons critically regulate cortical computation through exquisite spatiotemporal control over excitatory networks. Precision of this inhibitory control requires a remarkable diversity within interneuron populations that is largely specified during embryogenesis. Although interneurons expressing the neuronal isoform of nitric oxide synthase (nNOS) constitute the largest hippocampal interneuron cohort their origin and specification remain unknown.

Gestational diabetes--worth finding and actively treating.

Gestational diabetes affects around 5% of pregnant women, however the value of screening women for gestational diabetes has been hotly debated. On the positive side there has been potential benefits for the baby and, on the negative side, the costs of managing gestational diabetes to the mother. This controversy has largely been settled with the publication of the Australasian Carbohydrate Intolerance Study (ACHOIS).

Endogenous inhibitors of nitric oxide and preeclampsia: a review.

Nitric oxide (NO) is a potent vasodilator. NO is synthesized by NO synthases (NOS) and NOS are inhibited by asymmetrical dimethylarginine (ADMA). ADMA is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) and excreted in the kidneys.

TASK-like conductances are present within hippocampal CA1 stratum oriens interneuron subpopulations.

TASK-1 (KCNK3) and TASK-3 (KCNK9) are members of the two-pore domain potassium channel family and form either homomeric or heteromeric open-rectifier (leak) channels. Recent evidence suggests that these channels contribute to the resting potential and input resistance in several neuron types, including hippocampal CA1 pyramidal cells. However, the evidence for TWIK-related acid-sensitive potassium (TASK)-like conductances in inhibitory interneurons is less clear, and mRNA expression has suggested that TASK channels are expressed in only a subpopulation of interneurons.

p53 interacts with hRAD51 and hRAD54, and directly modulates homologous recombination.

p53 inhibits tumorigenesis through a variety of functions, including mediation of cell cycle arrest, premature senescence, and apoptosis.p53 also can associate with several DNA helicases and proteins involved in homologous recombination. In this study, we show that p53, hRAD51, and hRAD54 coimmunoprecipitated and colocalized with each other at endogenous levels in normal cells.

Gestational diabetes versus obesity as risk factors for pregnancy-induced hypertensive disorders and fetal macrosomia.

Objective: To assess whether obesity and/or gestational diabetes mellitus (GDM) are independent risk factors for fetal macrosomia and/or pregnancy-induced hypertensive disorders.

Design: Retrospective computerised database review.

Setting: Lyell McEwin Health Service, South Australia.

American Indian college students: an exploration into resiliency factors revealed through personal stories.

Resilient factors affecting the retention and completion of American Indian people in higher education were explored using qualitative methods. Interviews were conducted with 14 American Indian students or graduates regarding personal, familial, and tribal experiences that influenced their interest, persistence, and adjustment in higher education. Interviews were audiotaped, transcribed, and analyzed for common themes.

Redox cycling of phenol induces oxidative stress in human epidermal keratinocytes.

A variety of phenolic compounds are utilized for industrial production of phenol-formaldehyde resins, paints, lacquers, cosmetics, and pharmaceuticals. Skin exposure to industrial phenolics is known to cause skin rash, dermal inflammation, contact dermatitis, leucoderma, and cancer promotion. The biochemical mechanisms of cytotoxicity of phenolic compounds are not well understood.