Water discharge variations control fluvial stratigraphic architecture in the Middle Eocene Escanilla formation, Spain.

Ancient fluvial deposits typically display repetitive changes in their depositional architecture such as alternating intervals of coarse-grained highly amalgamated (HA), laterally-stacked, channel bodies, and finer-grained less amalgamated (LA), vertically-stacked, channels encased in floodplain deposits. Such patterns are usually ascribed to slower, respectively higher, rates of base level rise (accommodation). However, "upstream" factors such as water discharge and sediment flux also play a potential role in determining stratigraphic architecture, yet this possibility has never been tested despite the recent advances in the field of palaeohydraulic reconstructions from fluvial accumulations. Here, we chronicle riverbed gradient evolution within three Middle Eocene (~ 40 Ma) fluvial HA-LA sequences in the Escanilla Formation in the south-Pyrenean foreland basin. This work documents, for the first time in a fossil fluvial system, how the ancient riverbed systematically evolved from lower slopes in coarser-grained HA intervals, and higher slopes in finer-grained LA intervals, suggesting that bed slope changes were determined primarily by climate-controlled water discharge variations rather than base level changes as often hypothesized. This highlights the important connection between climate and landscape evolution and has fundamental implications for our ability to reconstruct ancient hydroclimates from the interpretation of fluvial sedimentary sequences.

Risk Assessment in Drug Hypersensitivity: Detecting Small Molecules Which Outsmart the Immune System.

Drug hypersensitivity (DH) reactions are clinically unusual because the underlying immune stimulations are not antigen-driven, but due to non-covalent drug-protein binding. The drugs may bind to immune receptors like HLA or TCR which elicits a strong T cell reaction (p-i concept), the binding may enhance the affinity of antibodies (enhanced affinity model), or drug binding may occur on soluble proteins which imitate a true antigen (fake antigen model). These novel models of DH could have a major impact on how to perform risk assessments in drug development. Herein, we discuss the difficulties of detecting such non-covalent, labile and reversible, but immunologically relevant drug-protein interactions early on in drug development. The enormous diversity of the immune system, varying interactions, and heterogeneous functional consequences make it to a challenging task. We propose that a realistic approach to detect clinically relevant non-covalent drug interactions for a new drug could be based on a combination of in vitro cell culture assays (using a panel of HLA typed donor cells) and functional analyses, supplemented by structural analysis (computational data) of the reactive cells/molecules. When drug-reactive cells/molecules with functional impact are detected in these risk assessments, a close clinical monitoring of the drug may reveal the true incidence of DH, as suppressing but also enhancing factors occurring in vivo can influence the clinical manifestation of a DH.

What You Don't Know About Combustible Dust, But Should.

By understanding the risks of this hazard and the regulations surrounding it, you can better equip your facility to prevent "near misses" so they never turn into catastrophic explosions.

Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors.

Small chemicals like drugs tend to bind to proteins via noncovalent bonds, e.g. hydrogen bonds, salt bridges or electrostatic interactions. Some chemicals interact with other molecules than the actual target ligand, representing so-called 'off-target' activities of drugs. Such interactions are a main cause of adverse side effects to drugs and are normally classified as predictable type A reactions. Detailed analysis of drug-induced immune reactions revealed that off-target activities also affect immune receptors, such as highly polymorphic human leukocyte antigens (HLA) or T cell receptors (TCR). Such drug interactions with immune receptors may lead to T cell stimulation, resulting in clinical symptoms of delayed-type hypersensitivity. They are assigned the 'pharmacological interaction with immune receptors' (p-i) concept. Analysis of p-i has revealed that drugs bind preferentially or exclusively to distinct HLA molecules (p-i HLA) or to distinct TCR (p-i TCR). P-i reactions differ from 'conventional' off-target drug reactions as the outcome is not due to the effect on the drug-modified cells themselves, but is the consequence of reactive T cells. Hence, the complex and diverse clinical manifestations of delayed-type hypersensitivity are caused by the functional heterogeneity of T cells. In the abacavir model of p-i HLA, the drug binding to HLA may result in alteration of the presenting peptides. More importantly, the drug binding to HLA generates a drug-modified HLA, which stimulates T cells directly, like an allo-HLA. In the sulfamethoxazole model of p-i TCR, responsive T cells likely require costimulation for full T cell activation. These findings may explain the similarity of delayed-type hypersensitivity reactions to graft-versus-host disease, and how systemic viral infections increase the risk of delayed-type hypersensitivity reactions.

Are cars the new tobacco?

BACKGROUND: Public health must continually respond to new threats reflecting wider societal changes. Ecological public health recognizes the links between human health and global sustainability. We argue that these links are typified by the harms caused by dependence on private cars. METHODS: We present routine data and literature on the health impacts of private car use; the activities of the 'car lobby' and factors underpinning car dependence. We compare these with experience of tobacco. RESULTS: Private cars cause significant health harm. The impacts include physical inactivity, obesity, death and injury from crashes, cardio-respiratory disease from air pollution, noise, community severance and climate change. The car lobby resists measures that would restrict car use, using tactics similar to the tobacco industry. Decisions about location and design of neighbourhoods have created environments that reinforce and reflect car dependence. Car ownership and use has greatly increased in recent decades and there is little public support for measures that would reduce this. CONCLUSIONS: Car dependence is a potent example of an issue that ecological public health should address. The public health community should advocate strongly for effective policies that reduce car use and increase active travel.

Effects of a specially designed fermented milk product containing probiotic Lactobacillus casei DN-114 001 and the eradication of H. pylori in children: a prospective randomized double-blind study.

GOALS: To determine the efficacy of triple therapy supplemented with a specially designed fermented milk product containing specific probiotic Lactobacillus casei (L. casei) DN-114 001 strain on Helicobacter pylori eradication in children. BACKGROUND: Lactobacillus species possess in vitro activity against H. pylori. There are no consistent data on the impact of eradication therapy supplemented with probiotics on H. pylori cure rates in childhood in vivo. STUDY: Multicenter, prospective, randomized, double-blind controlled study. Eighty-six symptomatic H. pylori-positive children were randomized either to receive the control treatment of omeprazole, amoxicillin, and clarithromycin (OAC) for 7 days or the test treatment of omeprazole, amoxicillin, and clarithromycin for 7 days supplemented with fermented milk (Actimel) containing L. casei DN-114 001 (OAC-LC), for 14 days. H. pylori status was assessed at 4 weeks following therapy using two noninvasive tests. RESULTS: Intention-to-treat (ITT) based eradication rates for the OAC-LC group were 84.6% (95% CI, 71.2%-95.5%), and 91.6% (95% CI, 76.9%-98.2%) by per-protocol (PP) analysis. Eradication in the OAC group was 57.5% (95% CI, 42.2%-72.3%) in the ITT set and 61.3% (95% CI, 44.4%-75.0%) in the PP group. Eradication success was higher in the OAC-LC group compared with the OAC group in both ITT (P=0.0045) and PP analysis (P=0.0019). Primary resistance for clarithromycin could be determined in 21.2%. Side effects were infrequent. Drug compliance was good throughout the study. CONCLUSION: Supplementation with fermented milk, containing live special probiotic L. casei DN-114 001, confers an enhanced therapeutic benefit on H. pylori eradication in children with gastritis on triple therapy.