Global metabolic changes induced by plant-derived pyrrolizidine alkaloids following a human poisoning outbreak and in a mouse model

Several hundred cases of Hirmi Valley Liver Disease (HVLD), an often fatal liver injury, occurred from 2001 to 2011 in a cluster of rural villages in Tigray, Ethiopia. HVLD is principally caused by contamination of the food supply with plant derived pyrrolizidine alkaloids (PAs), with high exposure to the pesticide DDT among villagers increasing their susceptibility. In an untargeted global approach we aimed to identify metabolic changes induced by PA exposure through 1H NMR spectroscopic based metabolic profiling. We analysed spectra acquired from urine collected from HVLD cases and controls and a murine model of PA exposure and PA/DDT co-exposure, using multivariate partial least squares discriminant analysis. In the human models we identified changes in urinary concentrations of tyrosine, pyruvate, bile acids, N-acetylglycoproteins, N-methylnicotinamide and formate, hippurate, p-cresol sulphate, p-hydroxybenzoate and 3-(3-hydroxyphenyl) propionic acid. Tyrosine and p-cresol sulphate were associated with both exposure and disease. Similar changes to tyrosine, one-carbon intermediates and microbial associated metabolites were observed in the mouse model, with tyrosine correlated with the extent of liver damage. These results provide mechanistic insight and implicate the gut microflora in the human response to challenge with toxins. Pathways identified here may be useful in translational research and as “exposome” signals

Patterns and localized structures in bistable semiconductor resonators

We report experiments on spatial switching dynamics and steady state structures of passive nonlinear semiconductor resonators of large Fresnel number. Extended patterns and switching front dynamics are observed and investigated. Evidence of localization of structures is given.Comment: 5 pages with 9 figure

Occupational Therapy on College Campuses: Facilitating Student Success Through Occupation

Purpose: To explore how occupational therapy services fit into a supported education model on college campuses. Rationale: College students present with many strengths and challenges in college settings. There are limited services for young adults to succeed in college and students with various diagnoses face challenges in the areas of time management, organization, academic skills, and in social areas of college (Orentlicher, & Olson, 2010; Rogers, Kash-MacDonald, Bruker, & Maru, 2010). Higher education is a role emerging area for occupational therapists, and there are some pioneering occupational therapists who have discovered multiple ways to provide services to students who are challenged by aspects of college life. Objectives: Describe the history and current practice of supported education and its fit within the domain of OT. Describe a variety of OT supported education programmes Identify aspects of the supported education programmes that participants could apply to their college or practice setting Format: This workshop will begin by describing the history and models of supported education. The presenters will define six examples of OT programmes on college campuses. Finally, the presenters will encourage participants to share ideas and identify aspects of the various programs that they could apply to their college or practice setting

Metabolism and Effects on Endogenous Metabolism of Paracetamol (Acetaminophen) in a Porcine Model of Liver Failure

The metabolic fate, toxicity and effects on endogenous metabolism of paracetamol (acetaminophen, APAP) in 22 female Landrace cross large white pigs were evaluated in a model of acute liver failure (ALF). Anaesthetized pigs were initially dosed at 250 mg/kg via an oroduodenal tube with APAP serum concentrations maintained above 300 mg/L using maintenance doses of 0.5-4g/h until ALF. Studies were undertaken to determine both the metabolic fate of APAP and its effects on the endogenous metabolic phenotype of ALF in using 1H NMR spectroscopy. Increased concentrations of citrate combined with pre-ALF increases in circulating lactate, pyruvate and alanine in plasma suggest mitochondrial dysfunction and a switch in hepatic energy metabolism to glycolysis in response to APAP treatment. A specific liquid chromatography-tandem mass spectrometry assay was used to quantify APAP and metabolites. The major circulating and urinary metabolite of APAP was the phenolic glucuronide (APAP-G), followed by p-aminophenol glucuronide (PAP-G) formed from N-deacetylated APAP. The PAP produced by N-deacetylation was the likely cause of the methaemoglobinemia and kidney toxicity observed in this, and previous, studies in the pig. The phenolic sulfate of APAP, and the glutathione-derived metabolites of the drug were only found as minor components (with the cysteinyl conjugate detected but not the mercapturate). Given its low sulfation, combined with significant capacity for N-deacetylation the pig may represent a poor translational model for toxicology studies for compounds undergoing significant metabolism by sulfation, or which contain amide bonds which when hydrolysed to unmask an aniline lead to toxicity. However, the pig may provide a useful model where extensive amide hydrolysis is seen for drugs or environmental chemicals in humans, but not in e.g., the rat and dog which are the pre-clinical species normally employed for safety assessment

Investigation of the Planetary Boundary Layer in the Swiss Alps Using Remote Sensing and In Situ Measurements

The development of the planetary boundary layer (PBL) has been studied in a complex terrain using various remote sensing and in situ techniques. The high-altitude research station at Jungfraujoch (3,580m a.s.l.) in the Swiss Alps lies for most of the time in the free troposphere except when it is influenced by the PBL reaching the station, especially during the summer season. A ceilometer and a wind profiler were installed at Kleine Scheidegg, a mountain pass close to Jungfraujoch, located at an altitude of 2,061ma.s.l. Data from the ceilometer were analyzed using two different algorithms, while the signal-to-noise ratio of the wind profiler was studied to compare the retrieved PBL heights. The retrieved values from the ceilometer and wind profiler agreed well during daytime and cloud-free conditions. The results were additionally compared with the PBL height estimated by the numerical weather prediction model COSMO-2, which showed a clear underestimation of the PBL height for most of the cases but occasionally also a slight overestimation especially around noon, when the PBL showed its maximum extent. Air parcels were transported upwards by slope winds towards Jungfraujoch when the PBL was higher than 2,800ma.s.l. during cloud-free cases. This was confirmed by the in situ aerosol measurements at Jungfraujoch with a significant increase in particle number concentration, particle light absorption and scattering coefficients when PBL-influenced air masses reached the station in the afternoon hours. The continuous aerosol in situ measurements at Jungfraujoch were clearly influenced by the local PBL development but also by long-range transport phenomena such as Saharan dust or pollution from the south

Metabonomics and Intensive Care

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901

Acute TNFα levels predict cognitive impairment 6-9 months after COVID-19 infection.

A neurocognitive phenotype of post-COVID-19 infection has recently been described that is characterized by a lack of awareness of memory impairment (i.e., anosognosia), altered functional connectivity in the brain's default mode and limbic networks, and an elevated monocyte count. However, the relationship between these cognitive and brain functional connectivity alterations in the chronic phase with the level of cytokines during the acute phase has yet to be identified. Determine whether acute cytokine type and levels is associated with anosognosia and functional patterns of brain connectivity 6-9 months after infection. We analyzed the predictive value of the concentration of acute cytokines (IL-1RA, IL-1β, IL-6, IL-8, IFNγ, G-CSF, GM-CSF) (cytokine panel by multiplex immunoassay) in the plasma of 39 patients (mean age 59 yrs, 38-78) in relation to their anosognosia scores for memory deficits via stepwise linear regression. Then, associations between the different cytokines and brain functional connectivity patterns were analyzed by MRI and multivariate partial least squares correlations for the whole group. Stepwise regression modeling allowed us to show that acute TNFα levels predicted (R <sup>2</sup> = 0.145; β = -0.38; p = .017) and were associated (r = -0.587; p < .001) with scores of anosognosia for memory deficits observed 6-9 months post-infection. Finally, high TNFα levels were associated with hippocampal, temporal pole, accumbens nucleus, amygdala, and cerebellum connectivity. Increased plasma TNFα levels in the acute phase of COVID-19 predict the presence of long-term anosognosia scores and changes in limbic system functional connectivity

Thyrotropin-releasing hormone (TRH) promotes wound re-epithelialisation in frog and human skin

There remains a critical need for new therapeutics that promote wound healing in patients suffering from chronic skin wounds. This is, in part, due to a shortage of simple, physiologically and clinically relevant test systems for investigating candidate agents. The skin of amphibians possesses a remarkable regenerative capacity, which remains insufficiently explored for clinical purposes. Combining comparative biology with a translational medicine approach, we report the development and application of a simple ex vivo frog (Xenopus tropicalis) skin organ culture system that permits exploration of the effects of amphibian skin-derived agents on re-epithelialisation in both frog and human skin. Using this amphibian model, we identify thyrotropin-releasing hormone (TRH) as a novel stimulant of epidermal regeneration. Moving to a complementary human ex vivo wounded skin assay, we demonstrate that the effects of TRH are conserved across the amphibian-mammalian divide: TRH stimulates wound closure and formation of neo-epidermis in organ-cultured human skin, accompanied by increased keratinocyte proliferation and wound healing-associated differentiation (cytokeratin 6 expression). Thus, TRH represents a novel, clinically relevant neuroendocrine wound repair promoter that deserves further exploration. These complementary frog and human skin ex vivo assays encourage a comparative biology approach in future wound healing research so as to facilitate the rapid identification and preclinical testing of novel, evolutionarily conserved, and clinically relevant wound healing promoters

Non-monotonic variation with salt concentration of the second virial coefficient in protein solutions

The osmotic virial coefficient $B_2$ of globular protein solutions is calculated as a function of added salt concentration at fixed pH by computer simulations of the ``primitive model''. The salt and counter-ions as well as a discrete charge pattern on the protein surface are explicitly incorporated. For parameters roughly corresponding to lysozyme, we find that $B_2$ first decreases with added salt concentration up to a threshold concentration, then increases to a maximum, and then decreases again upon further raising the ionic strength. Our studies demonstrate that the existence of a discrete charge pattern on the protein surface profoundly influences the effective interactions and that non-linear Poisson Boltzmann and Derjaguin-Landau-Verwey-Overbeek (DLVO) theory fail for large ionic strength. The observed non-monotonicity of $B_2$ is compared to experiments. Implications for protein crystallization are discussed.Comment: 43 pages, including 17 figure