Pyrrolizidine alkaloids enhance alcohol-induced hepatocytotoxicity in vitro in normal human hepatocytes

OBJECTIVE : Herbal remedies containing pyrrilidozine alkaloids (PA)s can induce liver damage, including hepato-sinusoidal obstruction syndrome (HSOS) or veno-occlusive liver disease (VOD). Some individuals misusing alcohol consume also teas and/or herbal remedies containing PA. The interaction or additive toxicity of alcohol to PA toxicity needs to be addressed. The objectives of this study are 1) to review the scientific literature on the PA-induced liver toxicity; 2) identify possible mechanism(s) involved in PA-induced hepatocytotoxicity in the presence or absence of ethanol (EtOH) in vitro in normal human hepatocytes (NHH) in primary culture. To respond to the first objective, we systematically search all the literature engines (PubMed, Google Scholar) for liver induced damage due to PAs and summarize the results in an introductory systematic review. ORIGINAL ARTICLE EXPERIMENTAL DESIGN AND METHODS : Cells were exposed to one dose of 100 mmol/L EtOH for 24 hrs and to 2 doses of 100 mmol/L EtOH for consecutive 24 hrs periods, in the presence or absence of PAs (10 mg/mL), or the caspase-3 inhibitor IDN-1965 (50 μmol/L). Cells were analyzed for apoptosis by light microscopy, immuno-histochemistry, measuring cytokeratin-18 fragmentation, and transmission electron microscopy (TEM) (6000 cells/ treatment). Cytotoxicity was determined using succinate dehydrogenase (SDH) activity, an enzyme specific to the mitochondria. RESULTS : In NHH cells, a 100 mmol/L dose of Et-OH resulted in 22±2.5 apoptosis (p<0.001 vs. control). Two consecutive doses of 100 mmol/L Et-OH for 24 hrs each caused 36±3.0% apoptosis (p<0.001 vs. control and p<0.05 vs. one dose Et- OH). Pre-treatment with 50 μmol/L caspase inhibitor significantly reduced Et-OH-induced apoptosis [12±1.5% in 100 mmol/L (p<0.05) and 20±4.0% in 2×100 mmol/L (p<0.001)]. In addition, pre-treatment with 50 μmol caspase inhibitor in cells treated with PA + EtOH reduced apoptosis significantly (vs. non-exposed to caspase-inhibitor): Δ -22±3.0 % (p<0.05). HPC significantly decreased apoptosis compared to conditions lacking this supplementation in cells treated with EtOH-exposed cells present ballooning, Mallory bodies, changes in mitochondrial cristae and apoptosis by TEM. Pre-treatment with 50 μmol caspase inhibitor significantly reduced 100 mmol/L EtOH-induced (one dose) in NHH by 14±0.5% (p<0.05) compared to cells not exposed to the caspase-inhibitor. In cells treated concomitantly with PA and EtOH 100 mM Mallory-bodies and apo-necrotic cells have been observed. Pre-treatment with 50 μmol caspase inhibitor reduced the mitochondrial damage. A significant depletion in glutathione (GSH) was observed in Et-OH treated cells after 1 and 2 treatments (p<0.001 vs. control). Treatment with E t-OH enhanced PA-induced GSH-depletion and resulted in a significant increase in PA-induced cytotoxicity (p<0.001 vs. Et-untreated cells). Exposure to EtOH increased the cell culture media levels of the pro-inflammatory cytokine TNF. PA + EtOH-treated cells increased TNF-α levels in media compared to EtOH alone [86±8 vs. 53±5 pg/mL in cells exposed to 100 mmol/L EtOH (p<0.05) and 218±14 vs. 179±8 pg/mL in cells exposed to 2×100 mmol/L EtOH (p<0.05)]. CONCLUSIONS : PA up-regulates EtOH-induced hepatocytotoxicity by inducing the inflammatory cytokines and enhancing the apoptotic effects of ethanol. There is a need for monitoring herbal medicine in order to optimize traditional medicine use and maximize the clinical benefits. Additionally, there is necessary to communicate to physicians the possible negative results of herbal remedies use. Also, the interactions between herbal remedies and drugs of misuse should be communicated to consumers.The work was funded by In Vitro Drug Safety and Biotechnology. We are thankful for the financial contribution to Mahaffy -Gastroenterology Fund, Sunnybrook HSC, Toronto, ON, Canada.http://www.europeanreview.orgam2017Pharmacolog

Singularities in the Fermi liquid description of a partially filled Landau level and the energy gaps of fractional quantum Hall states

We consider a two dimensional electron system in an external magnetic field at and near an even denominator Landau level filling fraction. Using a fermionic Chern--Simons approach we study the description of the system's low energy excitations within an extension of Landau's Fermi liquid theory. We calculate perturbatively the effective mass and the quasi--particle interaction function characterizing this description. We find that at an even denominator filling fraction the fermion's effective mass diverges logarithmically at the Fermi level, and argue that this divergence allows for an {\it exact} calculation of the energy gaps of the fractional quantized Hall states asymptotically approaching these filling fractions. We find that the quasi--particle interaction function approaches a delta function. This singular behavior leads to a cancelation of the diverging effective mass from the long wavelength low frequency linear response functions at even denominator filling fractions.Comment: 46 pages, RevTeX, 5 figures included in a uuencoded postscript file. Minor revisions relative to the original version. The paper will be published in the Physical Review B, and can be retrieved from the World Wide Web, in http://cmtw.harvard.edu/~ster

A longitudinal investigation of repressive coping and ageing

This is an Accepted Manuscript of an article published by Taylor & Francis in Aging & Mental Health on October 2016, available online: http://www.tandfonline.com/doi/full/10.1080/13607863.2015.1060941.Two studies investigated the possibility that repressive coping is more prevalent in older adults and that this represents a developmental progression rather than a cohort effect. Study 1 examined repressive coping and mental health cross-sectionally in young and old adults. Study 2 examined whether there was a developmental progression of repressive coping prevalence rates in a longitudinal sample of older adults.Peer reviewedFinal Accepted Versio

Effect of a two-year national quality improvement program on surgical checklist implementation

Use of the surgical checklist in Switzerland is still incomplete and unsatisfactory. A national improvement program was developed and conducted in Switzerland to implement and improve the use of the surgical safety checklists. The aims of the implementation program were to implement comprehensive and correct checklist use in participating hospitals in every patient and in every surgical procedure; and to improve safety climate and teamwork as important cultural context variables. 10 hospitals were selected for participation in the implementation program. A questionnaire assessing use, knowledge, and attitudes towards the checklist and the Safety Climate Survey were conducted at two measurement occasions each in October/November 2013 and January/February 2015. Significant increases emerged for frequency of checklist use (F(1,1001)=340.9, p<0.001), satisfaction (F(1,1232)=25.6, p<0.001), and knowledge(F(1,1294)=184.5, p<0.001). While significant differences in norms (F(1,1284)=17.9, p<0.001) and intentions (F(1,1284)=7.8, p<0.01) were observed, this was not the case for attitudes (F(1,1283)=.8, n.s.) and acceptance (F(1,1284)=0.1, n.s.). Significant differences for safety climate and teamwork emerged in the present study (F(1,3555)=11.8, p<0.001 and F(1,3554)=24.6, p<0.001, respectively). However, although statistical significance was reached, effects are very small and practical relevance is thus questionable. The results of the present study suggest that the quality improvement program conducted by the Swiss Patient Safety Foundation in 10 hospitals led to successful checklist implementation. The strongest effects were seen in aspects concerning behaviour and knowledge specifically related to checklist use. Less impact was achieved on general cultural variables safety climate and teamwork. However, as a trend was observable, these variables may simply need more time in order to change substantially

A tetragonal-to-monoclinic phase transition in a ferroelectric perovskite: the structure of PbZr(0.52)Ti(0.48)O3

The perovskite-like ferroelectric system PbZr(1-x)Ti(x)O3 (PZT) has a nearly vertical morphotropic phase boundary (MPB) around x=0.45-0.50. Recent synchrotron x-ray powder diffraction measurements by Noheda et al. [Appl. Phys. Lett. 74, 2059 (1999)] have revealed a new monoclinic phase between the previously-established tetragonal and rhombohedral regions. In the present work we describe a Rietveld analysis of the detailed structure of the tetragonal and monoclinic PZT phases on a sample with x= 0.48 for which the lattice parameters are respectively: at= 4.044 A, ct= 4.138 A, at 325 K, and am= 5.721 A, bm= 5.708 A, cm= 4.138 A, beta= 90.496 deg., at 20K. In the tetragonal phase the shifts of the atoms along the polar [001] direction are similar to those in PbTiO3 but the refinement indicates that there are, in addition, local disordered shifts of the Pb atoms of ~0.2 A perpendicular to the polar axis.. The monoclinic structure can be viewed as a condensation along one of the directions of the local displacements present in the tetragonal phase. It equally well corresponds to a freezing-out of the local displacements along one of the directions recently reported by Corker et al.[J. Phys. Condens. Matter 10, 6251 (1998)] for rhombohedral PZT. The monoclinic structure therefore provides a microscopic picture of the MPB region in which one of the "locally" monoclinic phases in the "average" rhombohedral or tetragonal structures freezes out, and thus represents a bridge between these two phases.Comment: REVTeX, 7 figures. Modifications after referee's suggestion: new figure (figure 5), comments in 2nd para. (Sect.III) and in 2nd & 3rd para. (Sect. IV-a), in the abstract: "...of ~0.2 A perpendicular to the polar axis.

On twisted Fourier analysis and convergence of Fourier series on discrete groups

We study norm convergence and summability of Fourier series in the setting of reduced twisted group $C^*$-algebras of discrete groups. For amenable groups, F{\o}lner nets give the key to Fej\'er summation. We show that Abel-Poisson summation holds for a large class of groups, including e.g. all Coxeter groups and all Gromov hyperbolic groups. As a tool in our presentation, we introduce notions of polynomial and subexponential H-growth for countable groups w.r.t. proper scale functions, usually chosen as length functions. These coincide with the classical notions of growth in the case of amenable groups.Comment: 35 pages; abridged, revised and update

Lorentz breaking Effective Field Theory and observational tests

Analogue models of gravity have provided an experimentally realizable test field for our ideas on quantum field theory in curved spacetimes but they have also inspired the investigation of possible departures from exact Lorentz invariance at microscopic scales. In this role they have joined, and sometime anticipated, several quantum gravity models characterized by Lorentz breaking phenomenology. A crucial difference between these speculations and other ones associated to quantum gravity scenarios, is the possibility to carry out observational and experimental tests which have nowadays led to a broad range of constraints on departures from Lorentz invariance. We shall review here the effective field theory approach to Lorentz breaking in the matter sector, present the constraints provided by the available observations and finally discuss the implications of the persisting uncertainty on the composition of the ultra high energy cosmic rays for the constraints on the higher order, analogue gravity inspired, Lorentz violations.Comment: 47 pages, 4 figures. Lecture Notes for the IX SIGRAV School on "Analogue Gravity", Como (Italy), May 2011. V.3. Typo corrected, references adde