Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanistic basis of adverse drugreactions: the perils of inappropriate dose schedules

Adverse drug reactions (ADRs) have long been recognised as a significant cause of morbidity and mortality. They account for a substantial number of clinical consultations, hospital admissions and extended duration of in-patient stay as well as mortality. By far the most common ADRs are the concentration-dependent pharmacological reactions, the majority of which ought to be preventable. As a result of high concentrations of the parent drug and/or its metabolite(s), there is an augmentation of primary pharmacological activity and/or appearance of new and undesirable secondary pharmacological activity. Typically, these high concentrations result from administration of high doses in an attempt to maximise efficacy and/or modulation of the pharmacokinetics of a drug by either genetic or non-genetic factors. High plasma concentrations of parent drug may result from inherited impairment or drug-induced inhibition of its pharmacokinetic disposition. Conversely, inherited overcapacity or drug-induced induction of the metabolism of a drug may result in low concentrations of parent drug and frequently, rapid accumulation of its metabolites. Environmental, dietary and phytochemical factors may also influence the activity of drug metabolising enzymes. As with inherited polymorphisms of acetylation and cytochrome P450-based drug metabolising enzymes, polymorphisms of other conjugation reactions, such as glucuronidation, increasingly appear to be associated with drug toxicity. Diseases of organs involved in elimination of a drug also alter its pharmacokinetics, plasma concentration and, therefore, the profile of its concentration-dependent ADRs. Inherited mutations, concurrently administered drugs or presence of certain diseases may also alter the sensitivity of some pharmacological targets, accounting for a substantial number of ADRs and interactions. When there is enhanced pharmacodynamic sensitivity, plasma drug concentrations that are apparently within the normal ‘non-toxic’ range give rise to ADRs. Recent advances have also provided important insights into the wider scope of drug–drug interactions. Interactions that occur at P-glycoproteins, drug transporters and efflux pumps, at various transmembrane interfaces such as the gastrointestinal wall, renal tubules, hepatobiliary border and blood–brain barrier, are beginning to explain many non-metabolic interactions. These alter the systemic exposure to drugs and have so far, begun to explain unexpected neurotoxicity and hepatotoxicity. The function of these transporters is also genetically modulated. These advances, together with continued increased awareness and education of prescribers and pharmacists, offer great opportunities for substantially minimising concentration-related ADRs.
Modified cGA for electromagnetic optimization

Compact Genetic Algorithm (cGA), which uses a probability vector (PV) to represent the population, has been proposed as an alternative of the simple Genetic algorithm (sGA), which greatly reduces the memory storage requiring during its performance. The cGA, however, just performed equivalently to sGA. In this paper, a modified version of compact Genetic Algorithm (M-cGA), outperforming the standard cGA, is presented. The idea is to use more than one probability vector and add a suitable learning scheme to improve the cGA's capability. Numerical results of the application of M-cGA on high-order problem, i.e. four-bit problem, and electromagnetic optimization, i.e. thinned array synthesis, will be presented and compared with the results obtained by its ancestors and GA as well.
Selective PrP‐like protein, doppel immunoreactivity in dystrophic neurites of senile plaques in Alzheimer's disease

Doppel (Dpl) is a prion‐like protein encoded by the gene PRND, which has been found downstream of the prion gene PRNP in several species. The present study examines by immunohistochemistry Dpl expression in brain samples from 10 patients with Alzheimer's disease (AD), three patients with Pick's disease, four patients with Parkinson's disease, eight patients with diffuse Lewy body disease (DLBD), six patients with sporadic Creutzfeldt–Jakob disease (CJD) methionine/methionine at the codon 129, two patients with sporadic CJD methionine/valine at the codon 129 and numerous kuru plaques in the cerebellum, one patient with fatal familial insomnia (FFI), and 10 age‐matched controls. In the adult human brain, Dpl immunoreactivity was restricted to scattered granule cells of the cerebellum and scattered small granules in the cerebral cortex. Dpl immunoreactivity was seen around βA4 amyloid deposits in neuritic plaques, but not in diffuse plaques, AD and the common form of DLBD. Neurofibrillary tangles, Pick bodies and Lewy bodies were not stained with anti‐Dpl antibodies. No modifications in Dpl immunoreactivity were observed in CJD excepting those associated with accompanying senile plaques. No Dpl‐positive deposits were seen in FFI. Whether Dpl in neuritic plaques may attenuate amyloid‐induced oxidative stress and participate in the glial response around amyloid cores is discussed in light of the few available data on Dpl functions.
Detection of influenza by real time RT‐PCR is not affected by delays in respiratory specimen processing

Sample processing for real‐time reverse transcriptase polymerase chain reaction (rRT‐PCR) based diagnostic assays requires stabilizing sample ribonucleic acid (RNA) in lysis buffer prior to testing. The stability of viral RNA prior to processing is difficult to assure. It is unknown whether clinical sample integrity is compromised by delays in processing, as may occur due to weekends and holidays. We sought to examine the integrity of respiratory specimens with variable processing times. Upper respiratory specimens were collected during three influenza seasons 2009–2012 and tested for influenza virus and internal control human RNase P (RNP) RNA by rRT‐PCR. Time to processing was measured in hours from specimen collection to placement in lysis buffer. Six hundred thirty‐five (11.4%) of 5,583 samples were influenza positive. Mean and median times to processing were 11.5 hr and 6.0 hr, respectively (min 0.1 hr, max 105.2 hr). There were no significant associations between time to processing and presence of RNP (OR = 1.0, P = 0.740), or detection of influenza (OR = 1.0, P = 0.060). Longer duration of illness was associated with a lower likelihood of influenza detection (OR = 0.92, P < 0.001) and with increased influenza A cycle threshold (Ct) values (P < 0.001), while older age was associated with increased influenza B Ct values (P = 0.001), indicating the presence of less amplifiable RNA. Delays in time to processing of upper respiratory specimens up to 105 hr were not associated with decreased detection of amplifiable RNA, suggesting specimen integrity is not compromised by such delays. J. Med. Virol. 88:1891–1895, 2016. © 2016 Wiley Periodicals, Inc.
Integrating Conjugative Elements as Vectors of Antibiotic, Mercury, and Quaternary Ammonium Compound Resistance in Marine Aquaculture Environments

ABSTRACT The presence of SXT/R391-related integrating conjugative elements (ICEs) in bacterial strains isolated from fish obtained from marine aquaculture environments in 2001 to 2010 in the northwestern Iberian Peninsula was studied. ICEs were detected in 12 strains taxonomically related to Vibrio scophthalmi (3 strains), Vibrio splendidus (5 strains), Vibrio alginolyticus (1 strain), Shewanella haliotis (1 strain), and Enterovibrio nigricans (2 strains), broadening the known host range able to harbor SXT/R391-like ICEs. Variable DNA regions, which confer element-specific properties to ICEs of this family, were characterized. One of the ICEs encoded antibiotic resistance functions in variable region III, consisting of a tetracycline resistance locus. Interestingly, hot spot 4 included genes providing resistance to rifampin (ICEVspPor2 and ICEValPor1) and quaternary ammonium compounds (QACs) (ICEEniSpa1), and variable region IV included a mercury resistance operon (ICEVspSpa1 and ICEEniSpa1). The S exclusion group was more represented than the R exclusion group, accounting for two-thirds of the total ICEs. Mating experiments allowed ICE mobilization to Escherichia coli strains, showing the corresponding transconjugants' rifampin, mercury, and QAC resistance. These results show the first evidence of ICEs providing rifampin and QAC resistances, suggesting that these mobile genetic elements contribute to the dissemination of antimicrobial, heavy metal, and QAC resistance determinants in aquaculture environments.
Expression of IL‐10 in Th memory lymphocytes is conditional on IL‐12 or IL‐4, unless the IL‐10 gene is imprinted by GATA‐3

In Th1 and Th2 memory lymphocytes, the genes for the cytokines interleukin (IL)‐4 and interferon‐γ (IFN‐γ) are imprinted for expression upon restimulation. This cytokine memory is based on expression of the transcription factors T‐bet for IFN‐γ, and GATA‐3 for IL‐4, and epigenetic modification of the cytokine genes. In Th2 cells, expression of the cytokine IL‐10 is also induced by GATA‐3. Here, we show that this induction is initially not accompanied by epigenetic modification of the IL‐10 gene. Only after repeated restimulation of a memory Th2 cell in the presence of IL‐4, extensive histone acetylation of the IL‐10 gene is detectable. This epigenetic imprinting correlates with the development of a memory for IL‐10 in repeatedly restimulated Th2 cells. In Th1 cells, IL‐10 expression is induced by IL‐12, but the IL‐10 gene lacks detectable histone acetylation. Accordingly, IL‐10 expression in restimulated memory Th1 cells remains conditional on the presence of IL‐12. This finding defines a potential anti‐inflammatory role for IL‐12 in Th1 recall responses. While in primary Th1 responses IL‐12 is required to induce expression of the pro‐inflammatory cytokine IFN‐γ, in secondary Th1 responses IFN‐γ re‐expression is independent of IL‐12, which still is able to induce expression of the anti‐inflammatory cytokine IL‐10.
Le traitement cognitif : déterminant de la conception de documents procéduraux : le cas des guides d'utilisation SEB

L'objet du present travail est de proceder a l'exploitation de connaissances acquises dans le domaine de la psycholinguistique, mise en praique se traduisant par le transfert de ces connaissances au domaine de la conception des notices et modes d'emploi accompagnant les appareils vendus au grand public. Plusieurs etudes conduites sur le terrain et en laboratoire ont permis d'articuler recherche theorique et applications pratiques. Une observation exploratoire a permis d'apprehender les comportements d'utilisation de documents proceduraux en situation quasi-usuelle. Par ailleurs, trois experiences ont ete realisees pour etudier les effets de differents modes de presentation de l'information sur leur traitement. Dans une premiere experience, sept formats de presentation d'instructions ont ete examines sur deux populations (hauts niveaux vs. Bas niveaux de scolarisation). Une seconde experience a ete conduite pour etudier les effets de la presentation d'une information organisatrice sur l'elaboratoin de representation et sur les activites de controle effectuees au cours de l'execution des instructions. Enfin, une troisieme experience a ete concue pour apprehender la nature des representations induites par le traitement d'instructions textuelles ou graphiques. L'ensemble de ces tavaux a permis d'elaborer un modele procedural de traitement des instructions, destine a servir de support a la conception de documents. Ce "modele de l'utilisateur" a abouti notamment a la realisation de documents proceduraux permettant une "navigation " plus aisee a l'interieur du document et facilitant l'apprentissage a partir d'instructions.
Stimulation of human neutrophils with formyl-methionyl-leucyl-phenylalanine induces tyrosine phosphorylation and activation of two distinct mitogen-activated protein-kinases.

Stimulation of human polymorphonuclear neutrophils with the chemotactic peptide FMLP induces an increase in the phosphorylation of several proteins on tyrosine residues. Immunoblotting of whole cell lysates with antiphosphotyrosine antibodies demonstrated this increase to be predominant in two proteins with apparent m.w. of 40,000 and 42,000, respectively. We identify these two proteins as members of the mitogen-activated-protein (MAP) kinase family. These results are based on comigration of the tyrosine phosphorylated proteins with two proteins of same apparent m.w. , recognized by a series of antibodies raised against sequences contained within members of this family. This was further confirmed by immunoprecipitation with either an antiphosphotyrosine antibody or a MAP kinase-specific antibody. To assess whether neutrophil stimulation with FMLP increased MAP kinase activity, the cells were stimulated with various doses of FMLP and the phosphotransferase activity in cell lysates was measured against two identified substrates of MAP kinase: myelin basic protein and T-669, the epidermal growth factor receptor Thr 669 synthetic peptide modeled after the major site of phosphorylation of the receptor. A dose- and time-dependent increase in MAP kinase activity was detected in the lysates from FMLP-stimulated PMN, which closely correlated with the dose and time course of tyrosine phosphorylation of the 40- and 42-kDa proteins. Additionally, the MAP kinases in crude lysates were enriched by DEAE-cellulose chromatography and further resolved on a MonoQ column by fast performance liquid chromatography. The respective eluates contained the two proteins, each recognized by anti-MAP kinase antibodies and, after stimulation, each was phosphorylated on tyrosine residues and expressed T-669 phosphotransferase activity. Treatment with genistein, a tyrosine kinase inhibitor, reduced the tyrosine phosphorylation of the 40- and 42-kDa proteins in a dose-dependent manner, decreased the activation of the MAP kinases, and inhibited the production of superoxide anion by FMLP-stimulated neutrophils. Therefore, this study demonstrates that human polymorphonuclear neutrophils contain two distinct members of the MAP kinase family, antigenically related to sea star p44mpk and rat p43erk1 and that both MAP kinase isoforms are implicated in the cascade of protein phosphorylation induced by neutrophil stimulation with FMLP. Furthermore, these data suggest that tyrosine phosphorylation and activation of these two enzymes may play a regulatory role in the signal transduction pathway leading to the respiratory burst induced by FMLP.
Cause of deep venous thrombosis and pulmonary embolism in young patients from India as compared with other ethnic groups

Venous thromboembolism (VTE), which consists of deep vein thrombosis (DVT) and pulmonary embolism, is a potentially fatal disease. The existing Asian literature has shown a wide variation in the prevalence of VTE, with very limited data from India. In the present study, the risk factors for VTE in Indian patients were compared with Caucasians and Blacks. We used data prospectively collected from total of 1396 Indian patients (716 males, 680 females) enrolled over a decade and compared with White (n = 2002) and Black (n = 395) patients objectively diagnosed with VTE. When compared with females, males had significantly higher episodes of pulmonary embolism and VTE (P = 0.0001). Amongst the known thrombophilia markers, only homocysteine was found to be significantly higher in males as compared with females (P = 0.006). Males had a higher proportion of rheumatic heart disease (RHD) and ischaemic heart disease (IHD) as compared with females. The prevalence of DVT amongst Indians was significantly higher as compared with Whites and Blacks. However, the rate of pulmonary embolism and VTE was lower in Indians as compared with both the races. Amongst the baseline characteristics identified as risk factors for VTE, Indians had a higher prevalence of infection as compared to both Whites and Blacks, but lower HIV infection as compared to Blacks. As compared to Whites, Indians had lower prevalence of idiopathic VTE (but similar to blacks) and had higher prevalence of idiopathic pulmonary embolism (P < 0.0001). This can be explained by different inherited and environment risk factors between these three populations.
Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation

The G2 DNA damage checkpoint ensures maintenance of cell viability by delaying progression into mitosis in cells which have suffered genomic damage. It is controlled by a number of proteins which are hypothesized to transduce signals through cell cycle regulators to delay activation of p34cdc2. Studies in mammalian cells have correlated induction of inhibitory tyrosine 15 (Y15) phosphorylation on p34cdc2 with the response to DNA damage. However, genetic studies in fission yeast have suggested that the major Y15 kinase, p107wee1, is not required for the cell cycle delay in response to DNA damage, although it is required for survival after irradiation. Thus, the target of the checkpoint, and hence the mechanism of cell cycle delay, remains unknown. We show here that Y15 phosphorylation is maintained in checkpoint‐arrested fission yeast cells. Further, wee1 is required for cell cycle arrest induced by up‐regulation of an essential component of this checkpoint, chk1. We observed that p107wee1 is hyperphosphorylated in cells delayed by chk1 overexpression or UV irradiation, and that p56chk1 can phosphorylate p107wee1 directly in vitro. These observations suggest that in response to DNA damage p107wee1 is phosphorylated by p56chk1 in vivo, and this results in maintenance of Y15 phosphorylation and hence G2 delay. In the absence of wee1, other Y15 kinases, such as p66mik1, may partially substitute for p107wee1 to induce cell cycle delay, but this wee1‐independent delay is insufficient to maintain full viability. This study establishes a link between a G2 DNA damage checkpoint function and a core cell cycle regulator.
Correlation of electrophysiological and morphological characteristics of enteric neurons in the mouse colon

We report on the first correlative study of the electrophysiological properties, shapes, and projections of enteric neurons in the mouse. Neurons in the myenteric plexus of the mouse colon were impaled with microelectrodes containing biocytin, their passive and active electrophysiological properties determined, and their responses to activation of synaptic inputs investigated. Biocytin, injected into the neurons from which recordings were made, was converted to an optically dense product and used to determine the shapes of neurons. By electrophysiological properties, almost all neurons belonged to one of two classes, AH neurons or S neurons. AH neurons had a biphasic repolarization of the action potential, and slow afterhyperpolarizing potentials usually followed the action potentials. S neurons had monophasic repolarizations, no slow afterhyperpolarization, and fast excitatory postsynaptic potentials in response to fibre tract stimulation. By shape, neurons were divided into Dogiel type II (28/136 neurons) and uniaxonal neurons. Dogiel type II neurons had large, smooth‐surfaced cell bodies and several long processes that supplied branches within myenteric ganglia. All Dogiel type II neurons had AH electrophysiology; conversely, most AH neurons had Dogiel type II morphology. The majority of uniaxonal neurons had lamellar dendrites, i.e., Dogiel type I morphology. They projected to the circular muscle (circular muscle motor neurons), to the longitudinal muscle (longitudinal muscle motor neurons), and to other myenteric ganglia (interneurons) and in some cases could not be traced to target cells. All S neurons were uniaxonal. A small proportion of uniaxonal neurons (3/70) had AH electrophysiology. Fast excitatory synaptic potentials were only recorded from uniaxonal neurons and were in most cases blocked by nicotinic receptor antagonists. A small component of fast excitatory transmission in some neurons was antagonized by the purine receptor antagonist PPADS. Slow excitatory postsynaptic potentials were observed in both AH and S neurons. Slow inhibitory postsynaptic potentials were recorded from S neurons. We conclude that the major classes of neurons are Dogiel type II neurons with AH electrophysiological properties and Dogiel type I neurons with S electrophysiological properties. The S/Dogiel type I neurons include circular muscle motor neurons, longitudinal muscle motor neurons, and interneurons. J. Comp. Neurol. 468:112–124, 2004. © 2003 Wiley‐Liss, Inc.
Differential Effects of Fatty Acids and Exercise on Body Weight Regulation and Metabolism in Female Wistar Rats

High-fat diets made with different fats may have distinct effects on body weight regulation and metabolism. In the present study, the metabolic effects of high-fat (HF) diets made with fish oil, palm oil, and soybean oil were compared with a low-fat diet in female Wistar rats that were either exercised (EX, swimming) or that remained sedentary as controls. Each adult rat was exposed to the same diet that their dams consumed during pregnancy and lactation. When they were 9 weeks old, rats began an EX regimen that lasted for 6 weeks. Twenty-four hours after the last EX bout, rats were sacrificed in a fasted state. It was observed that HF feeding of soybean oil induced more body weight and fat gain, as well as insulin resistance, as indicated by insulin/glucose ratios, than other oils. Female rats fed a HF diet made with fish oil had body weight and insulin sensitivity not different from that observed in low fat fed control rats. For rats fed HF diets made with soybean oil or palm oil, EX also exerted beneficial effects by reducing body fat %, blood insulin, triglyceride and leptin levels, as well as improving insulin sensitivity.
THE EFFECT OF NALOXONE ON OPIOID‐INDUCED INHIBITION AND FACILITATION OF ACETYLCHOLINE RELEASE IN BRAIN SLICES

1 The effect of morphine, methionine‐enkephalin (Met‐enkephalin) and d‐Ala2‐d‐Leu5‐enkephalin (DADLE) were tested on the spontaneous and electrically‐evoked release of acetylcholine (ACh) from superfused slices of guinea‐pig thalamus, caudate nucleus and cerebral cortex. 2 At no concentration did morphine, Met‐enkephalin or DADLE modify the outflow of ACh at rest but Met‐enkephalin in the presence of naloxone, reduced the resting ACh release. 3 Morphine, at a low dose (3 μm) had no effect in slices of cerebral cortex, but it enhanced the evoked release of ACh in thalamic and caudate, slices. At higher doses of morphine (10–30 μm), the ACh release evoked by electrical pulses was significantly inhibited in every area. 4 Met‐enkephalin behaved like morphine in thalamic slices, whereas DADLE, a specific < 5 agonist, produced a slight inhibition of ACh outflow only at 10 μm. 5 Naloxone antagonized the inhibitory effect of morphine in the cerebral cortex and caudate nucleus slices. Naloxone and also spiroperidol blocked the releasing effect of morphine in caudate slices. In contrast naloxone did not affect the increase of ACh release caused by morphine and Met‐enkephalin in thalamic slices. The inhibitory effect of both opioids at high doses was reversed by naloxone so that they then enhanced ACh release. 6 A two fold increase of calcium concentration in the Krebs solution prevented the inhibitory effects of morphine 10 μm. 7 It is suggested that two receptors are present in thalamic slices, one of which inhibits and the other facilitates ACh release.