Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increase in the rate of absorption, probably caused by an effect on gastric emptying. In view of Marketing Authorizations (MAs) given in a number of countries to acetaminophen drug products with rapid onset of action, it is concluded that differences in rate of absorption were considered therapeutically not relevant by the Health Authorities. Moreover, in view of its therapeutic use, its wide therapeutic index and its uncomplicated pharmacokinetic properties, in vitro dissolution data collected according to the relevant Guidances can be safely used for declaring bioequivalence (BE) of two acetaminophen formulations. Therefore, accepting a biowaiver for immediate release (IR) acetaminophen solid oral drug products is considered scientifically justified, if the test product contains only those excipients reported in this paper in their usual amounts and the test product is rapidly dissolving, as well as the test product fulfils the criterion of similarity of dissolution profiles to the reference product

Suitability and optimisation of analytical indoor shelter model used for infiltration of carbon dioxide for typical dwellings

Carbon Capture Utilisation and Storage (CCUS) schemes involve transporting large quantities of carbon dioxide (CO2). A release of CO2 from CCUS transportation infrastructure could cause severe consequences for the surrounding population if the risk is not appropriately managed. Following a release of CO2, people in the surrounding environment could move away and seek shelter. The CO2 plume could drift past buildings causing the concentration of CO2 inside these buildings to build up. How much CO2 accumulates inside the buildings is key to the safety of their occupants. Previously an analytical infiltration model, based on wind and buoyancy driven ventilation, and a CFD infiltration model were created which can be used to predict the effect of CO2 exposure on building occupants following a release from an onshore CO2 pipeline [1]. These models can be used to determine the consequences of failure the dispersion behaviour of CO2 and the infiltration rate of a plume of CO2 into buildings and can form part of a Quantitative Risk Assessment (QRA) process for a CO2 pipeline. The models were validated against an experimental test of CO2 infiltration into a small enclosure. Comparisons were made between the analytical model, CFD model and experimental data for the build-up of CO2 in the enclosure and the changes in internal temperature. This paper investigates the suitability of the analytical model for buildings geometries more closely resembling domestic abodes and against a wider range of conditions by comparing its results to those of the CFD model for a set of representative case studies. It also tunes the parameters used in the model. Thirty test cases were created which explore the key parameters affecting the CO2 ventilation rate: wind speed, the area and height of the openings, internal temperature and building height, width and length. The analytical model’s predictions of the accumulation of CO2 inside a building are shown to be extremely close to the CFD results for all cases except one, where it makes an over prediction of the level of CO2. Furthermore, it is recommended that the analytical infiltration model is used with the tuned set of coefficients identified in this paper

Cortical Contributions to Saccadic Suppression

The stability of visual perception is partly maintained by saccadic suppression: the selective reduction of visual sensitivity that accompanies rapid eye movements. The neural mechanisms responsible for this reduced perisaccadic visibility remain unknown, but the Lateral Geniculate Nucleus (LGN) has been proposed as a likely site. Our data show, however, that the saccadic suppression of a target flashed in the right visual hemifield increased with an increase in background luminance in the left visual hemifield. Because each LGN only receives retinal input from a single hemifield, this hemifield interaction cannot be explained solely on the basis of neural mechanisms operating in the LGN. Instead, this suggests that saccadic suppression must involve processing in higher level cortical areas that have access to a considerable part of the ipsilateral hemifield

Osmotaxis in Escherichia coli through changes in motor speed

Bacterial motility, and in particular repulsion or attraction towards specific chemicals, has been a subject of investigation for over 100 years, resulting in detailed understanding of bacterial chemotaxis and the corresponding sensory network in many bacterial species. For Escherichia coli most of the current understanding comes from the experiments with low levels of chemotactically-active ligands. However, chemotactically-inactive chemical species at concentrations found in the human gastrointestinal tract produce significant changes in E. coli's osmotic pressure, and have been shown to lead to taxis. To understand how these nonspecific physical signals influence motility, we look at the response of individual bacterial flagellar motors under step-wise changes in external osmolarity. We combine these measurements with a population swimming assay under the same conditions. Unlike for chemotactic response, a long-term increase in swimming/motor speeds is observed, and in the motor rotational bias, both of which scale with the osmotic shock magnitude. We discuss how the speed changes we observe can lead to steady state bacterial accumulation.Comment: 24 pages, 11 figure

A Motion Illusion Reveals Mechanisms of Perceptual Stabilization

Visual illusions are valuable tools for the scientific examination of the mechanisms underlying perception. In the peripheral drift illusion special drift patterns appear to move although they are static. During fixation small involuntary eye movements generate retinal image slips which need to be suppressed for stable perception. Here we show that the peripheral drift illusion reveals the mechanisms of perceptual stabilization associated with these micromovements. In a series of experiments we found that illusory motion was only observed in the peripheral visual field. The strength of illusory motion varied with the degree of micromovements. However, drift patterns presented in the central (but not the peripheral) visual field modulated the strength of illusory peripheral motion. Moreover, although central drift patterns were not perceived as moving, they elicited illusory motion of neutral peripheral patterns. Central drift patterns modulated illusory peripheral motion even when micromovements remained constant. Interestingly, perceptual stabilization was only affected by static drift patterns, but not by real motion signals. Our findings suggest that perceptual instabilities caused by fixational eye movements are corrected by a mechanism that relies on visual rather than extraretinal (proprioceptive or motor) signals, and that drift patterns systematically bias this compensatory mechanism. These mechanisms may be revealed by utilizing static visual patterns that give rise to the peripheral drift illusion, but remain undetected with other patterns. Accordingly, the peripheral drift illusion is of unique value for examining processes of perceptual stabilization

Histological and immunohistochemical features suggesting aetiological differences in lymph node and (muco)cutaneous feline tuberculosis lesions

Objectives To identify and describe histological and immunohistochemical criteria that may differentiate between skin and lymph node lesions associated with Mycobacterium (M.) bovis and M. microti in a diagnostic pathology setting.Materials and Methods<jats:p/>Archived skin and lymph node biopsies of tuberculous lesions were stained with haematoxylin and eosin, Ziehl‐Neelsen and Masson's Trichrome. Immunohistochemistry was performed to detect the expression of calprotectin, CD3 and Pax5. Samples were scored for histological parameters (i.e. granulomas with central necrosis versus small granulomas without central necrosis, percentage necrosis and/or multinucleated giant cells), number of acid‐fast bacilli (bacterial index) and lesion percentage of fibrosis and positive immunohistochemical staining.Results Twenty‐two samples were examined (M. bovis n=11, M. microti n=11). When controlling for age, gender and tissue, feline M. bovis‐associated lesions more often featured large multi‐layered granulomas with central necrosis. Conversely, this presentation was infrequent in feline M. microti‐associated lesions, where small granulomas without central necrosis predominated. The presence of an outer fibrous capsule was variable in both groups, as was the bacterial index. There were no differences in intralesional expression of immunohistochemical markers.Clinical Significance Differences in the histological appearance of skin and lymph node lesions may help to infer feline infection with either M. bovis or M. microti at an earlier stage when investigating these cases, informing clinicians of the potential zoonotic risk. Importantly, cases of tuberculosis can present with numerous acid‐fast bacilli. This implies that a high bacterial index does not infer infection with non‐zoonotic non‐tuberculous mycobacteria

c-Myc regulates transcriptional pause release

Recruitment of the RNA polymerase II (Pol II) transcription initiation apparatus to promoters by specific DNA-binding transcription factors is well recognized as a key regulatory step in gene expression. We report here that promoter-proximal pausing is a general feature of transcription by Pol II in mammalian cells and thus an additional step where regulation of gene expression occurs. This suggests that some transcription factors recruit the transcription apparatus to promoters, whereas others effect promoter-proximal pause release. Indeed, we find that the transcription factor c-Myc, a key regulator of cellular proliferation, plays a major role in Pol II pause release rather than Pol II recruitment at its target genes. We discuss the implications of these results for the role of c-Myc amplification in human cancer.National Institutes of Health (U.S.) (Grant number RO1-HG002668)National Institutes of Health (U.S.) (Grant number RO1-GM34277)National Institutes of Health (U.S.) (Grant number RO1-CA133404)National Cancer Institute (U.S.) (Grant Number PO1- CA42063)National Cancer Institute (U.S.) Cancer Center Support Grant (Grant Number P30-CA14051)National Institutes of Health (U.S.) Postdoctoral Fellowship (5-F32-HD051190

Prediction of RNA Polymerase II recruitment, elongation and stalling from histone modification data

<p>Abstract</p> <p>Background</p> <p>Initiation and elongation of RNA polymerase II (RNAPII) transcription is regulated by both DNA sequence and chromatin signals. Recent breakthroughs make it possible to measure the chromatin state and activity of core promoters genome-wide, but dedicated computational strategies are needed to progress from descriptive annotation of data to quantitative, predictive models.</p> <p>Results</p> <p>Here, we describe a computational framework which with high accuracy can predict the locations of core promoters, the amount of recruited RNAPII at the promoter, the amount of elongating RNAPII in the gene body, the mRNA production originating from the promoter and finally also the stalling characteristics of RNAPII by considering both quantitative and spatial features of histone modifications around the transcription start site (TSS).</p> <p>As the model framework can also pinpoint the signals that are the most influential for prediction, it can be used to infer underlying regulatory biology. For example, we show that the H3K4 di- and tri- methylation signals are strongly predictive for promoter location while the acetylation marks H3K9 and H3K27 are highly important in estimating the promoter usage. All of these four marks are found to be necessary for recruitment of RNAPII but not sufficient for the elongation. We also show that the spatial distributions of histone marks are almost as predictive as the signal strength and that a set of histone marks immediately downstream of the TSS is highly predictive of RNAPII stalling.</p> <p>Conclusions</p> <p>In this study we introduce a general framework to accurately predict the level of RNAPII recruitment, elongation, stalling and mRNA expression from chromatin signals. The versatility of the method also makes it ideally suited to investigate other genomic data.</p