SciCombinator

Discover the most talked about and latest scientific content & concepts.

Journal: Naunyn-Schmiedeberg's archives of pharmacology

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Using two examples from the non-scientific literature, we show how choice of unit of measure and scaling of y-axis can caused a biased perception of data, a phenomenon we propose to call perception bias. We recommend to pre-specify unit of measure or how it will be determined, whether outcome variables will be shown as absolute or relative/normalized changes, and to typically start y-axis at 0 for ratio variables.

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Central cholinergic dysfunction contributes to acute spatial memory deficits produced by ethanol administration. Donepezil and rivastigmine elevate acetylcholine levels in the synaptic cleft through the inhibition of cholinesterases-enzymes involved in acetylcholine degradation. The aim of our study was to reveal whether donepezil (acetylcholinesterase inhibitor) and rivastigmine (also butyrylcholinesterase inhibitor) attenuate spatial memory impairment as induced by acute ethanol administration in the Barnes maze task (primary latency and number of errors in finding the escape box) in rats. Additionally, we compared the influence of these drugs on ethanol-disturbed memory. In the first experiment, the dose of ethanol (1.75 g/kg, i.p.) was selected that impaired spatial memory, but did not induce motor impairment. Next, we studied the influence of donepezil (1 and 3 mg/kg, i.p.), as well as rivastigmine (0.5 and 1 mg/kg, i.p.), given either before the probe trial or the reversal learning on ethanol-induced memory impairment. Our study demonstrated that these drugs, when given before the probe trial, were equally effective in attenuating ethanol-induced impairment in both test situations, whereas rivastigmine, at both doses (0.5 and 1 mg/kg, i.p.), and donepezil only at a higher dose (3 mg/kg, i.p.) given prior the reversal learning, attenuated the ethanol-induced impairment in cognitive flexibility. Thus, rivastigmine appears to exert more beneficial effect than donepezil in reversing ethanol-induced cognitive impairments-probably due to its wider spectrum of activity. In conclusion, the ethanol-induced spatial memory impairment may be attenuated by pharmacological manipulation of central cholinergic neurotransmission.

Concepts: Alzheimer's disease, Enzyme inhibitor, Inhibitor, Acetylcholine, Myasthenia gravis, Acetylcholinesterase, Acetylcholinesterase inhibitor, Acetylcholinesterase inhibitors

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Ideally, any experienced investigator with the right tools should be able to reproduce a finding published in a peer-reviewed biomedical science journal. In fact, the reproducibility of a large percentage of published findings has been questioned. Undoubtedly, there are many reasons for this, but one reason maybe that investigators fool themselves due to a poor understanding of statistical concepts. In particular, investigators often make these mistakes: 1. P-Hacking. This is when you reanalyze a data set in many different ways, or perhaps reanalyze with additional replicates, until you get the result you want. 2. Overemphasis on P values rather than on the actual size of the observed effect. 3. Overuse of statistical hypothesis testing, and being seduced by the word “significant”. 4. Overreliance on standard errors, which are often misunderstood.

Concepts: Scientific method, Statistics, Statistical significance, Data, Statistical hypothesis testing, Null hypothesis

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Green tea extract (GTE) is regarded to be effective against obesity and type 2 diabetes, but definitive evidences have not been proven. Based on the assumption that the gallated catechins (GCs) in GTE attenuate intestinal glucose and lipid absorption, while enhancing insulin resistance when GCs are present in the circulation through inhibiting cellular glucose uptake in various tissues, this study attempted to block the intestinal absorption of GCs and prolong their residence time in the lumen. We then observed whether GTE containing the nonabsorbable GCs could ameliorate body weight (BW) gain and glucose intolerance in db/db and high-fat diet mice. Inhibition of the intestinal absorption of GCs was accomplished by co-administering the nontoxic polymer polyethylene glycol-3350 (PEG). C57BLKS/J db/db and high-fat diet C57BL/6 mice were treated for 4 weeks with drugs as follows: GTE, PEG, GTE + PEG, voglibose, or pioglitazone. GTE mixed with meals did not have any ameliorating effects on BW gain and glucose intolerance. However, the administration of GTE plus PEG significantly reduced BW gain, insulin resistance, and glucose intolerance, without affecting food intake and appetite. The effect was comparable to the effects of an α-glucosidase inhibitor and a peroxisome proliferator-activated receptor-γ/α agonist. These results indicate that prolonging the action of GCs of GTE in the intestinal lumen and blocking their entry into the circulation may allow GTE to be used as a prevention and treatment for both obesity and obesity-induced type 2 diabetes.

Concepts: Nutrition, Insulin, Diabetes mellitus type 2, Diabetes mellitus, Obesity, Glucose tolerance test, Insulin resistance, Green tea

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Coronavirus disease 2019 (COVID-19) has been characterized by lymphopenia as well as a proinflammatory cytokine storm, which are responsible for the poor prognosis and multiorgan defects. The transcription factor nuclear factor-κB (NF-κB) modulates the functions of the immune cells and alters the gene expression profile of different cytokines in response to various pathogenic stimuli, while many proinflammatory factors have been known to induce NF-κB signalling cascade. Besides, NF-κB has been known to potentiate the production of reactive oxygen species (ROS) leading to apoptosis in various tissues in many diseases and viral infections. Though the reports on the involvement of the NF-κB signalling pathway in COVID-19 are limited, the therapeutic benefits of NF-κB inhibitors including dexamethasone, a synthetic form of glucocorticoid, have increasingly been realized. Considering the fact, the abnormal activation of the NF-κB resulting from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection might be associated with the pathogenic profile of immune cells, cytokine storm and multiorgan defects. Thus, the pharmacological inactivation of the NF-κB signalling pathway can strongly represent a potential therapeutic target to treat the symptomatology of COVID-19. This article signifies pharmacological blockade of the phosphorylation of inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ), a key downstream effector of NF-κB signalling, for a therapeutic consideration to attenuate COVID-19.

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Among the methods valuable for assessing spatial learning and memory impairments in rodents, the Barnes maze (BM) task deserves special attention. It is based on the assumption that the animal placed into the aversive environment should learn and remember the location of an escape box located below the surface of the platform. Different phases of the task allow to measure spatial learning, memory retrieval, and cognitive flexibility. Herein, we summarize current knowledge about the BM procedure, its variations and critical parameters measured in the task. We highlight confounding factors which should be taken into account when conducting BM task, discussing briefly its advantages and disadvantages. We then propose an extended version of the BM protocol which allows to measure different aspects of spatial learning and memory in rodents. We believe that this review will help to standardize the BM methodology across the laboratories and eventually make the results comparable.

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Loperamide is a μ-opioid receptor agonist commonly used to treat diarrhea and often available as an over-the-counter medication. Recently, numerous reports of QRS widening accompanied by dramatic QT interval prolongation, torsades de pointe arrhythmia, and death have been reported in opioid abusers consuming large amounts of the drug to produce euphoria or prevent opiate withdrawal. The present study was undertaken to determine the mechanisms of this cardiotoxicity. Using whole-cell patch clamp electrophysiology, we tested loperamide on the cloned human cardiac sodium channel (Nav1.5) and the two main repolarizing cardiac K(+) channels cloned from the human heart: KvLQT1/minK and the human ether-a-go-go-related gene (hERG) channel. Loperamide inhibited Nav1.5 with IC50 values of 297 and 239 nM at holding potentials of -90 and -70 mV, respectively. Loperamide was weakly active on KvLQT1/minK producing 17 and 65 % inhibition at concentrations of 1 and 10 μM, respectively. Conversely, loperamide was found to be a very high affinity inhibitor of the hERG channel with an IC50 value of 89 nM at room temperature and 33 nM when measured at physiological temperature. The QRS and QT interval prolongation and the attending arrhythmias, produced by loperamide, derive from high affinity inhibition of Nav1.5 and especially hERG. Since the drug has been widely available and safely used as directed for many years, we believe that the potent inhibition loperamide possesses for cardiac ion channels has only been uncovered because of the excessive misuse of the drug as a consequence of the recent opioid abuse epidemic.

Concepts: Physiology, Action potential, Ion channel, Electrophysiology, Cardiac electrophysiology, Opioid, Patch clamp, Codeine

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Histamine plays an important role in the development of symptoms in allergic, infectious, neoplastic and other diseases. Empirical findings have suggested beneficial effects of ascorbic acid supplementation in those diseases, and these effects are assumed to be related to a possible decrease in systemic histamine concentration. In the present study, we systematically investigated for the first time the effect of 7.5 g of intravenously administered ascorbic acid on serum histamine levels (as detected by ELISA) in 89 patients (19 with allergic and 70 with infectious diseases). When all patients were grouped together, there was a significant decline in histamine concentration from 0.83 to 0.57 ng/ml × m(2) body surface area (BSA, p < 0.0001). The decrease in serum histamine concentration in patients with allergic diseases (1.36 to 0.69 ng/ml × m(2) BSA, p = 0.0007) was greater than that in patients with infectious diseases (0.73 to 0.56 ng/ml × m(2) BSA, p = 0.01). Furthermore, the decline in histamine concentration after ascorbic acid administration was positively correlated with the basal, i.e. pre-therapeutic, histamine concentration. Intravenous infusion of ascorbic acid clearly reduced histamine concentrations in serum, and may represent a therapeutic option in patients presenting with symptoms and diseases associated with pathologically increased histamine concentration.

Concepts: Cancer, Disease, Infectious disease, Acid, Infection, Intravenous therapy, Ascorbic acid, Bolus

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A poor understanding of statistical analysis has been proposed as a key reason for lack of replicability of many studies in experimental biomedicine. While several authors have demonstrated the fickleness of calculated p values based on simulations, we have experienced that such simulations are difficult to understand for many biomedical scientists and often do not lead to a sound understanding of the role of variability between random samples in statistical analysis. Therefore, we as trainees and trainers in a course of statistics for biomedical scientists have used real data from a large published study to develop a tool that allows scientists to directly experience the fickleness of p values. A tool based on a commonly used software package was developed that allows using random samples from real data. The tool is described and together with the underlying database is made available. The tool has been tested successfully in multiple other groups of biomedical scientists. It can also let trainees experience the impact of randomness, sample sizes and choice of specific statistical test on measured p values. We propose that live exercises based on real data will be more impactful in the training of biomedical scientists on statistical concepts.

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Since March 2020, the world has been fighting a global pandemic caused by a new coronavirus SARS-CoV-2 (COVID-19). SARS-CoV-2 is responsible for severe acute respiratory syndrome, an airway disease that can be severe and fatal in a percentage of cases. Patients with severe COVID-19 can develop extrapulmonary lesions, with renal, hepatic, cardiac, neurological, and tissue involvement that can cause further severe complications. On December 21, 2021, the European Medicines Agency (EMA) authorized the marketing of the first COVID-19 vaccine. However, several randomized trials are ongoing to find effective, safe, and widely available treatments. The most severe stages of COVID-19 infection are characterized by a multi-system inflammatory state induced by a cytokine storm causing multi-organ injury. Epidemiologic evidence has shown that glucocorticoids (GCs), particularly dexamethasone, are used in severe, hospitalized patients with COVID-19 with good therapeutic benefit. COVID-19 can also damage the endothelial system, causing microcirculatory disturbances and consequently leading to functional organ disorders. The combination of endothelial dysfunction with a generalized inflammatory state may contribute to the general pro-coagulative state described in patients with COVID-19 with increased risk of venous and arterial occlusions. The aim of this article is to describe the therapeutic utility of GCs in stabilizing the vascular endothelial barrier in COVID-19 infection. Indeed, we believe that the stabilization of the endothelial barrier and the anti-inflammatory effect of GCs could be the main effect underlying the therapeutic efficacy in COVID-19 patients.