ResearchPad - intoxication https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Functional and structural consequences of epithelial cell invasion by <i>Bordetella pertussis</i> adenylate cyclase toxin]]> https://www.researchpad.co/article/elastic_article_7693 Bordetella pertussis, the causative agent of whopping cough, produces an adenylate cyclase toxin (CyaA) that plays a key role in the host colonization by targeting innate immune cells which express CD11b/CD18, the cellular receptor of CyaA. CyaA is also able to invade non-phagocytic cells, via a unique entry pathway consisting in a direct translocation of its catalytic domain across the cytoplasmic membrane of the cells. Within the cells, CyaA is activated by calmodulin to produce high levels of cyclic adenosine monophosphate (cAMP) and alter cellular physiology. In this study, we explored the effects of CyaA toxin on the cellular and molecular structure remodeling of A549 alveolar epithelial cells. Using classical imaging techniques, biochemical and functional tests, as well as advanced cell mechanics method, we quantify the structural and functional consequences of the massive increase of intracellular cyclic AMP induced by the toxin: cell shape rounding associated to adhesion weakening process, actin structure remodeling for the cortical and dense components, increase in cytoskeleton stiffness, and inhibition of migration and repair. We also show that, at low concentrations (0.5 nM), CyaA could significantly impair the migration and wound healing capacities of the intoxicated alveolar epithelial cells. As such concentrations might be reached locally during B. pertussis infection, our results suggest that the CyaA, beyond its major role in disabling innate immune cells, might also contribute to the local alteration of the epithelial barrier of the respiratory tract, a hallmark of pertussis.

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<![CDATA[Efficacy of equine botulism antitoxin in botulism poisoning in a guinea pig model]]> https://www.researchpad.co/article/5c424393d5eed0c4845e067e

Background

Botulism is a disease caused by neurogenic toxins that block acetylcholine release, resulting in potentially life threatening neuroparalysis. Seven distinct serotypes of botulinum neurotoxins (BoNTs) have been described and are found in nature world-wide. This, combined with ease of production, make BoNTs a significant bioweapon threat. An essential countermeasure to this threat is an antitoxin to remove circulating toxin. An antitoxin, tradename BAT (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)–(Equine)), has been developed and its efficacy evaluated against all seven serotypes in guinea pigs.

Methods and findings

Studies were conducted to establish the lethal dose and clinical course of intoxication for all seven toxins, and post-exposure prophylactic efficacy of BAT product. Animals were monitored for signs of intoxication and mortality for 14 days. Guinea pig intramuscular LD50s (GPIMLD50) for all BoNTs ranged from 2.0 (serotype C) to 73.2 (serotype E) of mouse intraperitoneal LD50 units. A dose of 4x GPIMLD50 was identified as the appropriate toxin dose for use in subsequent efficacy and post-exposure prophylaxis studies. The main clinical signs observed included hind limb paralysis, weak limb, change in breathing rate/pattern, and forced abdominal respiration. Mean time to onset of clinical signs ranged from 12 hours (serotype E) to 39 hours (serotype G). Twelve hours post-intoxication was selected as the appropriate time point for intervention for all serotypes apart from E where 6 hours was selected because of the rapid onset and progression of clinical signs. Post-exposure treatment with BAT product resulted in a significantly (p<0.0001) higher survival at >0.008 scaled human dose for serotypes A, B, C, F and G, at >0.2x for serotype D and >0.04x for serotype E.

Conclusions

These studies confirm the efficacy of BAT as a post-exposure prophylactic therapy against all seven known BoNT serotypes.

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<![CDATA[Carbon monoxide poisoning in Denmark with focus on mortality and factors contributing to mortality]]> https://www.researchpad.co/article/5c605a02d5eed0c4847cc683

Introduction

Carbon monoxide (CO) poisoning is frequent worldwide but knowledge regarding the epidemiology is insufficient. The aim of this study was to clarify the extent of this intoxication, its mortality and factors associated with mortality.

Materials and methods

National databases from Statistics Denmark were used to identify individuals who suffered from CO-poisoning during 1995–2015, as well as information regarding co-morbidities, mortality and manner of death.

Results

During the period from 1995 to 2015, 22,930 patients suffered from CO-poisoning in Denmark, and 21,138 of these patients (92%) were hospitalized. A total of 2,102 patients died within the first 30 days after poisoning (9.2%). Among these, 1,792 (85% of 2,102) were declared dead at the scene and 310 (15% of 2,102) died during hospitalization. Deaths due to CO-poisoning from smoke were intentional in 6.3% of cases, whereas deaths due to CO containing gases were intentional in 98.0% of cases. Among patients who survived >30 days, there was no significant difference in survival when comparing hyperbaric oxygen therapy (HBO) treatment with no HBO treatment after adjustment for age and co-morbidities such as drug abuse, psychiatric disease, stroke, alcohol abuse, arterial embolism, chronic obstructive pulmonary disease, cerebrovascular disease and atrial fibrillation. Several co-morbidities predicted poorer outcomes for patients who survived the initial 30 days.

Conclusions

Poisoning from smoke and/or CO is a frequent incident in Denmark accounting for numerous contacts with hospitals and deaths. Both intoxication and mortality are highly associated with co-morbidities interfering with cognitive and physical function. Treatment with HBO was not seen to have an effect on survival.

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<![CDATA[Attentional and working memory performance following alcohol and energy drink: A randomised, double-blind, placebo-controlled, factorial design laboratory study]]> https://www.researchpad.co/article/5c3fa5c9d5eed0c484ca8872

Alcohol mixed with energy drinks (AMED) studies have typically not shown antagonism of acute alcohol effects by energy drink (ED), particularly over relatively short time frames. This study investigated the effects of alcohol, ED, and AMED on attentional and working memory processes over a 3 h period. Twenty-four young adults took part in a randomised, double-blind, placebo-controlled, factorial, 4-arm study. They were administered 0.6g/kg alcohol and 250 ml ED (containing 80 mg caffeine), and matching placebos alone and in combination. A battery of attentional and working memory measures was completed at baseline then 45, 90 and 180 min post-treatment. Alcohol produced a characteristic shift in speed/accuracy trade-off, having little effect on reaction times while increasing errors on all attentional measures (4-choice Reaction Time, Number Pairs and Visual Search), as well as a composite Attentional error score and one working memory task (Serial Sevens). ED alone improved two working memory measures (Memory Scanning accuracy and Digit–Symbol reaction times) and improved speed of responding on a composite Working Memory score. There was no consistent pattern of AMED vs. alcohol effects; AMED produced more errors than alcohol alone on one attentional measure (Visual Search errors) at 45 min only whereas AMED resulted in fewer errors on the Serial Sevens task at 90 min and better Digit-Symbol accuracy and reaction time at 45 min. Alcohol consumption increases error rate across several attentional and working memory processes. Mutual antagonism between alcohol and ED showed no consistent pattern and likely reflects a complex interaction between caffeine and alcohol levels, phase of the blood alcohol limb, task domain and cognitive load.

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<![CDATA[Prediction of Patient Survival in Cases of Acute Paraquat Poisoning]]> https://www.researchpad.co/article/5989d9d8ab0ee8fa60b66b40

Paraquat concentration-time data have been used to predict the clinical outcome following ingestion. However, these studies have included only small populations, although paraquat poisoning has a very high mortality rate. The purpose of this study was to develop a simple and reliable model to predict survival according to the time interval post-ingestion in patients with acute paraquat poisoning. Data were retrospectively collected for patients who were admitted with paraquat poisoning to Soonchunhyang University Choenan Hospital between January 2005 and December 2012. Plasma paraquat levels were measured using high-performance liquid chromatography. To validate the model we developed, we used external data from 788 subjects admitted to the Presbyterian Medical Center, Jeonju, Korea, between January 2007 and December 2012. Two thousand one hundred thirty six patients were included in this study. The overall survival rate was 44% (939/2136). The probability of survival for any specified time and concentration could be predicted as (exp(logit))/(1+exp(logit)), where logit = 1.3544+[−3.4688×log10(plasma paraquat μg/M)]+[−2.3169×log10(hours since ingestion)]. The external validation study showed that our model was highly accurate for the prediction of survival (C statics 0.964; 95% CI [0.952–0.975]). We have developed a model that is effective for predicting survival after paraquat intoxication.

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<![CDATA[Correlation between clinical severity and different non-invasive measurements of carbon monoxide concentration: A population study]]> https://www.researchpad.co/article/5989db50ab0ee8fa60bdc14d

Objectives

Carbon monoxide (CO) poisoning is a major concern in industrialized countries. Each year, thousands of victims, resulting in approximately 100 fatalities, are encountered in France. The diagnosis of CO poisoning is challenging; while carboxyhemoglobin (COHb) may be useful, it is a weak indicator of the severity of CO poisoning. This weak indicator may be a result of the delay between poisoning occurrence and the blood assay. Two apparatuses, CO oximeters and exhaled CO analyzers, now permit COHb to be determined outside hospitals. Our hypothesis is that these instruments allow the early measurement of COHb concentrations, which are more correlated with the severity of poisoning, expressed using the poisoning severity score (PSS).

Design

In an observational and retrospective cohort study, the distribution of COHb measurements obtained by CO oximetry or by exhaled CO analyzers was compared between groups of severity expressed using the PSS.

Setting

Data were collected in the Paris area from January 2006 to December 2010 by the French Surveillance System of CO poisoning.

Participants

All patients with CO poisoning reported to the French Surveillance System of CO poisoning.

Results

There was a significant difference in the COHb values obtained by CO oximetry between groups stratified according to PSS (p<0.0001). A significant difference in the values of exhaled CO was also observed between PSS groups (p = 0.006), although the relationship was not linear.

Conclusions

The COHb concentrations measured using CO oximetry, but not those measured using exhaled CO analyzers, were well correlated with the severity of CO poisoning.

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<![CDATA[Chronic Vitamin D Intoxication in Captive Iberian Lynx (Lynx pardinus)]]> https://www.researchpad.co/article/5989da0dab0ee8fa60b78247

To document the biochemical and pathologic features of vitamin D intoxication in lynx and to characterize mineral metabolism in healthy lynx, blood samples were obtained from 40 captive lynx that had been receiving excessive (approximately 30 times the recommended dose) vitamin D3 in the diet, and from 29 healthy free ranging lynx. Tissue samples (kidney, stomach, lung, heart and aorta) were collected from 13 captive lynx that died as a result of renal disease and from 3 controls. Vitamin D intoxication resulted in renal failure in most lynx (n = 28), and widespread extraskeletal calcification was most severe in the kidneys and less prominent in cardiovascular tissues. Blood minerals and calciotropic hormones in healthy lynx were similar to values reported in domestic cats except for calcitriol which was higher in healthy lynx. Changes in mineral metabolism after vitamin D intoxication included hypercalcemia (12.0 ± 0.3 mg/dL), hyperphosphatemia (6.3 ± 0.4 mg/dL), increased plasma calcidiol (381.5 ± 28.2 ng/mL) and decreased plasma parathyroid hormone (1.2 ± 0.7 pg/mL). Hypercalcemia and, particularly, hyperphosphatemia were of lower magnitude that what has been previously reported in the course of vitamin D intoxication in other species. However, extraskeletal calcifications were severe. The data suggest that lynx are sensitive to excessive vitamin D and extreme care should be taken when supplementing this vitamin in captive lynx diets.

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<![CDATA[Intracellular Zn(II) Intoxication Leads to Dysregulation of the PerR Regulon Resulting in Heme Toxicity in Bacillus subtilis]]> https://www.researchpad.co/article/5989da1cab0ee8fa60b7d1fa

Transition metal ions (Zn(II), Cu(II)/(I), Fe(III)/(II), Mn(II)) are essential for life and participate in a wide range of biological functions. Cellular Zn(II) levels must be high enough to ensure that it can perform its essential roles. Yet, since Zn(II) binds to ligands with high avidity, excess Zn(II) can lead to protein mismetallation. The major targets of mismetallation, and the underlying causes of Zn(II) intoxication, are not well understood. Here, we use a forward genetic selection to identify targets of Zn(II) toxicity. In wild-type cells, in which Zn(II) efflux prevents intoxication of the cytoplasm, extracellular Zn(II) inhibits the electron transport chain due to the inactivation of the major aerobic cytochrome oxidase. This toxicity can be ameliorated by depression of an alternate oxidase or by mutations that restrict access of Zn(II) to the cell surface. Conversely, efflux deficient cells are sensitive to low levels of Zn(II) that do not inhibit the respiratory chain. Under these conditions, intracellular Zn(II) accumulates and leads to heme toxicity. Heme accumulation results from dysregulation of the regulon controlled by PerR, a metal-dependent repressor of peroxide stress genes. When metallated with Fe(II) or Mn(II), PerR represses both heme biosynthesis (hemAXCDBL operon) and the abundant heme protein catalase (katA). Metallation of PerR with Zn(II) disrupts this coordination, resulting in depression of heme biosynthesis but continued repression of catalase. Our results support a model in which excess heme partitions to the membrane and undergoes redox cycling catalyzed by reduced menaquinone thereby resulting in oxidative stress.

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<![CDATA[Essential Indicators Identifying Chronic Inorganic Mercury Intoxication: Pooled Analysis across Multiple Cross-Sectional Studies]]> https://www.researchpad.co/article/5989da81ab0ee8fa60b9ac7e

Background

The continuous exposure to inorganic mercury vapour in artisanal small-scale gold mining (ASGM) areas leads to chronic health problems. It is therefore essential to have a quick, but reliable risk assessing tool to diagnose chronic inorganic mercury intoxication. This study re-evaluates the state-of-the-art toolkit to diagnose chronic inorganic mercury intoxication by analysing data from multiple pooled cross-sectional studies. The primary research question aims to reduce the currently used set of indicators without affecting essentially the capability to diagnose chronic inorganic mercury intoxication. In addition, a sensitivity analysis is performed on established biomonitoring exposure limits for mercury in blood, hair, urine and urine adjusted by creatinine, where the biomonitoring exposure limits are compared to thresholds most associated with chronic inorganic mercury intoxication in artisanal small-scale gold mining.

Methods

Health data from miners and community members in Indonesia, Tanzania and Zimbabwe were obtained as part of the Global Mercury Project and pooled into one dataset together with their biomarkers mercury in urine, blood and hair. The individual prognostic impact of the indicators on the diagnosis of mercury intoxication is quantified using logistic regression models. The selection is performed by a stepwise forward/backward selection. Different models are compared based on the Bayesian information criterion (BIC) and Cohen`s kappa is used to evaluate the level of agreement between the diagnosis of mercury intoxication based on the currently used set of indicators and the result based on our reduced set of indicators. The sensitivity analysis of biomarker exposure limits of mercury is based on a sequence of chi square tests.

Results

The variable selection in logistic regression reduced the number of medical indicators from thirteen to ten in addition to the biomarkers. The estimated level of agreement using ten of thirteen medical indicators and all four biomarkers to diagnose chronic inorganic mercury intoxication yields a Cohen`s Kappa of 0.87. While in an additional stepwise selection the biomarker blood was not selected, the level of agreement based on ten medical indicators and only the three biomarkers urine, urine/creatinine and hair reduced Cohen`s Kappa to 0.46. The optimal cut-point for the biomarkers blood, hair, urine and urine/creatinine were estimated at 11. 6 μg/l, 3.84 μg/g, 24.4 μg/l and 4.26 μg/g, respectively.

Conclusion

The results show that a reduction down to only ten indicators still allows a reliable diagnosis of chronic inorganic mercury intoxication. This reduction of indicators will simplify health assessments in artisanal small-scale gold mining areas.

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<![CDATA[Methylmercury Causes Blood-Brain Barrier Damage in Rats via Upregulation of Vascular Endothelial Growth Factor Expression]]> https://www.researchpad.co/article/5989db53ab0ee8fa60bdccda

Clinical manifestations of methylmercury (MeHg) intoxication include cerebellar ataxia, concentric constriction of visual fields, and sensory and auditory disturbances. The symptoms depend on the site of MeHg damage, such as the cerebellum and occipital lobes. However, the underlying mechanism of MeHg-induced tissue vulnerability remains to be elucidated. In the present study, we used a rat model of subacute MeHg intoxication to investigate possible MeHg-induced blood-brain barrier (BBB) damage. The model was established by exposing the rats to 20-ppm MeHg for up to 4 weeks; the rats exhibited severe cerebellar pathological changes, although there were no significant differences in mercury content among the different brain regions. BBB damage in the cerebellum after MeHg exposure was confirmed based on extravasation of endogenous immunoglobulin G (IgG) and decreased expression of rat endothelial cell antigen-1. Furthermore, expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, increased markedly in the cerebellum and mildly in the occipital lobe following MeHg exposure. VEGF expression was detected mainly in astrocytes of the BBB. Intravenous administration of anti-VEGF neutralizing antibody mildly reduced the rate of hind-limb crossing signs observed in MeHg-exposed rats. In conclusion, we demonstrated for the first time that MeHg induces BBB damage via upregulation of VEGF expression at the BBB in vivo. Further studies are required in order to determine whether treatment targeted at VEGF can ameliorate MeHg-induced toxicity.

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<![CDATA[Hyperventilation with Maintenance of Isocapnia. An “Old New” Method in Carbon Monoxide Intoxication]]> https://www.researchpad.co/article/5989db54ab0ee8fa60bdcfdc

Introduction

Exposure to carbon monoxide (CO) is among the most common causes of acute and chronic poisonings worldwide. The crucial point of treatment of such acute poisonings is to eliminate CO from the body as fast as possible. There are currently two approaches to the management of the CO intoxication: hyperbaric oxygen therapy (HOT) and normobaric oxygen therapy (NOT). HOT is highly effective and capable of achieving the CO elimination half-time (T½) as low as 15 minutes. Unfortunately this method is expensive and not always readily available. The elimination of CO with the use of NOT (T½~70 min) is slower, but treatment can be started even on the site of the exposure and continued while the patient is transported to a hospital. The aim of the study was to evaluate the effectiveness of a method using therapeutic hyperventilation with maintenance of isocapnia (IH) in the elimination of CO in volunteers exposed to CO and to compare selected gasometric and respiratory parameters during IH with the values obtained during hyperventilation with pure oxygen (“non-isocapnic hyperventilation”–NIH).

Material and methods

The study involved 13 healthy, chronically-smoking volunteers. Each of them participated in two independent hyperventilation tests: IH and NIH. The levels of carboxyhemoglobin (COHb) and selected gasometric, cardiac and respiratory parameters were measured at 0, 10 and 20 minutes during both tests. Among 13 volunteers (8 women and 5 men) the initial COHb level was 5.0±1.5% (mean±SD) before the IH tests and 5.1±1.9% before the NIH tests (p>0.05). After 20 minutes of the procedures the mean COHb level was 2.9±0.9% for IH and 3.6±1.2% for NIH (p<0.01). The T½ of COHb was 29.6±12.2 min and 47.3±19.2 min respectively (p<0.01). After 10 minutes of NIH respiratory alkalosis was noted in 11 participants (84.6%). Such problem was not seen during the IH procedures. No serious adverse effects were recorded during either IH or NIH. Mild symptoms such as: dyspnea, headache and paresthesias were reported by 6 volunteers (46%) during both IH and NIH tests. It is worth noting that paresthesias were only reported during NIH, by 2 participants (15.4%).

Conclusions

The elimination T½ of CO during IH was comparable with the values reported during HOT, and lower than can be achieved with NOT or NIH. No serious adverse effects were reported during IH procedures. Further studies, especially direct comparisons with NOT and HOT, are necessary to evaluate the effectiveness of IH in the treatment of acute CO poisoning.

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<![CDATA[Is Low Non-Lethal Concentration of Methylmercury Really Safe? A Report on Genotoxicity with Delayed Cell Proliferation]]> https://www.researchpad.co/article/5989dacdab0ee8fa60bb4f41

Human exposure to relatively low levels of methylmercury is worrying, especially in terms of its genotoxicity. It is currently unknown as to whether exposure to low levels of mercury (below established limits) is safe. Genotoxicity was already shown in lymphocytes, but studies with cells of the CNS (as the main target organ) are scarce. Moreover, disturbances in the cell cycle and cellular proliferation have previously been observed in neuronal cells, but no data are presently available for glial cells. Interestingly, cells of glial origin accumulate higher concentrations of methylmercury than those of neuronal origin. Thus, the aim of this work was to analyze the possible genotoxicity and alterations in the cell cycle and cell proliferation of a glioma cell line (C6) exposed to a low, non-lethal and non-apoptotic methylmercury concentration. Biochemical (mitochondrial activity) and morphological (integrity of the membrane) assessments confirmed the absence of cell death after exposure to 3 μM methylmercury for 24 hours. Even without promoting cell death, this treatment significantly increased genotoxicity markers (DNA fragmentation, micronuclei, nucleoplasmic bridges and nuclear buds). Changes in the cell cycle profile (increased mitotic index and cell populations in the S and G2/M phases) were observed, suggesting arrest of the cycle. This delay in the cycle was followed, 24 hours after methylmercury withdrawal, by a decrease number of viable cells, reduced cellular confluence and increased doubling time of the culture. Our work demonstrates that exposure to a low sublethal concentration of MeHg considered relatively safe according to current limits promotes genotoxicity and disturbances in the proliferation of cells of glial origin with sustained consequences after methylmercury withdrawal. This fact becomes especially important, since this cellular type accumulates more methylmercury than neurons and displays a vital role protecting the CNS, especially in chronic intoxication with this heavy metal.

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<![CDATA[Effect of Alcoholic Intoxication on the Risk of Inflammatory Bowel Disease: A Nationwide Retrospective Cohort Study]]> https://www.researchpad.co/article/5989da10ab0ee8fa60b79404

Purpose

This study investigated whether alcoholic intoxication (AI) increases the risk of inflammatory bowel disease (IBD) by using a population-based database in Taiwan.

Methods

This retrospective matched-cohort study included 57 611 inpatients with new-onset AI (AI cohort) and 230 444 randomly selected controls (non-AI cohort). Each patient was monitored for 10 years to individually identify those who were subsequently diagnosed with Crohn disease (CD) and ulcerative colitis (UC) during the follow-up period. Cox proportional hazard regression analysis was conducted to determine the risk of IBD in patients with AI compared with controls without AI.

Results

The incidence rate of IBD during the 10-year follow-up period was 2.69 per 1 000 person-years and 0.49 per 1 000 person-years in the AI and non-AI cohorts, respectively. After adjustment for age, sex, and comorbidity, the AI cohort exhibited a 3.17-fold increased risk of IBD compared with the non-AI cohort (hazard ratio [HR] = 3.17, 95% confidence interval [CI] = 2.19–4.58). Compared with the non-AI cohort, the HRs of CD and UC were 4.40 and 2.33 for the AI cohort, respectively. After stratification for the severity of AI according to the duration of hospital stay, the adjusted HRs exhibited a significant correlation with the severity; the HRs of IBD were 1.76, 6.83, and 19.9 for patients with mild, moderate, and severe AI, respectively (p for the trend < .0001).

Conclusion

The risk of IBD was higher in patients with AI and increased with the length of hospital stay.

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<![CDATA[Hepatoprotective Effect of Wheat-Based Solid-State Fermented Antrodia cinnamomea in Carbon Tetrachloride-Induced Liver Injury in Rat]]> https://www.researchpad.co/article/5989daedab0ee8fa60bc00d3

Antrodia cinnamomea (A. cinnamomea) is an indigenous medical fungus in Taiwan and has multiple biological functions, including hepatoprotective and immune-modulatory effects. Currently, the commercially available A. cinnamomea are mainly liquid- and solid-state fermented A. cinnamomea. However, the hepatoprotective effect of solid-state fermented A. cinnamomea has never been reported. Here we evaluate the ability of air-dried, ground and non-extracted wheat-based solid-state fermented A. cinnamomea (WFAC) to protect against carbon tetrachloride (CCl4)-induced hepatic injury in vivo. The results showed that oral administration of WFAC dose dependently (180, 540 and 1080 mg/kg) ameliorated the increase in plasma aspartate aminotransferase and alanine aminotransferase levels caused by chronic repeated CCl4 intoxication in rats. WFAC significantly reduced the CCl4-induced increase in hepatic lipid peroxidation levels and hydroxyproline contents, as well as reducing the spleen weight and water content of the liver. WFAC also restored the hepatic soluble protein synthesis and plasma albumin concentration in CCl4-intoxicated rats, but it did not affect the activities of superoxide dismutase, catalase, or glutathione peroxidase. In addition, a hepatic morphological analysis showed that the hepatic fibrosis and necrosis induced by CCl4 were significantly ameliorated by WFAC. Furthermore, the body weights of control rats and WFAC-administered rats were not significantly different, and no adverse effects were observed in WFAC-administered rats. These results indicate that WFAC is a nontoxic hepatoprotective agent against chronic CCl4-induced hepatic injury.

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<![CDATA[Drinking Songs: Alcohol Effects on Learned Song of Zebra Finches]]> https://www.researchpad.co/article/5989db0bab0ee8fa60bca12a

Speech impairment is one of the most intriguing and least understood effects of alcohol on cognitive function, largely due to the lack of data on alcohol effects on vocalizations in the context of an appropriate experimental model organism. Zebra finches, a representative songbird and a premier model for understanding the neurobiology of vocal production and learning, learn song in a manner analogous to how humans learn speech. Here we show that when allowed access, finches readily drink alcohol, increase their blood ethanol concentrations (BEC) significantly, and sing a song with altered acoustic structure. The most pronounced effects were decreased amplitude and increased entropy, the latter likely reflecting a disruption in the birds’ ability to maintain the spectral structure of song under alcohol. Furthermore, specific syllables, which have distinct acoustic structures, were differentially influenced by alcohol, likely reflecting a diversity in the neural mechanisms required for their production. Remarkably, these effects on vocalizations occurred without overt effects on general behavioral measures, and importantly, they occurred within a range of BEC that can be considered risky for humans. Our results suggest that the variable effects of alcohol on finch song reflect differential alcohol sensitivity of the brain circuitry elements that control different aspects of song production. They also point to finches as an informative model for understanding how alcohol affects the neuronal circuits that control the production of learned motor behaviors.

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<![CDATA[Cultural Orientation and Its Associations with Alcohol Use by University Students in China]]> https://www.researchpad.co/article/5989dae2ab0ee8fa60bbc4b9

Cultural orientation is defined as an individual’s cultural preferences when encountering imported culture while still living in the native culture. Data was analyzed from 1305 Chinese university students attending universities in Beijing, Kunming, and Wuhan. Cultural orientation was assessed with the Chinese Cultural Orientation Questionnaire, which assesses both Western and Traditional Chinese cultural orientations. The analysis used hierarchical logistic regression with nondrinkers as the reference group and controlling for demographic factors (age, gender, and urban/rural background). Western cultural orientation was found to significantly increase the odds of recent drinking. The results indicated that higher Western cultural orientation was, after gender, the second most important factor associated with Chinese college student drinking frequency. Traditional Chinese cultural orientation was not associated with drinking frequency. This study highlights an unexpected outcome of globalization on students who have not left their home cultures.

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<![CDATA[p62/Sequestosome-1 Is Indispensable for Maturation and Stabilization of Mallory-Denk Bodies]]> https://www.researchpad.co/article/5989da00ab0ee8fa60b73b2e

Mallory-Denk bodies (MDBs) are hepatocytic protein aggregates found in steatohepatitis and several other chronic liver diseases as well as hepatocellular carcinoma. MDBs are mainly composed of phosphorylated keratins and stress protein p62/Sequestosome-1 (p62), which is a common component of cytoplasmic aggregates in a variety of protein aggregation diseases. In contrast to the well-established role of keratins, the role of p62 in MDB pathogenesis is still elusive. We have generated total and hepatocyte-specific p62 knockout mice, fed them with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to induce MDBs and allowed the mice to recover from DDC intoxication on a standard diet to investigate the role of p62 in MDB formation and elimination. In the absence of p62, smaller, granular and less distinct MDBs appeared, which failed to mature to larger and compact inclusions. Moreover, p62 deficiency impaired the binding of other proteins such as NBR1 and Hsp25 to MDBs and altered the cellular defense mechanism by downregulation of Nrf2 target genes. Upon recovery from DDC intoxication on a standard diet, there was an enhanced reduction of p62-deficient MDBs, which was accompanied by a pronounced decrease in ubiquitinated proteins. Our data provide strong evidence that keratin aggregation is the initial step in MDB formation in steatohepatitis-related mouse models. Interaction of p62 with keratin aggregates then leads to maturation i.e., enlargement and stabilization of the MDBs as well as recruitment of other MDB-associated proteins.

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<![CDATA[Verbal Memory Impairment in Polydrug Ecstasy Users: A Clinical Perspective]]> https://www.researchpad.co/article/5989db49ab0ee8fa60bd97ee

Background

Ecstasy use has been associated with short-term and long-term memory deficits on a standard Word Learning Task (WLT). The clinical relevance of this has been debated and is currently unknown. The present study aimed at evaluating the clinical relevance of verbal memory impairment in Ecstasy users. To that end, clinical memory impairment was defined as decrement in memory performance that exceeded the cut-off value of 1.5 times the standard deviation of the average score in the healthy control sample. The primary question was whether being an Ecstasy user (E-user) was predictive of having clinically deficient memory performance compared to a healthy control group.

Methods

WLT data were pooled from four experimental MDMA studies that compared memory performance during placebo and MDMA intoxication. Control data were taken from healthy volunteers with no drug use history who completed the WLT as part of a placebo-controlled clinical trial. This resulted in a sample size of 65 E-users and 65 age- and gender-matched healthy drug-naïve controls. All participants were recruited by similar means and were tested at the same testing facilities using identical standard operating procedures. Data were analyzed using linear mixed-effects models, Bayes factor, and logistic regressions.

Results

Findings were that verbal memory performance of placebo-treated E-users did not differ from that of controls, and there was substantial evidence in favor of the null hypothesis. History of use was not predictive of memory impairment. During MDMA intoxication of E-users, verbal memory was impaired.

Conclusion

The combination of the acute and long-term findings demonstrates that, while clinically relevant memory impairment is present during intoxication, it is absent during abstinence. This suggests that use of Ecstasy/MDMA does not lead to clinically deficient memory performance in the long term. Additionally, it has to be investigated whether the current findings apply to more complex cognitive measures in diverse ‘user categories’ using a combination of genetics, imaging techniques and neuropsychological assessments.

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<![CDATA[Emergency department outpatient treatment of alcohol-intoxicated bicyclists increases the cost of medical care in Japan]]> https://www.researchpad.co/article/5989db50ab0ee8fa60bdbfc6

Riding a bicycle under the influence of alcohol is illegal in Japan. Nevertheless, intoxicated bicyclists are frequently treated at hospital emergency departments for bicycle-related injuries. This patient population usually requires more hospital resources, even for relatively minor injuries. Therefore, we hypothesized that bicycle-related crashes involving bicyclists under the influence of alcohol cost more to treat than those that do not involve alcohol intoxication. The aim of the present study was to examine the costs associated with bicycle-related minor injuries and alcohol intoxication of the bicyclist. The study was conducted at the Tokyo Bay Urayasu Ichikawa Medical Center Emergency Department, Japan. All minor bicycle crashes involving 217 individuals aged ≥20 years treated from September 1, 2012 to August 31, 2013 were included in the analysis of data obtained from medical records. Variables included alcohol intoxication, sex, age, collision with a motor vehicle, Glasgow Coma Scale, injury severity score (ISS), laboratory tests, treatment of wounds, number of X-ray images, number of computed tomography scans, and medical costs. Multiple linear regression analysis was performed to evaluate the association between alcohol intoxication and medical costs. Seventy (32%) patients consumed alcohol, and the median medical cost was 253 USD (interquartile range [IQR], 164–330). Multivariable analysis showed that alcohol intoxication was independently associated with higher medical costs (p = 0.030, adjusted R-square value = 0.55). These findings support our hypothesis and should encourage authorities to implement comprehensive measures to prohibit bicycling under the influence of alcohol to prevent injuries and to reduce medical costs.

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