CYP2D6 increases toxicity of the designer drug 4-methylthioamphetamine (4-MTA)

4-Methylthioamphetamine (4-MTA) belongs to a group of new amphetamine derivatives that is usually sold as "ecstasy" or "flatliners" on the illicit drug market. Large interindividual differences in 4-MTA mediated toxicity have been reported in humans. Therefore, we tested whether CYP2D6 or its variant alleles as well as CYP3A4 influence the susceptibility to 4-MTA. For this purpose, we used the colony formation assay with Chinese hamster lung fibroblast V79 cells expressing human wild-type CYP2D6 (CYP2D6*1), the low activity alleles CYP2D6*2, CYP2D6*9, as well as human CYP3A4. The obtained results showed that the expression of wild type CYP2D6*1 clearly enhanced the susceptibility to the cytotoxic effects of 4-MTA compared with the parental cells devoid of CYP-dependent enzymatic activity. Toxicity in V79 CYP2D6*1 was also higher compared to the V79 cell lines expressing the low activity alleles CYP2D6*2 and CYP2D6*9. In contrast to CYP2D6, the CYP3A4 isoenzyme did not enhance 4-MTA toxicity. In conclusion, our results suggest that CYP2D6 rapid metabolizers may be more susceptible to 4-MTA toxicity than CYP2D6 poor metabolizers.     

Correlation between Protein Accumulation Profiles and Conventional Toxicological Findings Using a Model Antiandrogenic Compound, Flutamide

In conventional rodent toxicity studies the characterizationof the adverse effects of a chemical relies primarily on gravimetric,and histopathological data. The aim of this study was to evaluateif the use of two-dimensional gel electrophoresis could generateprotein accumulation profiles, which were in accordance withconventional toxicological findings by investigating a modelantiandrogen, flutamide (FM), whose toxic effects, as measuredusing standard approaches, are well characterized. Male Sprague-Dawleyrats were orally exposed to FM (0, 6, 30, and 150 mg/kg/day)for 28 days. The expected inhibition of androgen-dependent tissuestimulation, increased luteinizing hormone and testosteroneplasma levels, and Leydig cell hyperplasia were observed. Changesin testicular protein accumulation profiles were evaluated inrats exposed to 150 mg/kg/day FM. Several proteins involvedin steroidogenesis (e.g., StAR, ApoE, Hmgcs1, Idi1), cell cycle,and cancer (e.g., Ddx1, Hspd1) were modulated by FM, and thesedata provided molecular evidence for the hormonal and testicularhistopathology changes recorded. Changes in proteins associatedwith spermatogenesis were also recorded, and these are discussedwithin the context of the testicular phenotype observed followingFM treatment (i.e., normal spermatogenesis but Leydig cell hyperplasia).Overall, our data indicate that the combination of conventionaltoxicology measurements with omic observations has the potentialto improve our global understanding of the toxicity of a compound.     

Plasma water as a diagnostic tool in the assessment of dehydration in children with acute gastroenteritis

Acute gastroenteritis is common in childhood. The estimation of the degree of dehydration is essential for management of acute gastroenteritis. Plasma water was assessed as a diagnostic tool in children with acute gastroenteritis and dehydration admitted to hospital. In a prospective cohort study, 101 patients presenting at the emergency department with dehydration were included. Clinical assessment, routine laboratory tests, and plasma water measurement were performed. Plasma water was measured as a percentage of water content using dry weight method. During admission, patients were rehydrated in 12 h. Weight gain at the end of the rehydration period and 2 weeks thereafter was used to determine the percentage of weight loss as a gold standard for the severity of dehydration. Clinical assessment of dehydration was not significantly associated with the percentage of weight loss. Blood urea nitrogen (r = 0.3, p = 0.03), base excess (r =−0.31, p = 0.03), and serum bicarbonate (r = 0.32, p = 0.02) were significantly correlated with the percentage of weight loss. Plasma water did not correlate with the percentage of weight loss. On the basis of the presented data, plasma water should not be used as a diagnostic tool in the assessment of dehydration in children with acute gastroenteritis.     

Lack of Evidence for Crimean–Congo Hemorrhagic Fever Virus in Ticks Collected from Animals,Corsica, France

In Corsica, France, 9.1% of livestock serum samples collected during 2014–2016 were found to have antibodies against Crimean–Congo hemorrhagic fever virus (CCHFV), an emerging tickborne zoonotic disease. We tested 8,051 ticks for CCHFV RNA and Nairovirus RNA. The results indicate that Corsica is not a hotspot for CCHFV.     

Identification of typical medullary breast carcinoma as a genomic sub-group of basal-like carcinomas, a heterogeneous new molecular entity

Introduction

Typical medullary breast carcinoma (MBC) has recently been recognized to be part of the basal-like carcinoma spectrum, a feature in agreement with the high rate of TP53 mutations previously reported in MBCs. The present study was therefore designed to identify phenotypic and genetic alterations that distinguish MBCs from basal-like carcinomas (BLC).

Methods

Expression levels of estrogen receptor (ER), progesterone receptor (PR), ERBB2, TP53, cytokeratins (KRTs) 5/6, 14, 8/18, epidermal growth factor receptor and KIT, as well as TP53 gene sequence and high-density array comparative genomic hybridization (CGH) profiles, were assessed and compared in a series of 33 MBCs and 26 BLCs.

Results

All tumors were negative for ER, PR and ERBB2. KRTs 5/6 were more frequently expressed in MBCs (94%) than in BLCs (56%) (p = 0.0004). TP53 mutations were disclosed in 20/26 MBCs (77%) and 20/24 BLCs (83%). Array CGH analysis showed that a higher number of gains (95 regions) and losses (34 regions) was observed in MBCs than in BLCs (36 regions of gain; 13 regions of losses). In addition, gains of 1q and 8q, and losses of X were found to be common to the two groups, whereas gains of 10p (53% of the cases), 9p (30.8% of the cases) and 16q (25.8% of the cases), and losses of 4p (34.8% of the cases), and amplicons of 1q, 8p, 10p and 12p were the genetic alterations found to characterize MBC.

Conclusion

Our study has revealed that MBCs are part of the basal-like group and share common genomic alterations with BLCs, the most frequent being 1q and 8q gains and X losses; however, MBCs are a distinct entity within the basal-like spectrum, characterized by a higher rate of KRT 5/6 expression, a higher rate of gains and losses than BLCs, recurrent 10p, 9p and 16q gains, 4p losses, and 1q, 8p, 10p and 12p amplicons. Our results thus contribute to a better understanding of the heterogeneity in basal-like breast tumors and provide potential diagnostic tools.     

Physical and mental health status of former smokers and non-smokers patients with bipolar disorder

Objectives

Up to 70% individuals with bipolar disorder (BD) are lifetime tobacco smokers, a major modifiable risk factor for morbidity. However, quitting smoking is rarely proposed to individuals with BD, mainly because of fear of unfavorable metabolic or psychiatric changes. Evaluating the physical and mental impact of tobacco cessation is primordial. The aim of this study was to characterize the psychiatric and nonpsychiatric correlates of tobacco smoking status (never- vs. current vs. former smokers) in individuals with BD.

Methods

3860 individuals with ascertained BD recruited in the network of Fondamental expert centers for BD between 2009 and 2020 were categorized into current, former, and never tobacco smokers. We compared the sociodemographic and clinical characteristics assessed by standard instruments (e.g., BD type, current symptoms load, and non-psychiatric morbidity—including anthropometric and biological data) of the three groups using multinomial regression logistic models. Corrections for multiple testing were applied.

Results

Current smokers had higher depression, anxiety, and impulsivity levels than former and never-smokers, and also higher risk of comorbid substance use disorders with a gradient from never to former to current smokers—suggesting shared liability. Current smokers were at higher risk to have a metabolic syndrome than never-smokers, although this was only evidenced in cases, who were not using antipsychotics.

Conclusions

Tobacco smoking was associated with high morbidity level. Strikingly, as in the general population, quitting smoking seemed associated with their return to the never-smokers' levels. Our findings strongly highlight the need to spread strategies to treat tobacco addiction in the BD population.     

Distinct genetic basis of common epilepsies and structural magnetic resonance imaging measures

Focal and generalized epilepsies are associated with robust differences in magnetic resonance imaging (MRI) measures of subcortical structures, gray matter, and white matter. However, it is unknown whether such structural brain differences reflect the cause or consequence of epilepsy or its treatment. Analyses of common genetic variants underlying both common epilepsy risk and variability in structural brain measures can give further insights, as such inherited variants are not influenced by disease or treatment. Here, we performed genetic correlation analyses using data from the largest genome-wide association study (GWAS) on common epilepsy (n = 27 559 cases and 42 436 controls) and GWASs on MRI measures of white (n = 33 292) or gray matter (n = 51 665). We did not detect any significant genetic correlation between any type of common epilepsy and any of 280 measures of gray matter, white matter, or subcortical structures. These results suggest that there are distinct genetic bases underlying risk of common epilepsy and for structural brain measures. This would imply that the genetic basis of normal structural brain variation is unrelated to that of common epilepsy. Structural changes in epilepsy could rather be the consequence of epilepsy, its comorbidities, or its treatment, offering a cumulative record of disease.