Use of mefloquine in children - a review of dosage, pharmacokinetics and tolerability data

Currently available data provide a scientific basis for the use of mefloquine in small children in the chemoprophylaxis setting and as a part of treatment regimens for children living in endemic areas

Adipose tissue-specific ablation of PGC-1β impairs thermogenesis in brown fat

Adrenergic control; Lipid metabolism; MiceControl adrenèrgic; Metabolisme dels lípids; RatolinsControl adrenérgico; Metabolismo de los lípidos; RatonesImpaired thermogenesis observed in mice with whole-body ablation of peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β; officially known as PPARGC1B) may result from impaired brown fat (brown adipose tissue; BAT) function, but other mechanism(s) could be involved. Here, using adipose-specific PGC-1β knockout mice (PGC-1β-AT-KO mice) we aimed to learn whether specific PGC-1β ablation in adipocytes is sufficient to drive cold sensitivity. Indeed, we found that warm-adapted (30°C) mutant mice were relatively sensitive to acute cold exposure (6°C). When these mice were subjected to cold exposure for 7 days (7-day-CE), adrenergic stimulation of their metabolism was impaired, despite similar levels of thermogenic uncoupling protein 1 in BAT in PGC-1β-AT-KO and wild-type mice. Gene expression in BAT of mutant mice suggested a compensatory increase in lipid metabolism to counteract the thermogenic defect. Interestingly, a reduced number of contacts between mitochondria and lipid droplets associated with low levels of L-form of optic atrophy 1 was found in BAT of PGC-1β-AT-KO mice. These genotypic differences were observed in warm-adapted mutant mice, but they were partially masked by 7-day-CE. Collectively, our results suggest a role for PGC-1β in controlling BAT lipid metabolism and thermogenesis.The research was supported by the Czech Science Foundation (Grantová Agentura České Republiky; 18-04483S) and by a grant from the Ministerio de Economía y Competitividad, co-funded by the European Regional Development Fund (ERDF) (RTI2018-099250-B-100 to J.A.V.)

Problems of Hydraulic Conductivity Estimation in Clayey Karst Soils

Even in karst areas, considerably thick soils can be found in accumulation zones. Here, the degree of groundwater vulnerability depends not only on the thickness, but also on the hydraulic conductivity and retention properties of the soil cover. The hydraulic conductivity of fine-grained karst soils from Slovakia, Croatia and Austria was studied within several international research projects, by the application of four different test methods. Results are discussed from different points of view. Triaxial tests yielded a very broad interval between the maximum and minimum hydraulic conductivity (from 5.83x10-7 m.s-1 to 3.50x10-11 m.s-1), therefore the mean value cannot be used in any calculations. The consolidometer method gave lower values in general, between 9.40x10-10 m.s-1 to 3.59x10-8 m.s-1. However, this method overestimates the soil “impermeability”. Estimates based on grain size are unsuitable, as fine-grained soils did not fulfil the random conditions of known formula. Finally, the “in situ” hydraulic conductivity was measured using a Guelph permeameter. As expected, “in situ” tests showed 100 to 1000-times higher kf than the laboratory tests. This method best reflects the real conditions. Therefore, only this type of data should be considered in any environmental modelling. In a soil profile, hydraulic conductivity depends on the mineral composition, depth, secondary compaction, etc. The degree and duration of saturation with water is very important for young soils containing smectite. Their hydraulic conductivity might be very low when saturated for long time, but also very high, when open desiccation cracks occur. A very slight trend was found, but only in Slovak soils, showing a decrease in the hydraulic conductivity with increasing content of the clay fraction <0.002 mm. These results should contribute to a better estimate of the protective role of soils in groundwater vulnerability maps

Pregnancy and Fetal Outcomes After Exposure to Mefloquine in the Pre- and Periconception Period and During Pregnancy

Pregnant women who travel to malarious areas and their clinicians need data on the safety of malaria chemoprophylaxis. The drug safety database analysis of mefloquine exposure in pregnancy showed that the birth defect prevalence and fetal loss in maternal, prospectively-monitored cases were comparable to background rate

Dysregulation of epicardial adipose tissue in cachexia due to heart failure. the role of natriuretic peptides and cardiolipin

Background: Cachexia worsens long-term prognosis of patients with heart failure (HF). Effective treatment of cachexia is missing. We seek to characterize mechanisms of cachexia in adipose tissue, which could serve as novel targets for the treatment. Methods: The study was conducted in advanced HF patients (n&nbsp;=&nbsp;52; 83% male patients) undergoing heart transplantation. Patients with ≥7.5% non-intentional body weight (BW) loss during the last 6&nbsp;months were rated cachectic. Clinical characteristics and circulating markers were compared between cachectic (n&nbsp;=&nbsp;17) and the remaining, BW-stable patients. In epicardial adipose tissue (EAT), expression of selected genes was evaluated, and a combined metabolomic/lipidomic analysis was performed to assess (i) the role of adipose tissue metabolism in the development of cachexia and (ii) potential impact of cachexia-associated changes on EAT-myocardium environment. Results: Cachectic vs. BW-stable patients had higher plasma levels of natriuretic peptide B (BNP; 2007&nbsp;±&nbsp;1229 vs. 1411&nbsp;±&nbsp;1272&nbsp;pg/mL; P&nbsp;=&nbsp;0.010) and lower EAT thickness (2.1&nbsp;±&nbsp;0.8 vs. 2.9&nbsp;±&nbsp;1.4&nbsp;mm; P&nbsp;=&nbsp;0.010), and they were treated with ~2.5-fold lower dose of both β-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACE/ARB-inhibitors). The overall pattern of EAT gene expression suggested simultaneous activation of lipolysis and lipogenesis in cachexia. Lower ratio between expression levels of natriuretic peptide receptors C and A was observed in cachectic vs. BW-stable patients (0.47 vs. 1.30), supporting activation of EAT lipolysis by natriuretic peptides. Fundamental differences in metabolome/lipidome between BW-stable and cachectic patients were found. Mitochondrial phospholipid cardiolipin (CL), specifically the least abundant CL 70:6 species (containing C16:1, C18:1, and C18:2 acyls), was the most discriminating analyte (partial least squares discriminant analysis; variable importance in projection score&nbsp;=&nbsp;4). Its EAT levels were higher in cachectic as compared with BW-stable patients and correlated with the degree of BW loss during the last 6&nbsp;months (r&nbsp;=&nbsp;−0.94; P&nbsp;=&nbsp;0.036). Conclusions: Our results suggest that (i) BNP signalling contributes to changes in EAT metabolism in cardiac cachexia and (ii) maintenance of stable BW and ‘healthy’ EAT-myocardium microenvironment depends on the ability to tolerate higher doses of both ACE/ARB inhibitors and β-adrenergic blockers. In line with preclinical studies, we show for the first time in humans the association of cachexia with increased adipose tissue levels of CL. Specifically, CL 70:6 could precipitate wasting of adipose tissue, and thus, it could represent a therapeutic target to ameliorate cachexia

Pregnancy and Fetal Outcomes After Exposure to Mefloquine in the Pre- and Periconception Period and During Pregnancy

Pregnant women who travel to malarious areas and their clinicians need data on the safety of malaria chemoprophylaxis. The drug safety database analysis of mefloquine exposure in pregnancy showed that the birth defect prevalence and fetal loss in maternal, prospectively-monitored cases were comparable to background rates

Cardiac miRNA expression during the development of chronic anthracycline-induced cardiomyopathy using an experimental rabbit model

Background: Anthracycline cardiotoxicity is a well-known complication of cancer treatment, and miRNAs have emerged as a key driver in the pathogenesis of cardiovascular diseases. This study aimed to investigate the expression of miRNAs in the myocardium in early and late stages of chronic anthracycline induced cardiotoxicity to determine whether this expression is associated with the severity of cardiac damage.Method: Cardiotoxicity was induced in rabbits via daunorubicin administration (daunorubicin, 3 mg/kg/week; for five and 10 weeks), while the control group received saline solution. Myocardial miRNA expression was first screened using TaqMan Advanced miRNA microfluidic card assays, after which 32 miRNAs were selected for targeted analysis using qRT-PCR.Results: The first subclinical signs of cardiotoxicity (significant increase in plasma cardiac troponin T) were observed after 5 weeks of daunorubicin treatment. At this time point, 10 miRNAs (including members of the miRNA-34 and 21 families) showed significant upregulation relative to the control group, with the most intense change observed for miRNA-1298-5p (29-fold change, p &lt; 0.01). After 10 weeks of daunorubicin treatment, when a further rise in cTnT was accompanied by significant left ventricle systolic dysfunction, only miR-504-5p was significantly (p &lt; 0.01) downregulated, whereas 10 miRNAs were significantly upregulated relative to the control group; at this time-point, the most intense change was observed for miR-34a-5p (76-fold change). Strong correlations were found between the expression of multiple miRNAs (including miR-34 and mir-21 family and miR-1298-5p) and quantitative indices of toxic damage in both the early and late phases of cardiotoxicity development. Furthermore, plasma levels of miR-34a-5p were strongly correlated with the myocardial expression of this miRNA.Conclusion: To the best of our knowledge, this is the first study that describes alterations in miRNA expression in the myocardium during the transition from subclinical, ANT-induced cardiotoxicity to an overt cardiotoxic phenotype; we also revealed how these changes in miRNA expression are strongly correlated with quantitative markers of cardiotoxicity