Multi-targets of antimicrobial photodynamic therapy mediated by erythrosine against Staphylococcus aureus identified by proteomic approach.

Staphylococcus aureus is a global challenge to the clinical field and food industry. Therefore, the development of antimicrobial photodynamic therapy (aPDT) has become one of the valuable methods to control this pathogen. The antibacterial activity of photoinactivation by erythrosine (Ery) against S. aureus has been reported, but its modes of action are unclear. This study aimed to employ a proteomic approach to analyze modes of action of Ery-aPDT against S. aureus. We determined the antibacterial effect by Ery-aPDT assays, quantified reactive oxygen species (ROS) and injury to the cell membrane, and determined protein expression using a proteomic approach combined with bioinformatic tools. Ery-aPDT was effective in reducing S. aureus to undetectable levels. In addition, the increment of ROS accompanied the increase in the reduction of cell viability, and damage to cellular membranes was shown by sublethal injury. In proteomic analysis, we found 17 differentially expressed proteins. These proteins revealed changes mainly associated with defense to oxidative stress, energy metabolism, translation, and protein biosynthesis. Thus, these results suggest that the effectiveness of Ery-aPDT is due to multi-targets in the bacterial cell that cause the death of S. aureus.

Antimicrobial activity of carvacrol and its derivatives on Mycobacterium spp.: systematic review of preclinical studies.

Background: The scope of the study was to analyze original preclinical studies on the antimicrobial effects of carvacrol and derivatives on the Mycobacterium genus. Materials & methods: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, four databases (PubMed, Web of Science, SCOPUS and EMBASE) were searched. Results: The search retrieved 392 records, of which 11 papers were selected. Heterogeneity in the techniques and mycobacterial targets was observed. Carvacrol demonstrated synergistic antimycobacterial activity with rifampicin against multidrug-resistant Mycobacterium tuberculosis on membranes and biofilms. In silico approaches showed specific targets in mycobacteria, by inhibition and molecular docking assays, on the enzyme chorismate mutase and the heat shock protein 16.3. Conclusion: Carvacrol has been shown to be a scaffold candidate for future molecules with activity against mycobacteria.

"Antibacterial effect and possible mechanism of action of 1,3,4-oxadiazole in Staphylococcus aureus".

Staphylococcus aureus is one of the main etiological agents causing foodborne diseases, and the development of new antibacterial agents is urgent. This study evaluated the antibacterial activity and the possible mechanism of action of the 1,3,4-oxadiazole LMM6 against S. aureus. The minimum inhibitory concentration (MIC) of LMM6 ranged from 1.95 to 7.81 µg ml-1. The time-kill assay showed that 48-h treatment at 1× to 8× MIC reduced S. aureus by 4 log colony forming unit (CFU), indicating a bacteriostatic effect. Regarding the possible mechanism of action of LMM6, there was accumulation of reactive oxygen species (ROS) and an increase in the absorption of crystal violet (∼50%) by the cells treated with LMM6 at 1× and 2× MIC for 6-12 h. In addition, there was increased propidium iodide uptake (∼84%) after exposure to LMM6 for 12 h at 2× MIC. After 48 h of treatment, 100% of bacteria had been injured. Scanning electron microscopy observations demonstrated that LMM6-treated cells were smaller compared with the untreated group. LMM6 exhibited bacteriostatic activity and its mechanism of action involves increase of intracellular ROS and disturbance of the cell membrane, which can be considered a key target for controlling the growth of S. aureus.

Empathy and Psychopathy Traits in University Students in Belgium: a Network Approach.

Empathy is the complex prosocial cognitive capacity to recognize and react to the emotions of others. An empathic attitude from medical doctors is essential to build a good relationship with patients. In engineering education there is an hypervalorization of technical skills in disadvantage of these affective elements. Psychopathy is the lack of considerations toward others. These two important personality traits shape social interactions. In this study we analyzed, through the network theory, these characteristics in a young population of medical and engineering university students in Belgium. The aim of this study was therefore to estimate the individual network structure of these traits in both groups, as well as estimate whether there is a fundamental difference in the way that these traits connect in these two populations. Medical and engineering students completed online three self-report questionnaires about empathy and psychopathy traits. There were 178 responders without exclusions due outliers. No significant differences were found in psychopathic traits between the two groups. There was a statistically significant difference in empathic concerns, the medical students being more empathic than their peers in engineering. Psychopathic traits did not vary significantly between the two groups. This study provided insights into the differences in empathic and psychopathic traits among those students. Future research should explore the factors that contribute to these differences and investigate the potential impact of targeted interventions or curricular modifications in cultivating empathy and minimizing antisocial behaviors in both fields.

Comportamento da população em relação aos cuidados com os alimentos durante a pandemia da COVID-19 / Population behavior in relation to food care during the COVID-19 pandemic

Este estudo analisou o conhecimento e comportamento em relação aos cuidados e higiene alimentar antes e durante a pandemia da COVID-19 no Brasil. Os participantes foram recrutados pelas redes sociais para responder um questionário sobre aspectos sociodemográficos, conhecimento sobre coronavírus, isolamento social e recebimento de informações sobre higienização de alimentos e suas embalagens. Participaram da pesquisa 1.061 indivíduos, sendo a maioria do sexo feminino (87%), com até 35 anos (69,9%); 82,8% tinham ou estavam a concluir o ensino superior; e a renda mensal de 63,2% era de até 6 salários mínimos. Sobre a higiene de frutas e hortaliças, 56,59% dos participantes passaram a usar água e sabão durante a pandemia. Quanto a limpeza das embalagens dos alimentos recebidos por delivery, 71,85% dos participantes passaram a limpar as embalagens durante a pandemia. De forma geral, pode-se observar modificações significativas nos cuidados com os alimentos durante a pandemia da COVID-19.

This study during knowledge and behavior in food care and hygiene before and that of COVID-19 in Brazil. Participants were recruited through social networks for respondents on the sociodemographic aspects of the population's knowledge about coronavirus, social isolation and receiving information on hygiene of food and its packaging. A total of 1,061 participated in the survey, the majority being female (87%), aged up to 35 years (69.9%); 8.8% had or 2.8% had higher education; and 63.6% monthly income was up to 6% monthly. Regarding the hygiene of fruits and vegetables, 56.59% of the participants chose soap and water during the. As for cleaning packages received by delivery, 71% of patients choose to clean packages during the pandemic. In general, the pandemic can be considered in the care with food of COVID-19.

Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic ß cells.

Male mice lacking the androgen receptor (AR) in pancreatic ß cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in ß cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male ß cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of CO2, activating the HCO3--sensitive soluble adenylate cyclase; and (2) increased Gαs recruitment to GLP-1 receptor and AR complexes, activating transmembrane adenylate cyclase. Additionally, testosterone enhances GSIS in human islets via a focal adhesion kinase/SRC/phosphatidylinositol 3-kinase/mammalian target of rapamycin complex 2 actin remodeling cascade. We describe the testosterone-stimulated AR interactome, transcriptome, proteome, and metabolome that contribute to these effects. This study identifies AR genomic and non-genomic actions that enhance GLP-1-stimulated insulin exocytosis in male ß cells.

Synergistic inhibition of Salmonella Typhimurium and Staphylococcus aureus in apple jam by cinnamaldehyde and potassium sorbate.

The objective of this study was to evaluate the antimicrobial effectiveness of cinnamaldehyde (CIN) and potassium sorbate (P.S.), alone and in combination, against Salmonella Typhimurium and Staphylococcus aureus in vitro and in apple jam. Antimicrobial activity in vitro was investigated by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), time-kill assay and determination of fractional inhibitory concentration index. CIN MIC and MBC was 312 µg/mL. P.S. MIC and MBC were 2500 and 5000 µg/mL, respectively, against S. Typhimurium; and 10,000 and 20,000 µg/mL, respectively, against S. aureus. The compounds combined exhibited a synergistic effect (FIC < 0.5), inhibiting S. Typhimurium growth after 12 h and S. aureus after 24 h. The effect of CIN and P.S., at sub-inhibitory concentrations, against bacterial strains in apple jam was evaluated during storage. Physicochemical and sensory analyses were also performed. No cultivable S. Typhimurium or S. aureus cells were recovered in apple jam supplemented with CIN + P.S. on the third day of storage. The addition of CIN and P.S. did not affect the physicochemical properties and sensory evaluation showed a score above 7.0. CIN and P.S. association at sub-inhibitory concentrations was effective in controlling foodborne pathogens and improved the shelf life of apple jam.

Proteomic Investigation over the Antimicrobial Photodynamic Therapy Mediated by Rose Bengal Against Staphylococcus aureus.

In order, understanding the antimicrobial action of photodynamic therapy and how this technique can contribute to its application in the control of pathogens. The objective of the study was to employ a proteomic approach to investigate the protein profile of Staphylococcus aureus after antimicrobial photodynamic therapy mediated by rose bengal (RB-aPDT). S. aureus was treated with RB (10 nmoL L-1 ) and illuminated with green LED (0.17 J cm-2 ) for cell viability evaluation. Afterward, proteomic analysis was employed for protein identification and bioinformatic tools to classify the differentially expressed proteins. The reduction in S. aureus after photoinactivation was ~2.5 log CFU mL-1 . A total of 12 proteins (four up-regulated and eight down-regulated) correspond exclusively to alteration by RB-aPDT. Functionally, these proteins are distributed in protein binding, structural constituent of ribosome, proton transmembrane transporter activity and ATPase activity. The effects of photodamage include alterations of levels of several proteins resulting in an activated stress response, altered membrane potential and effects on energy metabolism. These 12 proteins required the presence of both light and RB suggesting a unique response to photodynamic effects. The information about this technique contributes valuable insights into bacterial mechanisms and the mode of action of photodynamic therapy.

Aspectos psicológicos e jurídicos envolvidos na alienação parental: uma revisão sistemática / Psychological and legal aspects involved in parental alienation: a systematic review

A Alienação Parental (AP) trata-se de uma conduta de um dos genitores para difamar o outro perante os filhos, podendo levá-los ao distanciamento do genitor alienado. O objetivo deste estudo é analisar os aspectos psicojurídicos envolvidos no processo de AP, a partir de estudos brasileiros publicados entre 2015 e 2020. Foi feita uma revisão sistemática da literatura, por meio de método descritivo e qualitativo, através da qual foi possível destacar duas categorias de análise: 1. Caracterização da Alienação Parental e 2. Intervenções Psicojurídicas em casos de Alienação Parental. Tais categorias foram destrinchadas entre aspectos psicológicos e jurídicos e nessas mesmas abordagens, respectivamente. Observou-se uma tendência do ponto de vista psicológico de patologização da Alienação Parental e, do ponto de vista jurídico, percebeu-se que, apesar da existência da lei, ela não é suficiente para lidar com os aspectos psicológicos dos envolvidos, buscando-se assim, técnicas alternativas para a resolução dos conflitos, tais quais a mediação e a conciliação.

Parental Alienation (PA) is a type of conduct by one of the genitors to defame the other before their children, potentially making them distance themselves from the alienated parent. The purpose of this study is to analyze the psycho-legal aspects throughout in the PA process, based on Brazilian studies published between 2015 and 2020. We used the systematic review through the description and qualitative method which it was created two categories of analysis: 1. Characterization of Parental Alienation and 2. Psycho-legal interventions in cases of Parental Alienation. Such categories were separated between psychological and legal aspects; and in these same approaches, respectively. Across the selected studies, a tendency was found in regards to pathologization of parental alienation and besides of the existence of the Law, it was found that that the legal terms of Parental Alienation is not sufficient to solve the psychological problems of those involved, which are applied to seek solving conflicts, such as mediation and conciliation.

Hematological and biochemical values in Breton breed horses in Brasília-DF.

Due to the scarcity of information on Breton horses, the objective was to study hematobiochemical values of this breed. Blood samples were collected from 29 Bretons, males and females, of different ages, in Brasília-DF, distributed into groups, according to age, without distinction of sex (G1): animals from 4 to 9 years old (n=16) and (G2): from 10 to 26 years old (n=13). The horses were also distributed into males and females for comparisons between the sexes. Values for red blood cells, hemoglobin, creatinine, and urea were statistically higher in females. Fibrinogen was higher in males. Lymphocyte values were higher in G1, but mean corpuscular volume, monocytes, neutrophils, and GGT in G2 were higher than G1. The hematocrit value differed between the ages of the females and was higher than that of the males, while the older male animals showed higher values than the young animals. Females presented lower platelet values than males, with older females having higher platelet values than younger females, in the same way as males. G1 females had the highest leukocyte values. The leukocyte values in males of G2 were higher than those of G1. This same behavior occurred for lymphocytes, eosinophils, and creatine kinase. Considering the albumin and aspartate aminotransferase variables, females had the highest values in the group of animals aged 4 to 9 years. Bretons are considered cold-blooded animals, which is consistent with the observed blood count values. However, it is concluded that these horses have biochemical values similar to warm-blooded breeds.

Devido à escassez de informações sobre equinos da raça Bretão, objetivou-se estudar valores hematobioquímicos da raça. Foram coletadas amostras de sangue de 29 Bretões, machos e fêmeas de diferentes idades, em Brasília-DF, distribuídos entre grupos, segundo idade, sem distinção de sexo (G1): animais de 4 a 9 anos (n=16) e (G2): de 10 a 26 anos (n=13). Os mesmos também foram distribuídos em machos e fêmeas para comparação entre os sexos. Valores para hemácia, hemoglobina, creatinina e ureia foram estatisticamente maiores nas fêmeas. Fibrinogênio foi maior nos machos. Valores de linfócitos do G1 foram maiores, mas o volume corpuscular médio, monócitos, neutrófilos e GGT do G1 foram menores que do G2. Valor do hematócrito difere entre idades das fêmeas e foi superior ao dos machos, os animais machos mais velhos apresentaram valores superiores aos jovens. As fêmeas apresentaram valores de plaquetas menores que os machos, sendo que as mais velhas apresentaram valores de plaqueta maiores que as mais jovens, da mesma forma que os machos. No G1, as fêmeas apresentaram os maiores valores de leucócitos. Os valores de leucócitos nos machos do G2 foram maiores que os do G1. Esse mesmo comportamento ocorreu para linfócitos, eosinófilos e creatinaquinase. Já para as variáveis albumina e aspartato aminotransferase, no grupo de animais de 4 a 9 anos, as fêmeas tiveram os maiores valores. Bretões são animais de sangue frio, o que condiz com os valores do hemograma observados. Porém, conclui-se que estes equinos apresentam valores bioquímicos similares aos de sangue quente.

Synergistic activity of Stryphnodendron adstringens and potassium sorbate against foodborne bacteria.

Stryphnodendron adstringens is a medicinal plant that has a broad spectrum of action, including antibacterial activity. The aim of the present study was to evaluate the effect of S. adstringens alone and in combination with potassium sorbate (PS) against foodborne bacteria. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined and, for most of the bacteria tested, the crude extract (CE), aqueous fraction (AQF), and ethyl-acetate fraction (EAF) of S. adstringens had a MIC and MBC ranging from 500 to ≥ 1000 µg/mL. The AQF and EAF showed greater activity against S. aureus strains (MIC = 125 to 250 µg/mL; MBC = 500 to 1000 µg/m). Quantitative cell viability was determined and was observed reductions ranging from 3.0 to 5.8 log10 CFU/ml.The combination of S. adstringens and PS against seven S. aureus isolates was determined by the checkerboard method at neutral and acid pH. In a neutral medium, the AQF + PS combination presented synergistic or additive interactions against six S. aureus strains. The combination of EAF + PS resulted in additive interactions against four bacterial isolates. In an acidic medium, the AQF + PS combination was synergistic or additive against all S. aureus, while EAF + PS presented the same effect against six S. aureus strains S. adstringens showed important antibacterial effects against foodborne S. aureus strains. Moreover, the combination of S. adstringens fractions and PS improved the antibacterial activity compared to the compounds utilized individually. The combined use of these compounds may be an alternative to reduce bacterial food contamination and improve food safety.

Efficacy of glucagon-like peptide-1 and estrogen dual agonist in pancreatic islets protection and pre-clinical models of insulin-deficient diabetes.

We study the efficacy of a glucagon-like peptide-1 (GLP-1) and estrogen dual agonist (GLP1-E2) in pancreatic islet protection. GLP1-E2 provides superior protection from insulin-deficient diabetes induced by multiple low-dose streptozotocin (MLD-STZ-diabetes) and by the Akita mutation in mice than a GLP-1 monoagonist. GLP1-E2 does not protect from MLD-STZ-diabetes in estrogen receptor-α (ERα)-deficient mice and fails to prevent diabetes in Akita mice following GLP-1 receptor (GLP-1R) antagonism, demonstrating the requirement of GLP-1R and ERα for GLP1-E2 antidiabetic actions. In the MIN6 ß cell model, GLP1-E2 activates estrogen action following clathrin-dependent, GLP-1R-mediated internalization and lysosomal acidification. In cultured human islet, proteomic bioinformatic analysis reveals that GLP1-E2 amplifies the antiapoptotic pathways activated by monoagonists. However, in cultured mouse islets, GLP1-E2 provides antiapoptotic protection similar to monoagonists. Thus, GLP1-E2 promotes GLP-1 and E2 antiapoptotic signals in cultured islets, but in vivo, additional GLP1-E2 actions in non-islet cells expressing GLP-1R are instrumental to prevent diabetes.

Systematic review of disulfiram as an antibacterial agent: what is the evidence?

The objective of this systematic review was to retrieve and examine published studies related to in vitro and in vivo evaluation of disulfiram for the treatment of bacterial infections. Five scientific databases (PubMed, Embase, Scopus, Web of Science, and Latin American and Caribbean Health Sciences Literature) were searched to retrieve the maximum literature regarding the study's aim. The search strategy retrieved a total of 870 studies, of which 31 were included and 19 approached disulfiram as the primary aim and 12 included it as a secondary finding from other investigational objectives. The evidence pointed out five main aspects of pre-clinical testing regarding disulfiram antibacterial activity, namely spectrum of antimicrobial action, drug combinations, intracellular studies, animal studies and bacterial targets. Findings to emerge from this study are the observed potential of disulfiram as a non-antibiotic drug being proposed as a potential drug to contribute to the treatment of bacterial diseases usually with few treatment alternatives in the context of drug resistance. We evaluated the potency and selectivity of disulfiram, which indeed until now shows potential to be explored for use as an adjunctive chemical to antimicrobial ones. Even with the level of evidence being reserved, the potential of combining disulfiram with other drugs, already used or new to be used for the treatment of mycobacterial diseases, as well as its likely immunomodulatory effect, deserve to be further investigated. Furthermore, the copper-dependent mode of action in Gram-positive bacteria is an alternative to be explored in drug design or repurposing of chemicals.

Automatic and renewable micro-solid-phase extraction based on bead injection lab-on-valve system for determination of tranexamic acid in urine by UHPLC coupled with tandem mass spectrometry.

An automatic micro-solid-phase extraction (µSPE) method using on-line renewable sorbent beads followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was established for the determination of tranexamic acid (TXA) in urine. The µSPE method was based on the bead injection (BI) concept combined with the mesofluidic lab-on-valve (LOV) platform. All steps of the µSPE-BI-LOV were implemented by computer programming, rendering enhanced precision on time and flow events. Several parameters, including the type of sorbent, volume and composition of the conditioning solution, washing solution, and eluent composition, were evaluated to improve the extraction efficiency. The best results were obtained with a hydrophilic-lipophilic balanced mixed-mode sorbent, decorated with sulfonic acid groups (Oasis MCX), and 99% acetonitrile-water (50:50, v/v)-1% ammonium hydroxide as eluent. Chromatographic separation was performed using a BEH amide column coupled to MS/MS detection in positive ionization mode. Good linearity was achieved (R2 > 0.998) for TXA concentrations in urine ranging from 300 to 3000 ng mL-1, with LOD and LOQ of 30 and 65 ng mL-1, respectively. Dilution integrity was observed for dilution factors up to 20,000 times, providing the extension of the upper limit of quantification to 12 mg mL-1. The method was validated according to international guidelines and successfully applied to urine samples collected during scoliosis surgery of pediatric patients treated with TXA.

The ancient Tuberculosis in the novel COVID-19 scenario

Abstract Recently, the world has coped with the challenge of the novel SARS-CoV-2 rapid spreading, causing COVID-19. This scenario has overburdened health systems, forced social isolation, and interrupted some services, changing the way how health assistance is provided. The management of chronic infectious diseases such as tuberculosis is a sensitive matter in times when the control strategies are at risk. In this sense, how could a high burden disease such as tuberculosis affect or be affected when combined with the COVID-19 pandemic? Patients with tuberculosis have a social background and lung impairment that represent risks in the pandemic scenario of another widely transmitted respiratory disease. Thus, even with several questions remaining unanswered, research and public policies should be addressed to control the effects of the current highly contagious COVID-19 without forgetting how it will affect the natural progression of patients suffering from tuberculosis.

Acetonitrile Adducts of Tranexamic Acid as Sensitive Ions for Quantification at Residue Levels in Human Plasma by UHPLC-MS/MS.

The quantitative analysis of pharmaceuticals in biomatrices by liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) is often hampered by adduct formation. The use of the molecular ion resulting from solvent adducts for quantification is uncommon, even if formed in high abundance. In this work, we propose the use of a protonated acetonitrile adduct for the quantitative analysis of tranexamic acid (TXA) by LC-MS/MS. The high abundance of the protonated acetonitrile adduct [M + ACN + H]+ was found to be independent of source-dependent parameters and mobile phase composition. The results obtained for TXA analysis in clinical samples were comparable for both [M + ACN + H]+ and [M + H]+, and no statistically significant differences were observed. The relative stability and structure of the [M + ACN + H]+ ions were also studied by analyzing probable structures from an energetic point of view and by quantum chemical calculations. These findings, and the studied fragmentation pathways, allowed the definition of an acetimidium structure as the best ion to describe the observed acetonitrile protonated adduct of TXA.

PanB over-representation as part of pyrazinamide action: a proteomic insight.

Background: Pyrazinamide (PZA) represents a milestone as a first-line antituberculosis drug due to its sterilizing activity against Mycobacterium tuberculosis. Materials & Methods: The protein changes induced by subinhibitory PZA exposure of M. tuberculosis in acidic pH were evaluated by a proteomic approach. Results: Among the 1059 M. tuberculosis proteins identified, the specific acidification in the culture medium induced the over-representation of MurF (Rv2157c), and its under-representation was induced by 12 h of PZA exposure. PanB (Rv2225) was over-represented at 24 h of PZA exposure. Conclusion: The authors highlight the over-representation of PanB in M. tuberculosis correlates of PZA action in acidic pH, reinforcing the role of the pantothenate pathway as a bacillus drug target to be explored.

MEFAS, a hybrid of artesunate-mefloquine active against asexual stages of Plasmodium vivax in field isolates, inhibits malaria transmission.

Human malaria continues to be a public health problem and an important cause of morbidity and mortality in the world. Malaria control is achieved through both individual protection against mosquito bites and drug treatment, which is hampered by the spread of Plasmodium falciparum resistance to most antimalarials, including artemisinin derivatives. One of the key pharmacological strategies for controlling malaria is to block transmission of the parasites to their mosquito vectors. Following this rational, MEFAS, a synthetic hybrid salt derived from artesunate (AS) and mefloquine has been previously reported for its activity against asexual P. falciparum parasites in vitro, in addition to a pronounced reduction in the viability of mature gametocytes. Herein, MEFAS was tested against asexual forms of Plasmodium vivax and for its ability to block malaria transmission in Anopheles darlingi mosquitoes in a membrane feeding assay using P. vivax field isolates. MEFAS demonstrated high potency, with a IC50 of 6.5 nM against asexual forms of P. vivax. At 50 µM, MEFAS completely blocked oocyst formation in mosquitoes, regardless of the oocyst number in the control group. At lower doses, MEFAS reduced oocyst prevalence by greater than 20%. At equivalent doses, AS irregularly reduced oocyst formation and caused only slight inhibition of mosquito infections. These results highlight the potential of MEFAS as a novel transmission-blocking molecule, as well as its high blood schizonticidal activity against P. vivax and P. falciparum field isolates, representing a starting point for further development of a new drug with dual antimalarial activity.

Functional Testing for Tranexamic Acid Duration of Action Using Modified Viscoelastometry.

INTRODUCTION: Tranexamic acid (TXA) is the standard medication to prevent or treat hyperfibrinolysis. However, prolonged inhibition of lysis (so-called "fibrinolytic shutdown") correlates with increased mortality. A new viscoelastometric test enables bedside quantification of the antifibrinolytic activity of TXA using tissue plasminogen activator (TPA). MATERIALS AND METHODS: Twenty-five cardiac surgery patients were included in this prospective observational study. In vivo, the viscoelastometric TPA test was used to determine lysis time (LT) and maximum lysis (ML) over 96 h after TXA bolus. Additionally, plasma concentrations of TXA and plasminogen activator inhibitor 1 (PAI-1) were measured. Moreover, dose effect curves from the blood of healthy volunteers were performed in vitro. Data are presented as median (25-75th percentile). RESULTS: In vivo TXA plasma concentration correlated with LT (r = 0.55; p < 0.0001) and ML (r = 0.62; p < 0.0001) at all time points. Lysis was inhibited up to 96 h (LTTPA-test: baseline: 398 s [229-421 s] vs. at 96 h: 886 s [626-2,175 s]; p = 0.0013). After 24 h, some patients (n = 8) had normalized lysis, but others (n = 17) had strong lysis inhibition (ML <30%; p < 0.001). The high- and low-lysis groups differed regarding kidney function (cystatin C: 1.64 [1.42-2.02] vs. 1.28 [1.01-1.52] mg/L; p = 0.002) in a post hoc analysis. Of note, TXA plasma concentration after 24 h was significantly higher in patients with impaired renal function (9.70 [2.89-13.45] vs.1.41 [1.30-2.34] µg/mL; p < 0.0001). In vitro, TXA concentrations of 10 µg/mL effectively inhibited fibrinolysis in all blood samples. CONCLUSIONS: Determination of antifibrinolytic activity using the TPA test is feasible, and individual fibrinolytic capacity, e.g., in critically ill patients, can potentially be measured. This is of interest since TXA-induced lysis inhibition varies depending on kidney function.

Activity of (-)-Camphene Derivatives Against Mycobacterium tuberculosis in Acidic pH.

BACKGROUND: For more than 60 years, the lack of new anti-tuberculosis drugs and the increase of resistant Mycobacterium tuberculosis lineages exhibit a therapeutic challenge, demanding new options for the treatment of resistant tuberculosis. OBJECTIVE: Herein, we determined the (i) activities of (-)-camphene and its derivatives and (ii) combinatory effect with pyrazinamide (PZA) against Mycobacterium tuberculosis in acidic pH and (iii) cytotoxicity on VERO cells. METHODS: The activity of (-)-camphene and its 15 derivatives was determined in M. tuberculosis H37Rv in culture medium at pH 6.0 by Resazurin Microtiter Assay Plate (REMA). The activity and combinatory study of three (-)-camphene derivatives with PZA was carried out on seven multidrugresistant (MDR) clinical isolates by REMA and Checkerboard, respectively. The assay of 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide in VERO cells was used to determine the derivatives' cytotoxicity. RESULTS: Four (-)-camphene derivatives, (4), (5a) (5d) and (5h), showed a reduction in the MIC value at pH 6.0 compared to the MIC detected at pH 6.8 in M. tuberculosis H37Rv and multidrug resistant clinical isolates. Three (-)-camphene derivatives, (4), (5d) and (5h), showed synergistic effect (FICI ≤ 0.5) combined with PZA and were more selective for M. tuberculosis than VERO cell (selective index from 7.7 to 84.2). CONCLUSION: Three (-)-camphene derivatives have shown to be promising anti-TB molecule scaffolds due to their low MIC values in acidic pH against MDR M. tuberculosis clinical isolates, synergism with PZA and low cytotoxicity.