Summary Background In November, 2015, an epidemic of microcephaly was reported in Brazil, which was later attributed to congenital Zika virus infection. 7830 suspected cases had been reported to the ...Brazilian Ministry of Health by June 4, 2016, but little is known about their characteristics. We aimed to describe these newborn babies in terms of clinical findings, anthropometry, and survival. Methods We reviewed all 1501 liveborn infants for whom investigation by medical teams at State level had been completed as of Feb 27, 2016, and classified suspected cases into five categories based on neuroimaging and laboratory results for Zika virus and other relevant infections. Definite cases had laboratory evidence of Zika virus infection; highly probable cases presented specific neuroimaging findings, and negative laboratory results for other congenital infections; moderately probable cases had specific imaging findings but other infections could not be ruled out; somewhat probable cases had imaging findings, but these were not reported in detail by the local teams; all other newborn babies were classified as discarded cases. Head circumference by gestational age was assessed with InterGrowth standards. First week mortality and history of rash were provided by the State medical teams. Findings Between Nov 19, 2015, and Feb 27, 2015, investigations were completed for 1501 suspected cases reported to the Brazilian Ministry of Health, of whom 899 were discarded. Of the remainder 602 cases, 76 were definite, 54 highly probable, 181 moderately probable, and 291 somewhat probable of congenital Zika virus syndrome. Clinical, anthropometric, and survival differences were small among the four groups. Compared with these four groups, the 899 discarded cases had larger head circumferences (mean Z scores −1·54 vs −3·13, difference 1·58 95% CI 1·45–1·72); lower first-week mortality (14 per 1000 vs 51 per 1000; rate ratio 0·28 95% CI 0·14–0·56); and were less likely to have a history of rash during pregnancy (20·7% vs 61·4%, ratio 0·34 95% CI 0·27–0·42). Rashes in the third trimester of pregnancy were associated with brain abnormalities despite normal sized heads. One in five definite or probable cases presented head circumferences in the normal range (above −2 SD below the median of the InterGrowth standard) and for one third of definite and probable cases there was no history of a rash during pregnancy. The peak of the epidemic occurred in late November, 2015. Interpretation Zika virus congenital syndrome is a new teratogenic disease. Because many definite or probable cases present normal head circumference values and their mothers do not report having a rash, screening criteria must be revised in order to detect all affected newborn babies. Funding Brazilian Ministry of Health, Pan American Health Organization, and Wellcome Trust.
Piperazine compounds as drugs of abuse Arbo, M.D; Bastos, M.L; Carmo, H.F
Drug and alcohol dependence,
05/2012, Letnik:
122, Številka:
3
Journal Article
Recenzirano
Abstract Synthetic drugs are among the most commonly abused drugs in the world. This abuse is widespread among young people, especially in the dance club and rave scenes. Over the last several years, ...piperazine derived drugs have appeared, mainly available via the internet, and sold as ecstasy pills or under the names of“ Frenzy”,“ Bliss”,“ Charge”,“ Herbal ecstasy”,“ A2”,“ Legal X” and“ Legal E”. Although in the market piperazine designer drugs have the reputation of being safe, several experimental and epidemiological studies indicate risks for humans. Piperazine designer drugs can be divided into two classes, the benzylpiperazines such as N-benzylpiperazine (BZP) and its methylenedioxy analogue 1-(3,4-methylenedioxybenzyl)piperazine (MDBP), and the phenylpiperazines such as 1-(3-chlorophenyl)piperazine (mCPP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), and 1-(4-methoxyphenyl)piperazine (MeOPP). Toxicokinetic properties, including metabolic pathways, actions and effects in animals and humans, with some hypothesis of mechanism of action, and analytical approaches for the identification of these drugs are summarized in this review.
Vanillin is the main component of natural vanilla extract and is responsible for its flavoring properties. Besides its well‐known applications as an additive in food and cosmetics, it has also been ...reported that vanillin can inhibit fungi of clinical interest, such as Candida spp., Cryptococcus spp., Aspergillus spp., as well as dermatophytes. Thus, the present work approaches the synthesis of a series of vanillin derivatives with 1,2,3‐triazole fragments and the evaluation of their antifungal activities against Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Cryptococcus gattii, Trichophyton rubrum, and Trichophyton interdigitale strains. Twenty‐two vanillin derivatives were obtained, with yields in the range of 60%–91%, from copper(I)‐catalyzed alkyne‐azide cycloaddition (CuAAC) click reaction between two terminal alkynes prepared from vanillin and different benzyl azides. In general, the evaluated compounds showed moderate activity against the microorganisms tested, with minimum inhibitory concentration (MIC) values ranging from 32 to >512 µg mL−1. Except for compound 3b against the C. gattii R265 strain, all vanillin derivatives showed fungicidal activity for the yeasts tested. The predicted physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties for the compounds indicated favorable profiles for drug development. In addition, a four‐dimensional structure‐activity relationship (4D‐SAR) analysis was carried out and provided useful insights concerning the structures of the compounds and their biological profile. Finally, molecular docking calculations showed that all compounds bind favorably at the lanosterol 14α‐demethylase enzyme active site with binding energies ranging from –9.1 to –12.2 kcal/mol.
Twenty‐two vanillin derivatives with 1,2,3‐triazole fragments were synthesized and evaluated for their activities against a number of fungal strains. The evaluated compounds showed moderate activity against the microorganisms tested, with minimum inhibitory concentration (MIC) values ranging from 32 to >512 µg mL−1. All compounds bind favorably at the lanosterol 14α‐demethylase enzyme active site.
Waterborne toxoplasmosis, Brazil, from field to gene de Moura, Lenildo; Bahia-Oliveira, Lilian Marcia Garcia; Wada, Marcelo Y ...
Emerging infectious diseases,
02/2006, Letnik:
12, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Water was the suspected vehicle of Toxoplasma gondii dissemination in a toxoplasmosis outbreak in Brazil. A case-control study and geographic mapping of cases were performed. T. gondii was isolated ...directly from the implicated water and genotyped as SAG 2 type I.
Candida albicans is the chief etiological agent of candidiasis, a mycosis prevalent in individuals with acquired immunodeficiency syndrome (AIDS). In recent years, the introduction of human ...immunodeficiency virus (HIV) protease inhibitors (HIV-PI) has reduced the prevalence of candidiasis in these patients. Seeking new therapeutic strategies based on the perspective of drug repositioning, we evaluated the effects of two second-generation HIV-PIs, atazanavir (ATV) and darunavir (DRV), on virulence factors of C. albicans and experimental candidiasis. For this, clinical strains of C. albicans were subjected to in vitro and in vivo treatments with ATV or DRV. As a result, ATV and DRV exhibited antifungal activity against fungal cells at 512 μg/mL, reduced the viability and biomass of biofilms, and inhibited filamentation of C. albicans. In addition, these HIV-PIs downregulated the expression of SAP2 and BRC1 genes of C. albicans. In an in vivo study, prophylactic use of ATV and DRV prolonged the survival rate of Galleria mellonella larvae infected with C. albicans. Therefore, ATV and DRV showed activity against C. albicans by reducing cell growth, biofilm formation, filamentation, and expression of virulence genes. Furthermore, ATV and DRV decreased experimental candidiasis, suggesting the repurposing of HIV-PIs as antifungal treatments for C. albicans infections.
Cryptococcus gattii (Cg) is one of the agents of cryptococcosis, a severe systemic mycosis with a higher prevalence in men than women, but the influence of the female sex hormone, 17‐β‐estradiol ...(E2), on cryptococcosis remains unclear. Our study shows that female mice presented delayed mortality, increased neutrophil recruitment in bronchoalveolar lavage fluid, and reduced fungal load after 24 hr of infection compared to male and ovariectomised female mice (OVX). E2 replacement restored OVX female survival. Female macrophages have more efficient fungicidal activity, which was increased by E2 and reversed by the antagonist of G‐protein‐coupled oestrogen receptor (GPER), which negatively modulates PI3K activation. Furthermore, E2 induces a reduction in Cg cell diameter, cell charge, and antioxidant peroxidase activity. In conclusion, female mice present improved control of Cg infection, and GPER is important for E2 modulation of the female response.
To obtain fundamental knowledge on the elastic response characteristics of a light-weight floating support structure of a FOWT (floating offshore wind turbine) with guywire supported tower, basic ...load transmission mechanism was investigated. Static analysis with elastic frame model, numerical analysis and wave tank experiment with elastically and dynamically similar segmented backbone model were conducted to clarify the dynamic elastic response characteristics of the structure. In the numerical analysis, analysis code of a rotor-floater-mooring-control coupled response NK-UTWind developed in University of Tokyo is used. It is clarified that when the rigidity of the frame structural part is low compared with guywire, the load is mainly borne by guywire under pitch motion. It was found that the tension fluctuation of guywire becomes large at wave period of 6 s when the inertial force due to pitch motion is large, and at wave period of 18–20 s when inclination of tower is larger the tension fluctuation also becomes large due to the overturning moment.
Cryptococcus neoformans
is an encapsulated yeast that can cause cryptococcosis and cryptococcal meningitis, which conventional treatment involves antifungal drugs such as polyenes, flucytosine, ...azoles, and their combinations. However, the high cost, toxicity, and increase in fungi resistance to antifungal agents stimulate the search for therapeutic strategies such as drug repurposing and combination therapy. This study evaluated the activity of the antihypertensive verapamil (VEH) alone and combined with amphotericin B (AmB) against
C. neoformans
. VEH exhibited antifungal activity against
C. neoformans
with minimum inhibitory concentration and minimum fungicidal concentration of 118 µg per mL. The combination of VEH and AmB exhibited synergism, reducing at least eightfold both drugs’ concentrations. Moreover, the combination decreased the size and glucuronoxylomannnan content of
C. neoformans
capsule
.
However, no difference was observed in ergosterol levels of
C. neoformans
after treatment with VEH and AmB in combination. Altogether, VEH in combination with AmB exhibits potential as a candidate as for the development of anti-cryptococcal drug.
Dermatophytosis is the most common human skin infection worldwide caused by dermatophytes, such as Trichophyton interdigitale and Trichophyton rubrum. Itraconazole (ITZ) is one of the main ...antifungals used to treat these infections. However, especially for onychomycosis, the treatment requires long-term regimens, increasing the possibility of drug resistance. We evaluated the effects of ITZ in the physiology, virulence, and interaction of T. interdigitale with phagocytes and mice cutaneous infection. In a screening test, fungal growth in the presence of ITZ led to the spontaneous selection of less susceptible T. interdigitale and T. rubrum strains. Interestingly, this phenotype was permanent for some T. interdigitale strains. Then, we studied three T. interdigitale strains: one susceptible and two ITZ-adapted. The ITZ-adapted strains were also less susceptible to the cell wall and membrane stressors, suggesting a multidrug resistance (MDR) phenotype associated with the increased ERG11 and MDR3 expression. These strains also presented substantial alterations in ergosterol content, lipid peroxidation, biofilm, and extracellular matrix production. During interaction with macrophages, ITZ-adapted strains were less engulfed but increased the intracellular oxidative and nitrosative bursts. In addition, ITZ-adapted strains presented a reduced ability to grow in a murine model of dermatophytosis, although causing the same tissue damage as the parental strain. In conclusion, the T. interdigitale ITZ adaptation increases tolerance to antifungals and alters the interaction with macrophages and a mammalian host. We hypothesized that successive exposure to ITZ may influence the emergence of adapted strains and lead to the recalcitrance of dermatophytosis.
Summary
Background
Trichophyton rubrum (Tr) is the main aetiological agent of human dermatophytosis, being isolated from the environment and keratinised tissues. In the environment, Tr can interact ...with other organisms, such as free‐living amoebas (FLA), which can act as an alternative host system to study the interaction between microbes and phagocytic cells.
Objectives
To characterise the Acanthamoeba castellanii (ALX)‐Tr interaction.
Methods
Interaction was characterised in three conditions: trophozoites (PYG), late (PYG/NES) and early (NES) encystation stimulus, evaluating encystation kinetics, phagocytosis, exocytosis and fungicidal activity dynamics.
Results
Tr was able to induce ALX encystation and be internalised by ALX. The number of internalised conidia was high at 1 hour, and ALX presented fungicidal activity with increased intracellular ROS production and exocytosis. In PYG/NES, phagocytosis and ROS production were reduced, with decreased ALX’s fungicidal activity. However, in NES there was an increased fungal engulfment, and a reduced ROS production and higher fungal burden. Furthermore, exogenous mannose decreased phagocytosis of Tr conidia, and divalent cations induced ROS production and increased ALX’s fungicidal activity. Interestingly, phagocytosis was reduced in the presence of cytoskeleton inhibitor, but exocytosis was increased, suggesting that Tr conidia may have alternative pathways to escape ALX's cells.
Conclusion
A castellanii is a proper model for studying Tr‐FLA interaction, since ALX can engulf, produce ROS and kill Tr, and all these parameters are influenced by an encystation stimulus and divalent cations. Moreover, this interaction is likely to occur in the environment implicating in the adaptation to environmental stressful conditions in both organisms.
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