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Pollyanna Álvaro Spósito,1 Ana Lia Mazzeti,1,2 Caroline de Oliveira Faria,1 Julio A Urbina,3 Gwenaelle Pound-Lana,1 Maria Terezinha Bahia,2 Vanessa Furtado Mosqueira1 1Laboratory of Pharmaceutics and Nanotechnology Research, Pharmacy Department, School of Pharmacy, Universidade Federal de Ouro Preto, Minas Gerais, Brazil; 2Parasite Diseases Research Laboratory, NUPEB, Medical School, Universidade Federal de Ouro Preto, MG, Brazil; 3Venezuelan Institute for Scientific Research, Apartado, Caracas, Venezuela Abstract: Self-emulsifying drug delivery systems (SEDDSs) are lipid-based anhydrous formulations composed of an isotropic mixture of oil, surfactant, and cosurfactants usually presented in gelatin capsules. Ravuconazole (Biopharmaceutics Classification System [BCS] Class II) is a poorly water-soluble drug, and a SEDDS type IIIA was designed to deliver it in a predissolved state, improving dissolution in gastrointestinal fluids. After emulsification, the droplets had mean hydrodynamic diameters

We investigated the in-vitro antiproliferative effects and mechanism of action of both enantiomers of the bis-triazole derivative ICI 195,739 against epimastigotes and amastigotes of Trypanosoma cruzi, the aetiological agent of Chagas' disease. It has recently been shown that the R(+) enantiomer, D0870, can induce radical parasitological cure in murine models of the acute and chronic forms of the disease. D0870 dose-dependently affected the growth rate of the epimastigote form (IC50 = 0.1 microM; MIC = 1-3 microM). The S(-) enantiomer was much less active (IC50 = 3 microM). Growth arrest and cell lysis induced by D0870 coincided with the complete depletion of endogenous 4,14-desmethyl sterols and their replacement by 4,14-trimethyl and dimethyl sterols. The S(-) enantiomer produced qualitatively similar changes but to a lesser extent. D0870 inhibited the incorporation of radioactivity from [2-14C]acetate into the epimastigote's 4,14-desmethyl sterols with an IC50 of 50 nM while the corresponding concentration for the S(-) enantiomer was 3 microM. D0870 eradicated the intracellular (amastigote) form of the parasite from cultured Vero cells at 10 nM; a 100-fold higher concentration of the S(-) enantiomer was required to produce a similar effect, and deleterious effects of the host cells were observed at > 100 nM. At the MIC of D0870 the endogenous amastigote sterols (ergosta-7-en-3beta-ol, 24-ethyl-cholesta-7-en-3beta-ol and ergosta-7, 24(24[1])-dien-3beta-ol) were also largely replaced by lanosterol and 24-methyl-dihydrolanosterol. Combinations of D0870 and inhibitors of sterol delta24(25) sterol methyltransferase (such as 22,26-azasterol and 24(R,S),25-epiminolanosterol) acted synergically against the intracellular forms. Taken together these results indicate that, although both enantiomers have anti-T. cruzi activity, the specific activity of the R(+) enantiomer (D0870) is nearly two orders of magnitude higher than that of its S(-) analogue. However, as the in-vitro activity of D0870 is comparable to that of standard azoles, such as ketoconazole, its remarkable in-vivo antiparasitic activity may only be explained by its particular pharmacokinetic properties. [ABSTRACT FROM AUTHOR]

Background: While there is literature on erectile dysfunction (ED) and premature ejaculation (PE) in men, conclusive evidence regarding these sexual health issues and potential associated factors in the young, single men who have sex with men (MSM) population is lacking., Aim: The study sought to determine the prevalence and factors associated with PE and ED in young single MSM in the capital of Peru., Methods: This was an analytical cross-sectional study in MSM using an online questionnaire. The presence of ED and PE was assessed using the 5-item International Index of Erectile Function and 5-item Premature Ejaculation Diagnostic Tool questionnaires, respectively. In addition, their association with personal, physical health, and sexual behavior variables was evaluated. Prevalence ratios (PRs) were estimated through regression models., Outcomes: Premature ejaculation and Erectile dysfunction in MSM., Results: Of 315 participants, most were between 20 to 29 years of age (71.8%), 43.5% identified as homosexual, 59.1% had between 2 and 5 sexual partners, and 40.6% reported that the duration of their sexual relationship was between 1 and 12 months. The prevalence of ED was 53.3% (95% confidence interval [CI], 47.66%-58.95%), and PE was present in 8.3% (95% CI, 5.46%-11.86%). Factors associated with a higher prevalence of ED were having between 6 and 9 sexual partners (PR, 1.48; 95% CI, 1.05-2.11) and having a sexual relationship lasting 13 to 24 months (PR, 0.70; 95% CI, 0.50-0.98). Furthermore, for each additional year from the onset of the first sexual encounter with another man, the prevalence of PE increased by 7% (PR, 1.07; 95% CI, 1.02-1.13)., Clinical Implications: These findings suggest that there is a relationship between an increased number of sexual partners and a higher prevalence of ED. It also suggests that relationships that last for some time may have a protective effect against ED., Strengths and Limitations: Strengths include the use of validated instruments, adequate sample size, robust multivariate analysis, and being one of the few studies in Latin America assessing PE and ED in the MSM population. Limitations include the cross-sectional design, nonprobability sampling, and access to participants., Conclusion: Having more sexual partners is associated with increased ED, while relationships lasting 13 to 24 months are associated with decreased ED. Each additional year from the onset of the first sexual relationship increases the prevalence of PE. These findings can guide the design of health policies and programs tailored to the MSM community to enhance their well-being and sexual quality of life., Competing Interests: The authors report no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Objective: We aimed to evaluate the association between sleep quality and erectile dysfunction in young university students., Methods: A cross-sectional survey was conducted in men aged 18-30 years from Universidad Ricardo Palma, Lima, Peru. The survey comprised the International Index of Erectile Function, Pittsburgh Sleep Quality Index, Berlin questionnaire, and questions related to sociodemographic data. Prevalence ratios were estimated with generalized linear models., Results: Of 381 participants, the median age was 23 years. Half of the students (50.9%) had poor sleep quality, of which 72.7% had mild erectile dysfunction and 20.6% mild to moderate dysfunction. Prevalence of erectile dysfunction was significantly higher in students with poor sleep quality than in students with good sleep quality (aPR = 6.48; 95% CI: 4.58-9.17) after adjusting for age, academic year, nutritional status, and sleep apnea. In a subsequent exploratory analysis, sleep apnea was associated with a higher prevalence of erectile dysfunction (aPR = 1.19; 95% CI: 1.01-1.39), while overweight (aPR = 0.85; 95% CI: 0.76-0.95) and obesity (aPR = 0.65; 95% CI: 0.52-0.82) were associated with a lower prevalence of this condition., Conclusion: Poor sleep quality was independently associated with erectile dysfunction in young university students. This finding suggests that male students are at risk for sexual problems due to possible academic demands and relationship issues., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gutierrez-Velarde, Valladares-Garrido, Peralta, Vera-Ponce and Grandez-Urbina.)

Introduction: Chagas disease (CD) affects ~7 million people worldwide. Benznidazole (BZN) and nifurtimox (NFX) are the only approved drugs for CD chemotherapy. Although both drugs are highly effective in acute and paediatric infections, their efficacy in adults with chronic CD (CCD) is lower and variable. Moreover, the high incidence of adverse events (AEs) with both drugs has hampered their widespread use. Trials in CCD adults showed that quantitative PCR (qPCR) assays remain negative for 12 months after standard-of-care (SoC) BZN treatment in ~80% patients. BZN pharmacokinetic data and the nonsynchronous nature of the proliferative mammal-dwelling parasite stage suggested that a lower BZN/NFX dosing frequency, combined with standard or extended treatment duration, might have the same or better efficacy than either drug SoC, with fewer AEs., Methods and Analysis: New ThErapies and Biomarkers for ChagaS infEctiOn (TESEO) is an open-label, randomised, prospective, phase-2 clinical trial, with six treatment arms (75 patients/arm, 450 patients). Primary objectives are to compare the safety and efficacy of two new proposed chemotherapy regimens of BZN and NFX in adults with CCD with the current SoC for BZN and NFX, evaluated by qPCR and biomarkers for 36 months posttreatment and correlated with CD conventional serology. Recruitment of patients was initiated on 18 December 2019 and on 20 May 2021, 450 patients (study goal) were randomised among the six treatment arms. The treatment phase was finalised on 18 August 2021. Secondary objectives include evaluation of population pharmacokinetics of both drugs in all treatment arms, the incidence of AEs, and parasite genotyping., Ethics and Dissemination: The TESEO study was approved by the National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), federal regulatory agency of the Plurinational State of Bolivia and the Ethics Committees of the participating institutions. The results will be disseminated via publications in peer-reviewed journals, conferences and reports to the NIH, FDA and participating institutions., Trial Registration Number: NCT03981523., Competing Interests: Competing interests: The TESEO study principal investigators declare no financial and competing interests for the overall trial and each study site., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pozol is a Mexican beverage prepared from fermented nixtamalized maize dough. To contribute to understanding its complex microbial ecology, the effect of inoculating on MRS-starch pure and mixed cultures of amylolytic Sii -25124 and non-amylolytic W. confusa 17, isolated from pozol, were studied on their interactions and fermentation parameters. These were compared with L. plantarum A6, an amylolytic strain isolated from cassava. Microbial growth, kinetic parameters, amylolytic activity, lactic acid production, and hydrolysis products from starch fermentation were measured. The population dynamics were followed by qPCR. L. plantarum A6 showed higher enzymatic activity, lactic acid, biomass production, and kinetic parameters than pozol LAB in pure cultures. Mixed culture of each pozol LAB with L. plantarum A6 showed a significant decrease in amylolytic activity, lactic acid yield, specific growth rate, and specific rate of amylase production. The interaction between Sii -25124 and W. confusa 17 increased the global maximum specific growth rate (µ), the lactic acid yield from starch (Y lac/s), lactic acid yield from biomass (Y lac/x ), and specific rate of lactic acid production (q lac ) by 15, 30, 30, and 40%, respectively, compared with the pure culture of Sii -25124. Interactions between the two strains are essential for this fermentation.

Objective: To determine the effectiveness and safety in the short, medium, and long term of LISWT in patients with Erectile Dysfunction who do not respond to PDE5 inhibitors., Methodology: Clinical study, quasi-experimental cohort and systematic review following the guidelines of the Cochrane collaboration and the PRISMA writing guides. The measurement of the variables was determined as a primary outcome to the evaluation of erectile function, by means of a validated questionnaire. The baseline scale was evaluated, as well as the difference at 1, 3 and 6 months, evidenced by the possibility of maintaining an erection or responding to therapy with PDEi5. An information search was carried out from its beginning to the current date, in the databases: Medline, Embase, Central, Science Direct and Lilacs., Results: The studies found used different outcome variables to show efficacy in the follow-up: All the studies used the IIEF-EF as outcome variable in its different variations., Conclusion: LISWT could be an effective and safe treatment in patients not responding to PDEi5. It is important to point out that the evidence is currently limited, randomized studies with greater methodological rigidity and follow-up longer than 12 months are needed in order to verify the medium and long-term effect of the application of shock waves in this group of patients., (Copyright © 2020 Asociación Española de Andrología, Medicina Sexual y Reproductiva. Publicado por Elsevier España, S.L.U. All rights reserved.)

We investigated the in vitro activity and selectivity, and in vivo efficacy of ravuconazole (RAV) in self-nanoemulsifying delivery system (SNEDDS) against Trypanosoma cruzi. Novel formulations of this poorly soluble C14-α-demethylase inhibitor may improve its efficacy in the experimental treatment. In vitro activity was determined in infected cardiomyocytes and efficacy in vivo evaluated in terms of parasitological cure induced in Y and Colombian strains of T. cruzi-infected mice. In vitro RAV-SNEDDS exhibited significantly higher potency of 1.9-fold at the IC 50 level and 2-fold at IC 90 level than free-RAV. No difference in activity with Colombian strain was observed in vitro. Oral treatment with a daily dose of 20 mg/kg for 30 days resulted in 70% of cure for RAV-SNEDDS versus 40% for free-RAV and 50% for 100 mg/kg benznidazole in acute infection (T. cruzi Y strain). Long-term treatment efficacy (40 days) was able to cure 100% of Y strain-infected animals with both RAV preparations. Longer treatment time was also efficient to increase the cure rate with benznidazole (Y and Colombian strains). RAV-SNEDDS shows greater efficacy in a shorter time treatment regimen, it is safe and could be a promising formulation to be evaluated in other pre-clinical models to treat T. cruzi and fungi infections., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Present different flap alternatives when performing microvascular free-flap reconstruction in acute hard-to-heal wounds., Method: A retrospective review of patients whose acute hard-to-heal wounds were treated with microvascular free-flap reconstruction. Data on demographics, wound aetiology, diagnostic, previous treatment, free-flap type, free-flap size, complications and follow up were analysed., Results: A total of 20 patients received microvascular free-flap reconstruction. The median age was 39.5 years. Twenty free-flap reconstructions were performed. These included: 3 cross-leg free flap, 1 cross-leg vascular cable bridge flap, 2 fibula osteocutaneous flap, 6 anterolateral thigh (ALT) flap, 3 thoracodorsal artery perforator (TDAP) flap, 3 fasciomyocutaneous flap, and 2 femoral artery fasciocutaneous flap. A patient required microvascular anastomosis due to hematoma; the rest did not present complications during their postoperative. Previous treatment included negative pressure wound therapy (12 patients) and surgical debridement with silver hydrogel dressings (8 patients)., Conclusion: Hard-to-heal wounds can be unresponsive to traditional wound healing practices or local flaps. They often require free-flap reconstruction, using tissues similar to those compromised. Microvascular techniques can be an effective alternative.

Introduction: Chagas disease treatment relies on the lengthy administration of benznidazole and/or nifurtimox, which have frequent toxicity associated. The disease, caused by the parasite Trypanosoma cruzi , is mostly diagnosed at its chronic phase when life-threatening symptomatology manifest in approximately 30% of those infected. Considering that both available drugs have variable efficacy by then, and there are over 6 million people infected, there is a pressing need to find safer, more efficacious drugs., Areas Covered: We provide an updated view of the path to achieve the aforementioned goal. From state-of-the-art in vitro and in vivo assays based on genetically engineered parasites that have allowed high throughput screenings of large chemical collections, to the unfulfilled requirement of having treatment-response biomarkers for the clinical evaluation of drugs. In between, we describe the most promising pre-clinical hits and the landscape of clinical trials with new drugs or new regimens of existing ones. Moreover, the use of monkey models to reduce the pre-clinical to clinical attrition rate is discussed., Expert Opinion: In addition to the necessary research on new drugs and much awaited biomarkers of treatment efficacy, a key step will be to generalize access to diagnosis and treatment and maximize efforts to impede transmission.

Posaconazole (POS) is an inhibitor of ergosterol biosynthesis in clinical use for treating invasive fungal infections. POS has potent and selective anti-Trypanosoma cruzi activity and has been evaluated as a possible treatment for Chagas disease. Microtissues are a 3D culture system that has been shown to reproduce better tissue architecture and functionality than cell cultures in monolayer (2D). It has been used to evaluate chemotropic response as in vitro disease models. We previously developed an in vitro model that reproduces aspects of cardiac fibrosis observed in Chagas cardiomyopathy, using microtissues formed by primary cardiac cells infected by the T. cruzi, here called T. cruzi fibrotic cardiac microtissue (TCFCM). We also showed that the treatment of TCFCM with a TGF-β pathway inhibitor reduces fibrosis. Here, we aimed to evaluate the effect of POS in TCFCM, observing parasite load and molecules involved in fibrosis. To choose the concentration of POS to be used in TCFCM we first performed experiments in a monolayer of primary cardiac cell cultures and, based on the results, TCFCM was treated with 5 nM of POS for 96 h, starting at 144 h post-infection. Our previous studies showed that at this time the TCFCM had established fibrosis, resulting from T. cruzi infection. Treatment with POS of TCFCM reduced 50 % of parasite load as observed by real-time PCR and reduced markedly the fibrosis as observed by western blot and immunofluorescence, associated with a strong reduction in the expression of fibronectin and laminin (45 % and 54 %, respectively). POS treatment also changed the expression of proteins involved in the regulation of extracellular matrix proteins (TGF-β and TIMP-4, increased by 50 % and decreased by 58 %, respectively) in TCFCM. In conclusion, POS presented a potent trypanocidal effect both in 2D and in TCFCM, and the reduction of the parasite load was associated with a reduction of fibrosis in the absence of external immunological effectors., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

The worldwide scarcity of psychiatrists makes the identification of the factors associated with the intention to choose this specialty an important issue. This study aims to evaluate the association between religious affiliation and the intention to choose psychiatry as a specialty among medical students from 11 Latin American countries. We conducted a cross-sectional, multi-country study that included first- and fifth-year students of 63 medical schools in 11 Latin-American countries between 2011 and 2012. The main outcome and measures were the intention to pursue psychiatry as a specialty over other specialties (yes/no) and religious affiliation (without: atheist/agnostic; with: any religion). A total of 8308 participants were included; 53.6% were women, and the average age was 20.4 (SD = 2.9) years. About 36% were fifth-year students, and 11.8% were not affiliated with any religion. Only 2.6% had the intention to choose psychiatry; the highest proportion of students with the intention to choose psychiatry was among students in Chile (8.1%) and the lowest among students in Mexico (1.1%). After adjusting for demographic, family, academic as well as personal and professional projection variable, we found that those who had no religious affiliation were more likely to report the intention to become a psychiatrist [OR: 2.92 (95%CI: 2.14-4.00)]. There is a strong positive association between not having a religious affiliation and the intention to become a psychiatrist. The possible factors that influence this phenomenon must be evaluated in greater depth, ideally through longitudinal research.

Background: Bladder adenocarcinoma (AC) is a scarce histological variant and there are few studies on its proper management. No previous case reports present the management of a urachal tumor and the incidental finding of bladder adenocarcinoma. Clinical case: We present the case of a young woman with nonspecific symptoms, who presented with a prior history of dysuria, bladder tenesmus, suprapubic pain and urinary urgency for one year, which had been treated as recurrent urinary tract infection. A partial cystectomy plus extended lymphadenectomy was scheduled. We found a bladder tumor with characteristics of a urachal tumor and the pathological report indicated a primary bladder AC. The patient had a complete recovery at one year of follow-up. Conclusions: A patient can present with a tumor with urachal characteristics; however, the pathology report can show primary AC. The decision to perform partial cystectomy was an appropriate option for the location of this tumor, with optimal surgical results. Still, a long-term follow-up is necessary. More specific management guidelines are required for the treatment of AC., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Tejeda-Mariaca JE et al.)

Neuromas of the bile duct develop from the sympathetic and parasympathetic nerve fibers that surround the wall of the bile duct. A 44-year-old woman with a history of conventional cholecystectomy six months prior to hospital admission attended emergency due to obstructive jaundice that lasted 15 days. In the imaging studies, the presence of a mass at the level of the bile ducts is considered, considering the diagnosis of a malignant neoplasm. Due to the antecedents, the absence of tumor markers, it was decided to perform a percutaneous biopsy without conclusive results, performing later a surgical intervention with anatomopathological study compatible with neuroma of biliary tract amputation. The amputation neuroma at the level of the bile duct is an infrequent tumor. It can manifest clinically as obstructive jaundice and usually simulates a malignant tumor of the bile ducts. Surgical management is the definitive treatment.

Objective: This PUBA study aimed to assess the efficacy of fractional CO2 laser in the treatment of genitourinary syndrome of menopause (GSM)., Methods: GSM symptoms were assessed before, 1 month after the first session and 1 month after the third session of laser (3 sessions with a 30 days interval between them) in 60 women (median, interquartile range: 55, 49-69). Subjective (visual analog scale) and objective (Vaginal Health Index, VHIS; Vaginal Maturity Index/Frost Index; Spanish Overactive Bladder Questionnaire-Short Form, USMEX Spanish OAB-qSF and Female Sexual Function Index, FSFI) measures were used during the study period to assess CO2 fractionated laser treatment outcomes compared to baseline., Results: Fractional CO 2 laser treatment was effective to improve GSM symptoms (vaginal dryness, vaginal itching, vaginal burning, dyspaurenia, dysuria, urinary urgency; P < 0.001) after three sessions, as well as VHIS (median, interquartile range: 13, 10-15 at baseline vs. 21, 20-23 at the fourth month follow up; P < 0.001), Frost Index (median, interquartile range: 28, 24-31 at baseline vs. 8, 6-10 at the fourth month follow up; P < 0.001), USMEX (median, interquartile range: 56, 46-68 at baseline vs 14, 13-16 at the fourth month follow up: P < 0,001) and FSFI (median, interquartile range: 5, 2-14 at baseline vs 30, 28-32)., Conclusions: In this sample, the data suggests that fractionated CO2 laser is an effective alternative for GSM treatment with positive outcomes that persists over time. Lasers Surg. Med. 51:509-515, 2019. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

Background : Penile necrosis is a rare condition that may present in patients with diabetes mellitus or chronic kidney disease (CKD). The recommended treatment is controversial. We report a case of penile necrosis in a diabetic patient caused by episode of paraphimosis associated with uremic arteriopathy treated with partial amputation. Clinical Case : A 53-year-old male with a background of arterial hypertension, diabetes mellitus and CKD in hemodialysis. The patient presented with paraphimosis and glans necrosis. An emergency circumcision was carried out. A doppler ultrasound found fluid collection in the left corpus cavernosum, parietal vascular calcifications and vascular insufficiency in the corpus cavernosum that suggested necrosis. A partial amputation of the penis was carried out. After three years of follow-up, the outcome has remained favorable. Conclusions : Penile necrosis is a rare but serious complication of terminal CKD. In these patients, systemic calciphylaxis is usually observed. The main take-away lesson is that a multidisciplinary approach is necessary., Competing Interests: No competing interests were disclosed.

In the past 5-10 years, Venezuela has faced a severe economic crisis, precipitated by political instability and declining oil revenue. Public health provision has been affected particularly. In this Review, we assess the impact of Venezuela's health-care crisis on vector-borne diseases, and the spillover into neighbouring countries. Between 2000 and 2015, Venezuela witnessed a 359% increase in malaria cases, followed by a 71% increase in 2017 (411 586 cases) compared with 2016 (240 613). Neighbouring countries, such as Brazil, have reported an escalating trend of imported malaria cases from Venezuela, from 1538 in 2014 to 3129 in 2017. In Venezuela, active Chagas disease transmission has been reported, with seroprevalence in children (<10 years), estimated to be as high as 12·5% in one community tested (n=64). Dengue incidence increased by more than four times between 1990 and 2016. The estimated incidence of chikungunya during its epidemic peak is 6975 cases per 100 000 people and that of Zika virus is 2057 cases per 100 000 people. The re-emergence of many vector-borne diseases represents a public health crisis in Venezuela and has the possibility of severely undermining regional disease elimination efforts. National, regional, and global authorities must take action to address these worsening epidemics and prevent their expansion beyond Venezuelan borders., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Sr. Editor: Los resultados de Cano-García et al. (1) en el último estudio publicado sobre la profilaxis antibiótica con ciprofloxacino en uretrocistoscopia flexible (UF) son claros y fuertes, si bien la pregunta clínica pudo ser respondida mediante un estudio de intervención (ensayo clínico), el diseño utilizado es bueno y aproximado pero difiriendo de algunos puntos claves: aleatorización, denominación de grupo control y asignación del tratamiento. Que le dan riesgo de sesgo, pero que no invalidan los resultados. Nosotros remarcamos que las conclusiones han sido equivalentes a los resultados de los ensayos clínicos realizados en poblaciones similares como el estudio de Jiménez-Pacheco et al. (2), que encuentran que una población seleccionada y con medidas de asepsia adecuadas, la profilaxis no muestra reducción clínicamente relevante en la incidencia de ITU en pacientes sometidos a UF, así mismo Arrabal et al. (3), quienes añadieron fosfomicina en su diseño, comparando tres grupos (no intervención, fosfomicina y ciprofloxacino) reportan que no disminuye la presencia de infección ni bacteriuria posterior a la UF. Sumándose a esta evidencia, una revisión sistemática con metaanálisis (RSM) publicado por Garcia-Perdomo et al. (4), concluye que la evidencia no es muy fuerte para recomendar profilaxis en UF y la necesidad de realizar ensayos clínicos con mejores diseños. Carey et al. (5), en otra RSM no recomiendan el uso de profilaxis antibiótica en UF de manera rutinaria, llevando a ser más robustos los resultados de Cano-Garcia et al...

Artisanal mezcal is produced by the natural fermentation of maguey juice, which frequently results in a process that becomes stuck or is sluggish. Using selected indigenous starter inoculums of Saccharomyces and non- Saccharomyces yeasts is considered beneficial in overcoming these problems and thereby preserving the essence of the artisanal process. In this work, three hundred and four yeast isolates were recovered from 17 distilleries and then grouped by the ARDRA analysis, their restriction profiles were clustered in 15 groups. Four of them included 90% of all isolates, and these were identified using the sequence of the D1/D2 domain of the large-subunit rDNA. Pichia kudriavzevii, Pichia manshurica, Saccharomyces cerevisiae , and Kluyveromyces marxianus were detected as predominant species. Both species belonging to the Pichia genus were detected in 88% of the distilleries, followed by S. cerevisiae (70%) and K. marxianus (50%). In order to evaluate the fermentative capacity, one strain of each species was assessed in a pure and mixed culture in two culture media, filtered maguey juice (MJ) and maguey juice including its bagasse (MJB). Findings demonstrated that non- Saccharomyces yeast presented better growth than that of S. cerevisiae . K . marxianus PA16 was more efficient for ethanol production than S. cerevisiae DI14. It produced 32 g/L of ethanol with a yield of 0.47 g/g and efficient of 90%. While, P. kudriavzevii produced more ethyl acetate (280 mg/L) than the others species. All fermentations were characterized by the presence of isobutyl and isoamyl alcohol. The presence of K. marxianus in a mixed culture, improved the ethanol production and volatile compounds increased using co-cultures.

Objective: Even though there is no established standard therapy for Eosinophilic cystitis (EC), the series of cases guide us in the treatment of patients. We report our therapeutic experience with hydrodistention and complementary methods. In order to establish a standard treatment in patients with EC., Methods: Retrospective review of the clinical history of a patient diagnosed with eosinophilic cystitis., Results: A 66-year-old woman presented female urethral syndrome 1 year before and was initially treated as a chronic cystitis. After further investigations including cystoscopy and bladder biopsy, she was diagnosed with EC.Urothelial mucosa bleeding was evidenced and cauterization and hydrodistention were performed. After the surgical treatment, corticosteroids and antibiotics were initiated.The maintenance treatment was continued with Vitamin C, Maurita flexuosa and Peumus boldus. The patient's condition has been improving and she is still asymptomatic one year later., Conclusion: The efficacy of treatment with hydrodistention, corticosteroids and antibiotics showed positive results in short and long term in this patient. Vitamin C, Maurita flexuosa and Peumus boldus showed favorable results in EC maintenance treatment.

In this study, 19 indigenous mezcal Saccharomyces cerevisiae strains were screened for their tolerance to grow under different stress conditions and their potential use in fermentation. All strains were able to tolerate pH value of 3, significant levels of glucose (30%), ethanol (12% v/v), and temperature of 37 °C. Eleven of them were able to grow in presence of 15% of ethanol, but only CH7 and PA18 strains grew at 42 °C. Both were selected for evaluation of their fermentative abilities in maguey juice and in a synthetic medium incubated at 30 and 40 °C. Temperature of 40 °C had a positive effect on the ethanol production, increasing the productivity and efficiency in maguey fermentation. Ethyl acetate, isobutanol and isoamyl alcohols production was favored at 30 °C. Both evaluated strains presented a good fermentative capacity and production of volatile compounds, suggesting their potential use as starter cultures in mezcal fermentation., Competing Interests: Compliance with ethical standardsThe authors declare no conflicts of interest.

Objectives: Leishmaniasis, one of the most significant neglected diseases around the world, is caused by protozoan parasites of the Leishmania genus. Nowadays, the available aetiological treatments for leishmaniasis have variable effectiveness and several problems such as serious side effects, toxicity, high cost and an increasing number of resistance cases. Thus, there is an urgent need for safe, oral and cost-effective drugs for leishmaniases. Previously, our group has shown the effect of the ergosterol biosynthesis inhibitors on Leishmania amazonensis. Herein, we showed the effect of ravuconazole against L. amazonensis; ravuconazole is a second-generation triazole antifungal drug that has good bioavailability after oral administration and a long terminal half-life in humans, a broad activity spectrum, high effectiveness in treatment of mycosis and negligible side effects., Methods: Several methodologies were used: cell culture, fluorescence and electron microscopy, high-resolution capillary GC coupled with MS, fluorimetry and flow cytometry., Results: Our results showed that ravuconazole was able to inhibit the proliferation of L. amazonensis promastigotes and intracellular amastigotes in vitro, with single-digit to sub-micromolar IC50 values, causing several alterations in the morphology, ultrastructure, cell viability and physiology of the parasites. The mitochondrion was significantly affected by the treatment, resulting in a collapse of the mitochondrial transmembrane potential that consequently led to inhibition of ATP production, combined with an increase in reactive oxygen species and mitochondrial superoxide production; by transmission electron microscopy, the organelle displayed a completely altered ultrastructure. The treatment changed the lipid profile, showing a profound depletion of the 14-desmethyl endogenous sterol pool., Conclusions: These results suggest that ravuconazole could be an alternative option for the treatment of leishmaniasis.

Two brothers with congenitally-acquired Chagas' disease (CD) diagnosed during adulthood are reported. The patients were born in the USA to a mother from Bolivia who on subsequent assessment was found to be serologically positive for Trypanosoma cruzi. Serologic screening of all pregnant women who migrated from countries with endemic CD is strongly recommended.

Leishmaniases comprise a spectrum of diseases caused by protozoan parasites of the Leishmania genus. Treatments available have limited safety and efficacy, high costs, and difficult administration. Thus, there is an urgent need for safer and more-effective therapies. Most trypanosomatids have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. In previous studies, we showed that Leishmania amazonensis is highly susceptible to aryl-quinuclidines, such as E5700, which inhibit squalene synthase, and to the azoles itraconazole (ITZ) and posaconazole (POSA), which inhibit C-14α-demethylase. Herein, we investigated the antiproliferative, ultrastructural, and biochemical effects of combinations of E5700 with ITZ and POSA against L. amazonensis. Potent synergistic antiproliferative effects were observed against promastigotes, with fractional inhibitory concentration (FIC) ratios of 0.0525 and 0.0162 for combinations of E5700 plus ITZ and of E5700 plus POSA, respectively. Against intracellular amastigotes, FIC values were 0.175 and 0.1125 for combinations of E5700 plus ITZ and E5700 plus POSA, respectively. Marked alterations of the ultrastructure of promastigotes treated with the combinations were observed, in particular mitochondrial swelling, which was consistent with a reduction of the mitochondrial transmembrane potential, and an increase in the production of reactive oxygen species. We also observed the presence of vacuoles similar to autophagosomes in close association with mitochondria and an increase in the number of lipid bodies. Both growth arrest and ultrastructural/biochemical alterations were strictly associated with the depletion of the 14-desmethyl endogenous sterol pool. These results suggest the possibility of a novel combination therapy for the treatment of leishmaniasis., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

We tested the antituberculosis drug SQ109, which is currently in advanced clinical trials for the treatment of drug-susceptible and drug-resistant tuberculosis, for its in vitro activity against the trypanosomatid parasite Trypanosoma cruzi, the causative agent of Chagas disease. SQ109 was found to be a potent inhibitor of the trypomastigote form of the parasite, with a 50% inhibitory concentration (IC50) for cell killing of 50 ± 8 nM, but it had little effect (50% effective concentration [EC50], ∼80 μM) in a red blood cell hemolysis assay. It also inhibited extracellular epimastigotes (IC50, 4.6 ± 1 μM) and the clinically relevant intracellular amastigotes (IC50, ∼0.5 to 1 μM), with a selectivity index of ∼10 to 20. SQ109 caused major ultrastructural changes in all three life cycle forms, as observed by light microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). It rapidly collapsed the inner mitochondrial membrane potential (Δψm) in succinate-energized mitochondria, acting in the same manner as the uncoupler FCCP [carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone], and it caused the alkalinization of internal acidic compartments, effects that are likely to make major contributions to its mechanism of action. The compound also had activity against squalene synthase, binding to its active site; it inhibited sterol side-chain reduction and, in the amastigote assay, acted synergistically with the antifungal drug posaconazole, with a fractional inhibitory concentration index (FICI) of 0.48, but these effects are unlikely to account for the rapid effects seen on cell morphology and cell killing. SQ109 thus most likely acts, at least in part, by collapsing Δψ/ΔpH, one of the major mechanisms demonstrated previously for its action against Mycobacterium tuberculosis. Overall, the results suggest that SQ109, which is currently in advanced clinical trials for the treatment of drug-susceptible and drug-resistant tuberculosis, may also have potential as a drug lead against Chagas disease., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

The aim of the present study was to build a population pharmacokinetic (popPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. This study was a prospective, open-label, single-center clinical trial approved by the local ethics committee. Patients received BNZ at 2.5 mg/kg of body weight/12 h (Abarax, Elea Laboratory, Argentina) for 60 days. Plasma BNZ samples were taken several times during the study and analyzed by high-performance liquid chromatography with UV-visible detection (HPLC-UV). The popPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion, and residual variabilities were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate BNZ concentration-time course profiles for different dosage regimens. A total of 358 plasma BNZ concentrations from 39 patients were included in the analysis. A one-compartment PK model characterized by clearance (CL/F) and the apparent volume of distribution (V/F), with first-order absorption (Ka) and elimination, adequately described the data (CL/F, 1.73 liters/h; V/F, 89.6 liters; and Ka, 1.15 h(-1)). No covariates were found to be significant for CL/F and V/F. Internal and external validations of the final model showed adequate results. Data from simulations revealed that a dose of 2.5 mg/kg/12 h might lead to overexposure in most patients. A lower dose (2.5 mg/kg/24 h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3 to 6 mg/liter. In summary, we developed a population PK model for BNZ in adults with chronic Chagas disease. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24 h will adequately keep BNZ trough plasma concentrations within the recommended target range for the majority of patients. (This study has been registered at EudraCT under number 2011-002900-34 and at ClinicalTrials.gov under number NCT01755403.)., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Chagas disease, a chronic systemic parasitosis caused by the Kinetoplastid protozoon Trypanosoma cruzi, is the first cause of cardiac morbidity and mortality in poor rural and suburban areas of Latin America and the largest parasitic disease burden in the continent, now spreading worldwide due to international migrations. A recent change in the scientific paradigm on the pathogenesis of chronic Chagas disease has led to a consensus that all T. cruzi-seropositive patients should receive etiological treatment. This important scientific advance has spurred the rigorous evaluation of the safety and efficacy of currently available drugs (benznidazole and nifurtimox) as well as novel anti-T. cruzi drug candidates in chronic patients, who were previously excluded from such treatment. The first results indicate that benznidazole is effective in inducing a marked and sustained reduction in the circulating parasites' level in the majority of these patients, but adverse effects can lead to treatment discontinuation in 10-20% of cases. Ergosterol biosynthesis inhibitors, such as posaconazole and ravuconazole, are better tolerated but their efficacy at the doses and treatment duration used in the initial studies was significantly lower; such results are probably related to suboptimal exposure and/or treatment duration. Combination therapies are a promising perspective but the lack of validated biomarkers of response to etiological treatment and eventual parasitological cures in chronic patients remains a serious challenge., (© 2014 The Author(s) Journal of Eukaryotic Microbiology © 2014 International Society of Protistologists.)

Trichomonas vaginalis causes trichomoniasis in humans, a sexually transmitted disease commonly treated with metronidazole (MTZ), a drug that presents some toxicity, causing undesirable side effects. In addition, an increase in metronidazole-resistant parasites has been reported. Thus, the development of alternative treatment is recommended. To date, the search for antiparasitic drugs has been based on different approaches: identification of active natural products, identification of parasite targets, and the use of available compounds active against other pathogenic microorganisms. Here, we analyzed the in vitro antiproliferative and ultrastructural effects on T. vaginalis of BPQ-OH, a hydroxiquinuclidine derivative that inhibits squalene synthase and is active against several protozoa and fungi. We also compared the effects of BPQ-OH on T. vaginalis and mammalian cells with those of MTZ. We found that BPQ-OH inhibits in vitro proliferation of T. vaginalis, with an IC50 of 46 μM after 24 h. Although this IC50 is 16 times higher than that of MTZ (1.8 μM), BPQ-OH is less toxic for human cell lines than MTZ, with LC50 values of 2,300 and 70 μM, and selective indexes of 50 and 39, respectively. Ultrastructural analyses demonstrated that BPQ-OH induced alterations in T. vaginalis, such as rounded and wrinkled cells, membrane blebbing and intense vacuolization, leading to cell death, whereas MTZ also caused significant changes, including a decrease in hydrogenosomes size and endoflagellar forms. Our observations identify BPQ-OH as a promising leading compound for the development of novel anti-T. vaginalis drugs and highlight the need for further testing this molecule using experimentally infected animals.

Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.