Synthesis, In Silico Study, and In Vitro Antifungal Activity of New 5-(1,3-Diphenyl-1H-Pyrazol-4-yl)-4-Tosyl-4,5-Dihydrooxazoles.

The increase in multi-drug resistant Candida strains has caused a sharp rise in life-threatening fungal infections in immunosuppressed patients, including those with SARS-CoV-2. Novel antifungal drugs are needed to combat multi-drug-resistant yeasts. This study aimed to synthesize a new series of 2-oxazolines and evaluate the ligands in vitro for the inhibition of six Candida species and in silico for affinity to the CYP51 enzymes (obtained with molecular modeling and protein homology) of the same species. The 5-(1,3-diphenyl-1H-pyrazol-4-yl)-4-tosyl-4,5-dihydrooxazoles 6a-j were synthesized using the Van Leusen reaction between 1,3-diphenyl-4-formylpyrazoles 4a-j and TosMIC 5 in the presence of K2CO3 or KOH without heating, resulting in short reaction times, high compound purity, and high yields. The docking studies revealed good affinity for the active site of the CYP51 enzymes of the Candida species in the following order: 6a-j > 4a-j > fluconazole (the reference drug). The in vitro testing of the compounds against the Candida species showed lower MIC values for 6a-j than 4a-j, and for 4a-j than fluconazole, thus correlating well with the in silico findings. According to growth rescue assays, 6a-j and 4a-j (like fluconazole) inhibit ergosterol synthesis. The in silico toxicity assessment evidenced the safety of compounds 6a-j, which merit further research as possible antifungal drugs.

Body mass index implications in intrahepatic cholestasis of pregnancy and placental histopathological alterations.

INTRODUCTION AND OBJECTIVES: Intrahepatic cholestasis is a frequent disease during pregnancy. It is unknown if liver function alterations produce specific placental lesions. The aim of this study was to evaluate placental histopathological changes in patients with intrahepatic cholestasis of pregnancy (ICP), and to explore correlations between the placental histopathology and hepatic function alteration or patient comorbidities, and body mass index. PATIENTS AND METHODS: A retrospective cohort study included women with ICP, most of them showing comorbidities such as overweight/obesity, preeclampsia and gestational diabetes. They were attended at the National Institute of Perinatology in Mexico City for three years. Placental histopathological alterations were evaluated according to the Amsterdam Placental Workshop Group Consensus Statement. Data was analyzed using Graph-Pad Prism 5. RESULTS: The results indicated that the placenta of ICP patients showed many histopathological alterations; however, no correlations were observed between the increase in bile acids or liver functional parameters and specific placental lesions. The most frequent comorbidities found in ICP patients were obesity, overweight and preeclampsia. Surprisingly, high percentage of ICP patients did not respond to UDCA treatment independently of the BMI group to which they belonged. CONCLUSION: The data suggest that ICP contribute to placental lesions. In addition, in patients with normal weight, an increase of chorangiosis and a reduced accelerated villous maturation without syncytial knots were observed in comparison with overweight and obese patients. It is necessary to improve the medical strategies in the treatment and liver disfunction surveillance of ICP patients.

Pentacoordinated Organotin(IV) Complexes as an Alternative in the Design of Highly Efficient Optoelectronic and Photovoltaic Devices: Synthesis and Photophysical Characterization.

The synthesis of four pentacoordinated organotin(IV) complexes prepared in a one-pot reaction from 2-hydroxy-1-naphthaldehyde, 2-amino-3-hydroxypyridine and organotin oxides is reported. The complexes were characterized by UV-Vis, IR, MS, 1H, 13C and 119Sn NMR techniques. The compound based on 2,2-diphenyl-6-aza-1,3-dioxa-2-stannanaphtho[1,2-h]pyrido[3,2-d]cyclononene revealed the formation of a monomeric complex with a distorted five-coordinated molecular geometry intermediate between the trigonal bipyramidal and square pyramidal. In order to find possible applications in photovoltaic devices, hybrid films of organotin(IV) complexes embedded in poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) with graphene were deposited. The topographic and mechanical properties were examined. The film with the complex integrated into the cyclohexyl substituent has high plastic deformation, with a maximum stress of 1.69 × 107 Pa and a Knoop hardness of 0.061. The lowest values of 1.85 eV for the onset gap and 3.53 eV for the energy gap were obtained for the heterostructure having the complex with the phenyl substituent. Bulk heterojunction devices were fabricated; these devices showed ohmic behavior at low voltages and a space-charge-limited current (SCLC) conduction mechanism at higher voltages. A value of 0.02 A was found for the maximum carried current. The SCLC mechanism suggests hole mobility values of between 2.62 × 10-2 and 3.63 cm2/V.s and concentrations of thermally excited holes between 2.96 × 1018 and 4.38 × 1018 m-3.

The Effect of Metformin and Carbohydrate-Controlled Diet on DNA Methylation and Gene Expression in the Endometrium of Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine disease associated with infertility and metabolic disorders in reproductive-aged women. In this study, we evaluated the expression of eight genes related to endometrial function and their DNA methylation levels in the endometrium of PCOS patients and women without the disease (control group). In addition, eight of the PCOS patients underwent intervention with metformin (1500 mg/day) and a carbohydrate-controlled diet (type and quantity) for three months. Clinical and metabolic parameters were determined, and RT-qPCR and MeDIP-qPCR were used to evaluate gene expression and DNA methylation levels, respectively. Decreased expression levels of HOXA10, GAB1, and SLC2A4 genes and increased DNA methylation levels of the HOXA10 promoter were found in the endometrium of PCOS patients compared to controls. After metformin and nutritional intervention, some metabolic and clinical variables improved in PCOS patients. This intervention was associated with increased expression of HOXA10, ESR1, GAB1, and SLC2A4 genes and reduced DNA methylation levels of the HOXA10 promoter in the endometrium of PCOS women. Our preliminary findings suggest that metformin and a carbohydrate-controlled diet improve endometrial function in PCOS patients, partly by modulating DNA methylation of the HOXA10 gene promoter and the expression of genes implicated in endometrial receptivity and insulin signaling.

Current findings in endometrial microbiome: impact on uterine diseases.

Microbiome or microbiota is essential to regulate many mammalian physiological processes, including reproduction. Like other organs or tissues, the upper female reproductive tract used to be considered as devoid of microorganisms; however, a non-infection-related bacterial community was discovered in the uterus from humans and other mammals, and its composition is related to reproductive success. The dysbiosis of endometrial microbiota is associated with benign and malign uterine diseases. Hence, this review addressed the current knowledge about uterine microbiota alterations and their association with common endometrial diseases, including endometrial polyposis, endometriosis, uterine myomatosis, endometrial hyperplasia, and endometrial cancer. There is a specific bacterial community in the endometrium in the most-analyzed uterine diseases. However, the constant finding consists in a reduced abundance of Firmicutes and Lactobacillus, while there is an increased abundance of Proteobacteria (such as Escherichia coli and Enterococcus), Bacteroidetes (Prevotella, for example), and Actinobacteria (as Gardnerella), in contrast to healthy endometrium. Besides, we discussed the future usefulness of the endometrial microbiota components as biomarkers to diagnose uterine diseases and their probable clinical outcomes. In addition, we analyzed their potential use as probiotics since they could provide an alternative or complement to existing therapies.

Development of Radiosterilized Porcine Skin Electrosprayed with Silver Nanoparticles Prevents Infections in Deep Burns.

Extensive burns represent a significant challenge in biomedicine due to the multiple systemic and localized complications resulting from the major skin barrier loss. The functionalization of xenografts with nanostructured antibacterial agents proposes a fast and accessible application to restore barrier function and prevent localized bacterial contamination. Based on this, the objective of this work was to functionalize a xenograft by electrospray deposition with silver nanoparticles (AgNPs) and to evaluate its antibiofilm and cytotoxic effects on human fibroblasts. Initially, AgNPs were synthesized by a green microwave route with sizes of 2.1, 6.8, and 12.2 nm and concentrations of 0.055, 0.167, and 0.500 M, respectively. The AgNPs showed a size relationship directly proportional to the concentration of AgNO3, with a spherical and homogeneous distribution determined by high-resolution transmission electron microscopy. The surface functionalization of radiosterilized porcine skin (RPS) via electrospray deposition with the three AgNP concentrations (0.055, 0.167, and 0.500 M) in the epidermis and the dermis showed a uniform distribution on both surfaces by energy-dispersive X-ray spectroscopy. The antibiofilm assays of clinical multidrug-resistant Pseudomonas aeruginosa showed significant effects at the concentrations of 0.167 and 0.500 M, with a log reduction of 1.3 and 2.6, respectively. Additionally, viability experiments with human dermal fibroblasts (HDF) exposed to AgNPs released from functionalized porcine skin showed favorable tolerance, with retention of viability more significant than 90% for concentrations of 0.05 and 0.167 M after 24 h exposure. Antibacterial activity combined with excellent biocompatibility makes this biomaterial a candidate for antibacterial protection by inhibiting bacterial biofilms in deep burns during early stages of development.

The impact of COVID-19 pandemic on frail health systems of low- and middle-income countries: The case of epilepsy in the rural areas of the Bolivian Chaco.

INTRODUCTION: The Coronavirus disease 2019 (COVID-19) has put some health systems under pressure, especially in low- and middle-income countries. We aimed at evaluating the impact of COVID-19 emergency on the management of people with epilepsy (PWE) living in the rural communities of the Gran Chaco area of the Plurinational State of Bolivia. MATERIALS AND METHODS: We selected a sample of PWE living in the rural communities of the Bolivian Chaco. A standardized questionnaire was developed, consisting of six questions addressing drug availability, drug discontinuation, personnel responsible for drug retrieval during the lockdown, and the presence of seizures in the two months preceding the interview. Questionnaires were administered by community health workers of the rural health centers in September 2020. RESULTS: Seventy PWE (38 men, 54.3%; mean age 26.9 ±â€¯16.7) were interviewed. During the lockdown the large majority of them (n = 51, 73.9%) reported an irregular medication intake mainly due to the lack of antiseizure medications in the local health posts, leading to an increase in seizure frequency. CONCLUSION: The COVID-19 pandemic has unmasked the frailty of the Bolivian health system, especially for the management of chronic diseases such as epilepsy in the rural communities.

Usefulness of a smartphone application for the diagnosis of epilepsy: Validation study in high-income and rural low-income countries.

INTRODUCTION: In low- and middle-income countries (LMIC), the diagnosis of epilepsy should be made by Non-Physician Health Workers (NPHW) who are widely available in these settings. Recently a smartphone app (Epilepsy Diagnosis Aid) has been developed and validated to be used by NPHW, in order to confirm the diagnosis of epilepsy. The aim of our study was to perform a validation of the app in two different contexts: a hospital-based setting of a high-income country (HIC) and a population-based setting of the rural communities of a LMIC. MATERIAL AND METHODS: For the hospital-based setting, the app was administered to a sample of patients with epilepsy (PWE) and to a sample of subjects affected by syncope attending the epilepsy center of the University of Catania. For the population-based setting, performed in the rural communities of the Gran Chaco region in Bolivia,the app was administered by NPHW to a sample of PWE previously identified. Sensitivity and specificity were calculated for the diagnosis of epilepsy. RESULTS: In the hospital-setting, the app was administered to 100 PWE and 20 syncopes. A probability score > 80 showed a sensitivity of 76% (95%CI 66.4-84) and a specificity of 100% (95%CI 83.2-100) for the diagnosis of epilepsy; higher values were found for active epilepsy with tonic-clonic seizures. In the rural-setting, the app was administered to 38 PWE, giving a sensitivity of 92.1% (95%CI 78.6-98.3). CONCLUSION: The app for epilepsy could represent a valuable instrument, which can be easily employed by trained NPHW to diagnose epilepsy in primary health-care settings of LMIC.

Costs and outcomes of "intermediate" vs "minimal" care for youth-onset type 1 diabetes in six countries.

OBJECTIVE: Data are needed to demonstrate that providing an "intermediate" level of type 1 diabetes (T1D) care is cost-effective compared to "minimal" care in less-resourced countries. We studied these care scenarios in six countries. METHODS: We modeled the complications/costs/mortality/healthy life years (HLYs) associated with "intermediate" care including two blood glucose tests/day (mean HbA1c 9.0% [75 mmol/mol]) in three lower-gross domestic product (GDP) countries (Mali, Tanzania, Pakistan), or three tests/day (mean HbA1c 8.5% [69 mmol/mol]) in three higher-GDP countries (Bolivia, Sri Lanka, Azerbaijan); and compared findings to "minimal" care (mean HbA1c 12.5% [113 mmol/mol]). A discrete time Markov illness-death model with age and calendar-year-dependent transition probabilities was developed, with inputs of 30 years of complications and Standardized Mortality Rate data from the youth cohort in the Pittsburgh Epidemiology of Diabetes Complications Study, background mortality, and costs determined from international and local prices. RESULTS: Cumulative 30 years incidences of complications were much lower for "intermediate care" than "minimal care", for example, for renal failure incidence was 68.1% (HbA1c 12.5%) compared to 3.9% (9%) and 2.4% (8.5%). For Mali, Tanzania, Pakistan, Bolivia, Sri Lanka, and Azerbaijan, 30 years survival was 50.1%/52.7%/76.7%/72.5%/82.8%/89.2% for "intermediate" and 8.5%/10.1%/39.4%/25.8%/45.5%/62.1% for "minimal" care, respectively. The cost of a HLY gained as a % GDP/capita was 141.1%/110.0%/52.3%/41.8%/17.0%/15.6%, respectively. CONCLUSIONS: Marked reductions in complications rates and mortality are achievable with "intermediate" T1D care achieving mean clinic HbA1c of 8.5% to 9% (69-75 mmol/mol). This is also "very cost-effective" in four of six countries according to the WHO "Fair Choices" approach which costs HLYs gained against GDP/capita.

Comic book-based educational program on epilepsy for high-school students: Results from a pilot study in the Gran Chaco region, Bolivia.

INTRODUCTION: In low- and middle-income countries (LMIC), epilepsy still represents a significant health challenge. In the Bolivian Chaco, we have previously found high levels of stigma towards people with epilepsy (PWE) especially expressed by high school students. In order to increase the knowledge about epilepsy, we have tested a comic book-based intervention on a sample of high school students. METHODS: The study has been conducted in the Bolivian Chaco region where two urban and two rural classrooms have been randomly selected. Students have been administered a knowledge, attitudes, and practices (KAP) questionnaire, and then they underwent a comic book-based educational program where they were randomly assigned either to an autonomous reading or a character interpretation methodology. The same KAP questionnaire has been administered after the teaching session and at a three months follow-up. Mean KAP scores at the baseline were compared with the after teaching and the three-month assessment. RESULTS: Eighty-three students with a mean age of 15.5 ±â€¯0.9 years, of whom 38 (45.8%) males, were recruited. After the comic book session, students improved in the global score (p < 0.001) and in the knowledge (p < 0.001), attitudes (p = 0.004), and practices (p < 0.001) subscores. Both the autonomous reading and the character interpretation groups significantly improved in the global score, but only the latter improved in all the subscores. At the three months follow-up, there were no differences in the global, knowledge, and attitudes subscores, compared with scores immediately after the intervention. CONCLUSION: Using a comic book to teach about epilepsy led to a significant improvement in the knowledge, attitudes, and practices about the disease in high school students of LMIC. This teaching strategy can be easily implemented in LMIC.

DNA methylation in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the leading endocrine and metabolic disorder in premenopausal women characterized by hyperandrogenism and abnormal development of ovarian follicles. To date, the PCOS etiology remains unclear and has been related to insulin resistance, obesity, type 2 diabetes mellitus, cardiovascular disease and infertility, among other morbidities. Substantial evidence illustrates the impact of genetic, intrauterine and environmental factors on the PCOS etiology. Lately, epigenetic factors have garnered considerable attention in the pathogenesis of PCOS considering that changes in the content of DNA methylation, histone acetylation and noncoding RNAs have been reported in various tissues of women with this disease. DNA methylation is changed in the peripheral and umbilical cord blood, as well as in ovarian and adipose tissue of women with PCOS, suggesting the involvement of this epigenetic modification in the pathogenesis of the disease. Perhaps, these defects in DNA methylation promote the deregulation of genes involved in inflammation, hormone synthesis and signaling and glucose and lipid metabolism. Research on the role of DNA methylation in the pathogenesis of PCOS is just beginning, and several issues await investigation. This review aims to provide an overview of current research focused on DNA methylation and PCOS, as well as discuss the perspectives regarding this topic.

Cellular and Humoral Responses to Cte f 2, a Cat Flea Allergen, in Children with Papular Urticaria.

BACKGROUND: Papular urticaria (PU) is a common insect bite skin hypersensitivity in tropical countries. In order to gain insight into its causal allergens, we aimed to evaluate cellular and humoral immune responses to the recombinant salivary antigen Cte f 2 from the cat flea Ctenocephalides felis. METHOD: Sixty patients with PU and 27 healthy controls were included in this study. Specific IgE, IgG, IgG1, and IgG4 against Cte f 2 and C. felis extract were determined by ELISA. The T-cell response was analyzed using a carboxyfluorescein succinimidyl ester (CFSE)-based dilution assay and Th1/Th2/Th17 cytokine measurements. In addition, a proteomic analysis of IgG and IgE reactive spots of C. felis extract was performed. RESULTS: The frequency of IgE sensitization to Cte f 2 was similar between patients (36.7%) and controls (40.7%). The specific IgE, IgG1, and IgG4 responses to Cte f 2 and C. felis extract were not significantly different between patients and controls. Among the 3 conditions (i.e., Cte f 2, C. felis extract, and only medium) Cte f 2 was the strongest inducer of CD3+CD4+ proliferation in the patients; however, the mean response was not significantly different from those in controls (Cte f 2: 4.5 vs. 2.5%; p = 0.46). No salivary proteins were identified in C. felis, and most of the spots were identified as muscle-skeletal components (tropomyosin, actin, myosin, and ankirin). CONCLUSIONS: Cte f 2 induces IgE and IgG production as well as T-cell proliferation in children living in a geographical area where PU induced by a flea bite is common. The use of C. felis extract is not recommended for the study of bite-induced hypersensitivity disease since salivary antigens are not well represented.

Knowledge, stigma, and quality of life in epilepsy: Results before and after a community-based epilepsy awareness program in rural Bolivia.

INTRODUCTION: Epilepsy represents around 0.7% of the overall global burden of diseases and is particularly prevalent and associated with significant disability in low- and middle-income countries (LMIC) in Latin American Countries (LAC). A community-based epilepsy awareness program was carried out by our group in the rural areas of the Chaco region, Plurinational state of Bolivia, to improve the knowledge about epilepsy, with a first part directed toward general practitioners and a second part toward nurses and community health workers (CHWs) of the rural communities with a positive outcome. The objective of the study was to assess the level of knowledge, attitudes, and practices toward epilepsy, the stigma related to epilepsy and the quality of life in people with epilepsy (PWE) before and after the interventional campaign directed toward representative members of the rural communities in the Chaco region in Bolivia. METHODS: The study was conducted in three areas of Bolivia. Key subjects from each community were randomly selected. Before and after the courses they answered a questionnaire to assess their knowledge, attitudes, beliefs, and practices about epilepsy, a validated Stigma Scale of Epilepsy (SSE) and Quality of Life in Epilepsy Inventory-10 (QOLIE-10). RESULTS: Two hundred sixteen subjects were involved in the program. Only 133 (61.6%) subjects completed the questionnaires a month after the educational program. A significant improvement was recorded in knowledge, attitudes, and practices toward epilepsy, and a significant reduction was found in the mean SSE total score (38.3 ±â€¯14.7 vs. 28.5 ±â€¯12.3; p < 0.01), reflecting a reduction of stigma levels. Regarding the quality of life, after the training, PWE stated to experience less depression, memory difficulties, work or social issues, and seizure worry. CONCLUSION: Our study confirms that continuous educational campaigns can lead to a significant change in the social perception and attitudes toward epilepsy.

On the Prediction of Upwelling Events at the Colombian Caribbean Coasts from Modis-SST Imagery.

The upwelling cores on the Caribbean Colombian coasts are mainly located at the Peninsula de la Guajira and Cabo de la Aguja. We used monthly averaged Moderate Resolution Imaging Spectroradiometer (MODIS) sea surface temperature as the only information to build up a prediction model for the upwelling events. This comprised two steps: (i) the reduction of the complexity by means of the Karhunen-Loève transform and (ii) a prediction model of time series. Two prediction models were considered: (a) a parametric autoregressive-moving average (ARMA) time series from the Box-Jenkins methodology and (b) a harmonic synthesis model. The harmonic synthesis also comprised of two steps: the maximum entropy spectral analysis and a least-squares harmonic analysis on the set of frequencies. The parametric ARMA time series model failed at the time of prediction with a very narrow range, and it was quite difficult to apply. The harmonic synthesis allowed prediction with a horizon of six months with a correlation of about 0.80. The results can be summarized using the time series of the weights of the different oscillation modes, their spatial structures with the nodal lines, and a high confidence model with a horizon of prediction of about four months.

Unhealthy Levels of Phthalates and Bisphenol A in Mexican Pregnant Women with Gestational Diabetes and Its Association to Altered Expression of miRNAs Involved with Metabolic Disease.

Several studies indicate that bisphenol A (BPA) and phthalates may have a role in the development of metabolic diseases using different molecular pathways, including epigenetic regulatory mechanisms. However, it is unclear whether exposure to these chemicals modifies serum levels of miRNAs associated with gestational diabetes mellitus (GDM) risk. In the present study, we evaluated the serum levels of miRNAs associated with GDM (miR-9-5p, miR-16-5p, miR-29a-3p and miR-330-3p) and urinary levels of phthalate metabolites (mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP) and mono(2-ethyl hexyl) phthalate (MEHP)) and bisphenol A in GDM patients and women without GDM during the second trimester of gestation. We observed higher levels of miR-9-5p, miR-29a-3p and miR-330-3p in sera of patients with GDM compared to non-diabetic subjects. Phthalates were detected in 97-100% of urine samples, while BPA only in 40%. Urinary MEHP and BPA concentrations were remarkably higher in both study groups compared to previously reported data. Unadjusted MEHP levels and adjusted BPA levels were higher in non-diabetics than in GDM patients (p = 0.03, p = 0.02). We found positive correlations between adjusted urinary MBzP levels and miR-16-5p expression levels (p < 0.05), adjusted MEHP concentrations and miR-29a-3p expression levels (p < 0.05). We also found negative correlations between unadjusted and adjusted MBP concentrations and miR-29a-3p expression levels (p < 0.0001, p < 0.05), unadjusted MiBP concentrations and miR-29a-3p expression levels (p < 0.01). Urinary MEHP levels reflect a striking exposure to di(2-ethylhexyl) phthalate (DEHP) in pregnant Mexican women. This study highlights the need for a regulatory strategy in the manufacture of several items containing endocrine disruptors in order to avoid involuntary ingestion of these compounds in the Mexican population.

Knowledge and attitudes towards epilepsy among nonmedical health workers in rural Bolivia: Results after a long-term activity in the Chaco region.

INTRODUCTION: Epilepsy represents a major global healthcare issue, particularly in low- and middle-income countries (LMIC), where nonmedical health workers play a key role in providing care to people with epilepsy (PWE). Over the last 20 years, many projects have been carried out by our group in the Chaco region, Plurinational State of Bolivia, with the aim of enhancing knowledge about epilepsy. However, the level of knowledge of epilepsy that nonmedical health workers have reached has never been assessed until now. The main objective of our study was to assess the level of knowledge, attitudes, and practices (KAP) towards epilepsy among nonmedical health staff of the rural communities of the Chaco region in Bolivia. METHODS: The study was conducted in three departments of Bolivia. The nonmedical health personnel were invited to participate in a training program. They answered a validated questionnaire to evaluate their knowledge and attitudes towards epilepsy before and after the courses. RESULTS: One hundred nineteen subjects [42 men (36.2%); mean age 29.3 ±â€¯1.1 years] were interviewed among community health workers and nurses before the courses, demonstrating a very good level of knowledge regarding epilepsy and its causes. Only 55 health workers participated in the second training module, and their answer did not significantly differ from the baseline. CONCLUSION: Our study confirms the usefulness of continuous educational campaigns, especially directed to nonspecialist healthcare providers of rural communities of LMIC, as they may be the only persons responsible for providing healthcare to PWE in that setting. Moreover, the importance of the baseline assessment of KAP was highlighted in order to adapt the educational campaigns to the baseline level of knowledge found.

Knowledge, attitudes, and practices towards epilepsy among general practitioners in rural Bolivia: Results before and after a training program on epilepsy.

INTRODUCTION: Epilepsy represents a major health problem in low- and middle-income countries where treatment gap (TG) levels are high. The reduction of epilepsy TG in the rural area of the Chaco region, Plurinational State of Bolivia, has been the aim of many projects based on the reinforcement of the primary care setting. To plan educational campaigns directed to the healthcare professionals, it is necessary to establish their baseline knowledge level. The objective of our study was to assess the baseline level of knowledge, attitudes, and practices (KAP) towards epilepsy among general practitioners (GPs) of the rural communities of the Chaco region. METHODS: The study was conducted in three departments of Bolivia. All the GPs living in these areas were invited to participate in the study consisting of two training modules six months apart from each other, each with two-day duration. They answered a validated questionnaire to evaluate the KAP towards epilepsy before and after the courses. RESULTS: Fifty GPs [30 men (60%); mean age: 32.1±5.8years] participated in the first training course. After six months, 31 GPs (62%) [19 men (61.3%); mean age: 33±5.0years] participated in the second module. Before the training, the majority of GPs declared a low level of satisfaction about their epilepsy knowledge, which improved after the courses. A change in practices was recorded after the training, with an increased confidence to manage antiepileptic treatment. CONCLUSION: Our study showed the significant impact of specific training programs on epilepsy among GPs.

Dibutyltin(IV) Complexes Derived from L-DOPA: Synthesis, Molecular Docking, Cytotoxic and Antifungal Activity.

A series of organotin(IV) complexes was herein prepared and characterized. A one-pot synthetic strategy afforded reasonable to high yields, depending on the nature of the ligand. All new complexes were fully characterized by spectroscopic techniques, consisting of IR, MS and NMR (1H, 13C and 119Sn). The in vitro cytotoxicity tests demonstrated that the organotin complexes produced a greater inhibition, versus cisplatin (the positive control), of the growth of six human cancer cell lines: U-251 (glioblastoma), K-562 (chronic myelogenous leukemia), HCT-15 (colorectal), MCF-7 (breast), MDA-MB-231 (breast) and SKLU-1 (non-small cell lung). The potency of this cytotoxic activity depended on the nature of the substituent bonded to the aromatic ring. All complexes exhibited excellent IC50 values. The test compounds were also screened in vitro for their antifungal effect against Candida glabrata and Candida albicans, showing minimum inhibitory concentration (MIC) values lower than those obtained for fluconazole. A brine shrimp bioassay was performed to examine the toxic properties. Molecular docking studies demonstrated that the organotin(IV) complexes bind at the active site of topoisomerase I in a similar manner to topotecan, sharing affinity for certain amino acid side chains (Ile535, Arg364 and Asp533), as well as for similar DNA regions (DA113, DC112 and DT10).

The 95ΔG mutation in the 5'untranslated region of the norA gene increases efflux activity in Staphylococcus epidermidis isolates.

In the Staphylococcus aureus ATCC25923 strain, the flqB mutation in the 5'untranslated region (5'UTR) of the norA gene causes increased norA mRNA expression and high efflux activity (HEA). The involvement of the norA gene 5'UTR in HEA has not been explored in S. epidermidis; therefore, we examined the function of this region in S. epidermidis clinical isolates. The selection of isolates with HEA was performed based on ethidium bromide (EtBr) MIC values and efflux efficiency (EF) using the semi-automated fluorometric method. The function of the 5'UTR was studied by quantifying the levels of norA expression (RT-qPCR) and by identifying 5'UTR mutations by sequence analysis. Only 10 isolates from a total of 165 (6.1%) had HEA (EtBr MIC = 300 µg/ml and EF ranged from 48.4 to 97.2%). Eight of 10 isolates with HEA had the 5'UTR 95ΔG mutation. Isolates carrying the 95ΔG mutation had higher levels of norA expression compared with those that did not. To corroborate that the 95ΔG mutation is involved in HEA, a strain adapted to EtBr was obtained in vitro. This strain also presented the 95ΔG mutation and had a high level of norA expression and EF, indicating that the 95ΔG mutation is important for the HEA phenotype. The 95ΔG mutation produces a different structure in the Shine-Dalgarno region, which may promote better translation of norA mRNA. To our knowledge, this is the first report to demonstrate the participation of the 5'UTR 95ΔG mutation of the norA gene in the HEA phenotype of S. epidermidis isolates. Here, we propose that the efflux of EtBr is caused by an increment in the transcription and/or translation of the norA gene.

An Efficient Strategy for the Synthesis of 1-(Trifluoromethylsulfonamido)propan-2-yl Esters and the Evaluation of Their Cytotoxic Activity.

An efficient method for the synthesis of 1-(trifluoromethylsulfonamido)propan-2-yl benzoates is described, the products of the reaction were characterized by heteronuclear single quantum coherence spectroscopy (HSQC), heteronuclear multiple bond correlation (HMBC) and NMR experiments. The overall process began with the activation of the oxazoline ring by triflic anhydride, followed by the opening of the five-membered ring in the 5-methyl-2-phenyl-4,5-dihydrooxazole system. The cytotoxic activity of the new trifluoromethyl sulfonamides was evaluated with six cancer cell lines and human gingival fibroblasts, posteriorly analyzing the influence on cytotoxicity exerted by the withdrawing and donor substituents at the para-position of the phenyl ring. Compounds 3b-e showed cytotoxic activity, with IC50 values ranging from 17-17.44 µM for the cell lines tested, finding the highest effect for compound 3e.