Publications by authors named "Roberto Martinez"

168 Publications

()-3-Hydroxy-3-(4-R-Phenyl)-Prop-2-Enedithioic Acids as New Antituberculosis Compounds.

Infect Drug Resist 2021 20;14:4323-4332. Epub 2021 Oct 20.

Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Cd. México, 04510, México.

Background: Tuberculosis is an infectious disease caused by the bacillus . Compounds including a sulfur-containing scaffold have been shown to be key scaffolds in various antituberculosis agents. Interestingly, the 3-hydroxy-3-phenyl-prop-2-enedithioic acids have, to the best of our knowledge, not been previously described as antituberculosis agents.

Purpose: In the present study, we investigated the role of substituents attached to the phenyl ring of a 3-hydroxy-3-phenyl-prop-2-enedithioic acid scaffold (compounds ) in inhibiting the growth of strain H37Rv.

Methods: (Z)-3-hydroxy-3-(4-R-phenyl)-prop-2-enedithioic acids , with R groups including various electron-donating or electron-withdrawing groups, were designed by structurally modifying the lead compound . The syntheses of involved each one-step procedure starting from the corresponding substituted acetophenone. Compounds were tested against strain H37Rv to evaluate their bacterial growth inhibitory activities. ADMET profiles were predicted by employing three different methods. In addition, molecular docking studies were carried out, based on the molecular similarities of the synthesized compounds with ethionamide (), on the active site of the H37Rv (3R)-hydroxyacyl-ACP (HadAB) dehydratase heterodimer.

Results: The antituberculosis activities of compounds could be explained in terms of the presence of electron-donating or electron-withdrawing substituents on the aromatic ring of the substituted 3-hydroxy-3-phenyl)-prop-2-enedithioic acid core. The activity and selectivity index (SI) value of ()-3-hydroxy-3-(4-nitrophenyl)-prop-2-enedithioic acid suggested that this compound could be used for the design of novel antituberculosis agents. Most of the synthesized molecules showed an acceptable ADME profile and a low probability of being toxic. Docking studies of and showed them forming hydrogen bonds with the ACys61 residue of the HadAB enzyme.

Conclusion: Our results suggested that the antituberculosis compound could be used for the design of novel antituberculosis agents.
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http://dx.doi.org/10.2147/IDR.S328132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543028PMC
October 2021

Total syntheses and antiproliferative activities of prenostodione and its analogues.

Org Biomol Chem 2021 Oct 6;19(38):8272-8280. Epub 2021 Oct 6.

Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán, Ciudad de México, 04510, Mexico.

A high-yielding total synthesis of the indole alkaloid prenostodione was completed in 4 steps and 44% overall yield from 1-indole-3-carboxylic acid. The expedient syntheses of prenostodiones containing distinct substituents at the position of the phenyl frame underscored the scope of this methodology. The cytotoxic activities of the -butyl esters of prenostodione analogues were tested using six tumor cell lines. Preliminary structure-activity studies revealed the importance of the identity of the aromatic substituent at the C-4 position for cytotoxic activity. The IC values of these compounds were found to compare satisfactorily with those of the commercially available drugs etoposide and cisplatin. Furthermore, the compounds with, respectively, -OMe (14d) and -NO (14f) groups at C-4 were more selective than these control compounds in PC-3, K-562, and MCF-7 cells. Also, computational studies were carried out to determine the ADMET profiles and passive membrane permeabilities of the compounds. The results suggested the promise of 14d and 14f as hit compounds for the development of new anticancer agents.
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http://dx.doi.org/10.1039/d1ob00897hDOI Listing
October 2021

Cryptococcosis by Cryptococcus neoformans/Cryptococcus gattii Species Complexes in non-HIV-Infected Patients in Southeastern Brazil.

Rev Soc Bras Med Trop 2021 6;54:e01692021. Epub 2021 Sep 6.

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Ribeirão Preto, SP, Brasil.

Introduction: The clinical manifestations of cryptococcosis are usually associated with the infecting agents Cryptococcus neoformans (CN) and C. gattii (CG) species complexes and the host. In this study, non-HIV-infected patients, at a university hospital in southeastern Brazil, had epidemiological and clinical data associated with cryptococcal disease and isolated Cryptococcus species: CN - 24 patients and CG - 12 patients.

Methods: The comparison was comprised of demographic data, predisposing factors, clinical and laboratory manifestations, and outcomes of cryptococcosis patients treated between 2000 and 2016. Immunocompetent and immunosuppressed patients were also compared, irrespective of the infecting species. Cryptococcus spp. were genotyped by PCR-RFLP analysis of the URA5 gene.

Results: Infections by the CN species complex (100% VNI genotype) were associated with drug immunosuppression and fungemia, and patients infected with the CG species complex (83% VG II and 17% VGI genotypes) had more evident environmental exposure and higher humoral response. CN and CG affected patients with or without comorbidities.

Conclusions: Diabetes mellitus, other chronic non-infectious diseases, and alcoholism were likely predisposing factors for infection by both CN and CG species. Immunocompetent patients, independent of the infecting Cryptococcus species complexes, showed a higher occurrence of meningitis and a trend toward less fungal dissemination and longer survival than immunosuppressed hosts.
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http://dx.doi.org/10.1590/0037-8682-0169-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437442PMC
September 2021

Serological diagnosis of paracoccidioidomycosis using a Paracoccidioides spp. comercial antigen and the counterimmunoelectrophoresis method.

Braz J Infect Dis 2021 Sep-Oct;25(5):101607. Epub 2021 Sep 1.

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Ribeirão Preto, SP, Brazil. Electronic address:

Purpose: In-house Paracoccidioides spp. antigens are commonly used in the serological diagnosis of paracoccidioidomycosis (PCM). The sensitivity and specificity of a commercial Paracoccidioides spp. antigen was assessed for PCM serological testing.

Method: Counterimmunoelectrophoresis and double immunodiffusion were used to evaluate the Paracoccidioides ID Antigen® reagent in sera from PCM cases and patients with other diseases.

Results: All active PCM sera (n=24) were reactive using counterimmunoelectrophoresis (sensitivity = 100%), including 11 cases of infection by P. brasiliensis sensu stricto and one by P. americana. Fifteen (88%) out of 17 sera from patients on treatment or cured were reactive, including one case of P. lutzii infection. One to three bands of antigen-antibody precipitate were observed on the agarose gel, with a predominance of two to three bands in the test with untreated PCM sera or at the beginning of antifungal therapy. All sera from patients with histoplasmosis (n=7), aspergillosis (n=5), and other diseases (n=27) tested negative (specificity = 100%). The overall sensitivity and specificity using the commercial antigen and double diffusion test were 75% and 100%, respectively.

Conclusion: The commercial antigen performed satisfactorily and may contribute to the dissemination of the use of serological tests for the PCM diagnosis.
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http://dx.doi.org/10.1016/j.bjid.2021.101607DOI Listing
November 2021

Nucleus-Independent Chemical Shift (NICS) as a Criterion for the Design of New Antifungal Benzofuranones.

Molecules 2021 Aug 21;26(16). Epub 2021 Aug 21.

Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior de Ciudad Universitaria, Ciudad de México 04510, Mexico.

The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related ( < 0.05); when aromaticity increased, the antifungal activity decreased for series I and increased for series II. To verify the validity of the obtained equations, a new set of 44 benzofuran-4-ones was designed by replacing the nitrogen atom of the five-membered ring with oxygen in indol-4-ones. The NICS(0) and NICS(1) of benzofuran-4-ones were calculated and used to predict their biological activities using the previous equations. A set of 10 benzofuran-4-ones was synthesized and tested in eight human pathogenic fungi, showing the validity of the equations. The minimum inhibitory concentration (MIC) in yeasts was 31.25 µg·mL for , and with compounds -, - and -. The MIC for filamentous fungi was 1.95 µg·mL for for compounds -, - and - The results obtained support the use of NICS in the molecular design of compounds with antifungal activity.
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http://dx.doi.org/10.3390/molecules26165078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401487PMC
August 2021

Pre- and post-COVID-19 evaluation of antimicrobial susceptibility for healthcare-associated infections in the intensive care unit of a tertiary hospital.

Rev Soc Bras Med Trop 2021 23;54:e00902021. Epub 2021 Jul 23.

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Divisão de Doenças Infecciosas e Tropicais, Departamento de Clínica Médica, Ribeirão Preto, SP, Brasil.

Introduction: Antimicrobial resistance has worsened since the onset of COVID-19.

Methods: This study involved patients admitted to the adult intensive care unit (ICU) of a tertiary hospital. Pre- and post-COVID-19 data were analyzed. The healthcare-related infections (HCRIs) reported between January 2018 and January 2020 and during the pandemic between February and July 2020 were compared.

Results: Antimicrobial resistance increased during the pandemic, especially for Klebsiella pneumoniae isolates, with a rate increase from 5% to 50% for Polymyxin B.

Conclusions: The susceptibilities of the main pathogens associated with HCRIs in the ICU changed and should be considered in managing severe COVID-19.
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http://dx.doi.org/10.1590/0037-8682-0090-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313097PMC
July 2021

Small flexible automated system for monitoring Caenorhabditis elegans lifespan based on active vision and image processing techniques.

Sci Rep 2021 06 10;11(1):12289. Epub 2021 Jun 10.

Cell Biology Laboratory/ADM Nutrition/Biopolis SL/Archer Daniels Midland, Paterna, Valencia, Spain.

Traditionally Caenorhabditis elegans lifespan assays are performed by manually inspecting nematodes with a dissection microscope, which involves daily counting of live/dead worms cultured in Petri plates for 21-25 days. This manual inspection requires the screening of hundreds of worms to ensure statistical robustness, and is therefore a time-consuming approach. In recent years, various automated artificial vision systems have been reported to increase the throughput, however they usually provide less accurate results than manual assays. The main problems identified when using these vision systems are the false positives and false negatives, which occur due to culture media changes, occluded zones, dirtiness or condensation of the Petri plates. In this work, we developed and described a new C. elegans monitoring machine, SiViS, which consists of a flexible and compact platform design to analyse C. elegans cultures using the standard Petri plates seeded with E. coli. Our system uses an active vision illumination technique and different image-processing pipelines for motion detection, both previously reported, providing a fully automated image processing pipeline. In addition, this study validated both these methods and the feasibility of the SiViS machine for lifespan experiments by comparing them with manual lifespan assays. Results demonstrated that the automated system yields consistent replicates (p-value log rank test 0.699), and there are no significant differences between automated system assays and traditionally manual assays (p-value 0.637). Finally, although we have focused on the use of SiViS in longevity assays, the system configuration is flexible and can, thus, be adapted to other C. elegans studies such as toxicity, mobility and behaviour.
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http://dx.doi.org/10.1038/s41598-021-91898-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192789PMC
June 2021

Dermatological and Genital Manifestations of Lyme Disease Including Morgellons Disease.

Clin Cosmet Investig Dermatol 2021 6;14:425-436. Epub 2021 May 6.

Union Square Medical Associates, San Francisco, CA, USA.

Although the erythema migrans (EM) skin rash is traditionally considered a hallmark of Lyme disease, other dermatological manifestations of the tickborne disease are less well known. We describe a 49-year-old woman with erosive genital ulcerations, secondary EM rashes and jagged skin lesions associated with Lyme disease. The skin rashes exhibited fibers characteristic of Morgellons disease. Molecular testing confirmed the presence of DNA in both vaginal culture and serum specimens. In further studies on a secondary EM lesion containing filaments, Gömöri trichrome staining revealed the presence of collagen in the filaments, while Dieterle and anti- immunostaining revealed intracellular and extracellular organisms. Intracellular staining for was also observed in lymphocytic infiltrates. Lyme disease may present with a variety of genital lesions and dermatological manifestations including Morgellons disease. Careful evaluation is required to determine the presence of organisms associated with these dermopathies.
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http://dx.doi.org/10.2147/CCID.S299526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110212PMC
May 2021

Genetic diversity assessed using PFGE, MLP and MLST in Candida spp. candidemia isolates obtained from a Brazilian hospital.

Braz J Microbiol 2021 Jun 20;52(2):503-516. Epub 2021 Feb 20.

Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Bloco S - Térreo - Sala 013A-S, Avenida do Café S/N, CEP 14040-903, Ribeirão Preto, São Paulo, Brazil.

Candida spp. are the main causative agents of invasive fungal infections in immunocompromised patients. Candidemia has attributable mortality rates of 15 to 35% and increases hospitalisation time and costs, thus making this disease a public health concern. This study aimed to use pulsed-field gel electrophoresis (PFGE), microsatellite length polymorphism (MLP) and multilocus sequence typing (MLST) to analyse the genetic relationships among 65 Candida spp. bloodstream isolates, including 35 Candida albicans, 15 Candida glabrata and 15 Candida tropicalis isolates, all of which were obtained from patients in a Brazilian hospital. Moreover, patient clinical data were assessed. All techniques resulted in high discriminatory indexes. C. albicans and C. tropicalis isolates showed high genetic variability, while C. glabrata isolates had relatively low genetic variability. Moreover, a cluster of C. glabrata isolates was identified in a hospital unit. New MLST sequence types, diploid sequence types and alleles are described. Relationships were not observed between the molecular typing results and clinical characteristics. The molecular typing of clinical strains increases our understanding of candidemia epidemiology and promotes the development of strategies that can reduce the incidence of this disease. Moreover, this study is the first to combine these techniques to genotype these three species in Brazil.
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http://dx.doi.org/10.1007/s42770-021-00446-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105495PMC
June 2021

Design and Validation of a Scalable, Reconfigurable and Low-Cost Structural Health Monitoring System.

Sensors (Basel) 2021 Jan 19;21(2). Epub 2021 Jan 19.

Research group of Timber Structures and Wood Technology, University of Valladolid, Av. de Salamanca, 18, 47014 Valladolid, Spain.

This paper presents the design, development and testing of a low-cost Structural Health Monitoring (SHM) system based on MEMS (Micro Electro-Mechanical Systems) triaxial accelerometers. A new control system composed by a myRIO platform, managed by specific LabVIEW software, has been developed. The LabVIEW software also computes the frequency response functions for the subsequent modal analysis. The proposed SHM system was validated by comparing the data measured by this set-up with a conventional SHM system based on piezoelectric accelerometers. After carrying out some validation tests, a high correlation can be appreciated in the behavior of both systems, being possible to conclude that the proposed system is sufficiently accurate and sensitive for operative purposes, apart from being significantly more affordable than the traditional one.
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http://dx.doi.org/10.3390/s21020648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832321PMC
January 2021

Paracoccidioidomycosis due to Paracoccidioides lutzii complicated with adrenal injury and pulmonary arterial hypertension.

Rev Inst Med Trop Sao Paulo 2020 13;62:e89. Epub 2020 Nov 13.

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Ribeirão Preto, São Paulo, Brazil.

Paracoccidioidomycosis caused by Paracoccidioides lutzii is endemic in the Midwest of Brazil and its clinical spectrum is still little known due to the recent identification of this fungal species. A patient resident in Southeast Brazil, but who had lived for many years in the Midwest region, presented with skin injuries, chronic cough and bilateral adrenal involvement. Paracoccidioides spp. was isolated in culture from a skin lesion biopsy. This isolate was later identified as P. lutzii using gene sequencing. A favorable initial response to treatment with itraconazole was observed, but a few weeks later, the patient developed respiratory failure and worsening of lung lesions. Evaluation by computed tomography and echocardiography were suggestive of pulmonary arterial hypertension, and a bronchoscopic biopsy showed peribronchial remodeling. The patient completed the antifungal treatment but maintained the respiratory dysfunction. The reported case shows that P. lutzii can be isolated from patients in a geographic area far from the place of infection acquisition and that, as P. brasiliensis , it can cause adrenal injury and cardio-respiratory complications as a consequence of excessive necrosis and fibrosis.
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http://dx.doi.org/10.1590/S1678-9946202062089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669275PMC
November 2020

Frontal Sinus Fracture Management Meta-analysis: Endoscopic Versus Open Repair.

J Craniofac Surg 2021 Jun;32(4):1311-1315

Department of Plastic Surgery, University of Virginia, Charlottesville, VA.

Introduction: Frontal sinus fracture management continues to be a point of controversy. Many systematic reviews have been done, but meta-analyses comparing various approaches to frontal sinus fractures are scarce. Our study focuses on open surgical repair versus endoscopic repair of frontal sinus fractures.

Materials And Methods: A MEDLINE search was performed to identify prospective RCTs, non-RCTs, guidelines, case-control, and observational studies published in English before April 2019. Search terms included (1) frontal sinus, (2) skull fractures, (3) frontal bone, alone or in combination. An in-depth review was conducted to identify publications relevant to this analysis. Studies that included pediatric patients, case reports, and review articles without original data were excluded. Postoperative outcomes included were cosmesis, sinus function, mucocele, sinusitis, cerebrospinal fluid leak, meningitis, and brain abscess. Meta-analysis of proportions, Fisher exact test, and relative risks were calculated.

Results: Seven studies were ultimately included in the meta-analysis. The assessment of heterogeneity indicated that the studies are comparable. The weighted outcome proportions of patients with postoperative cosmetic deformity and mucocele are found to be significantly higher in patients who underwent open repair compared to patients who received endoscopic treatment. No significant difference between the 2 intervention groups in regards to the other outcomes.

Conclusion: Based on this meta-analysis, no definitive conclusions regarding superiority of one approach over the other can be made. There are currently no universally accepted algorithms that aid in the decision to proceed with either approach. It is likely that these 2 techniques will come to serve different roles in treatment, as they can each be utilized to achieve different goals. At this time, the only recommendation is to proceed with whichever technique can be safely performed based upon surgeon experience and fracture pattern.
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http://dx.doi.org/10.1097/SCS.0000000000007181DOI Listing
June 2021

Dispersive liquid-liquid microextraction followed by green high-performance liquid chromatography for fluconazole determination in cerebrospinal fluid with the aid of chemometric tools.

Anal Methods 2020 06;12(24):3106-3114

Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.

A new method, simple and fast, for fluconazole (FLU) quantification in cerebrospinal fluid (CSF) samples using dispersive liquid-liquid microextraction (DLLME) and an eco-friendly mobile phase for HPLC-PDA was developed. The study of DLLME extraction condition covered the investigation of 12 combinations of extraction and disperser solvents followed by a fractional factorial design 2(7-3) to determine the influence of seven factors. After this stage, a central composite design was performed for three factors and a response surface was obtained. Aiming a compromise between a good recovery and a low organic solvent use it was established an extraction condition that consists of: 100 μL of chloroform, 100 μL of isopropyl alcohol, 200 μL of CSF, 200 μL of 50 mM phosphate buffer pH 7.3 and centrifugation for 5 min at 2200g and 4 °C. The HPLC analysis used an Ascentis® Express C18 column (100 mm × 4.6 mm, 2.7 μm) and an Ascentis® Express C18 guard column (3 mm × 4.6 mm, 2.7 μm), ethanol : water (15 : 85, v/v) as mobile phase, temperature of 45 °C, flow rate of 0.8 mL min-1 and phenacetin as internal standard. The method validation was performed according to European Agency's Guideline on Bioanalytical Validation Methodology and a linear range was obtained from 0.25 to 62.5 μg mL-1, with precision and accuracy within the recommended limits and recovery of 70% for FLU and 81% for phenacetin. Samples were stable in the studies performed and the method showed to be selective and with no carryover effect. The feasibility of the obtained method was confirmed by FLU determination at a CSF from a patient who was treated for neuromycosis. Therefore, here is described a method that meets many principles of green analytical chemistry and is useful for FLU therapeutic monitoring.
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http://dx.doi.org/10.1039/d0ay00704hDOI Listing
June 2020

Unexpected and Deadly: Three Cases of Bone Marrow Necrosis.

Cureus 2020 Aug 5;12(8):e9565. Epub 2020 Aug 5.

Hematology and Oncology, Sinai Hospital of Baltimore, Baltimore, USA.

Bone marrow necrosis (BMN) is a rare pathological diagnosis, with an incidence of 0.3% to 2%. It is most often associated with hematological malignancies and less commonly due to solid tumors, infections, medications, sickle cell disease, chemotherapy, radiotherapy, or idiopathic causes. We reviewed bone marrow biopsies performed in our institution from 2009 to 2019 and found three cases of BMN. Two cases were secondary to neoplastic causes, while the third one was possibly from alcohol abuse.
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http://dx.doi.org/10.7759/cureus.9565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473607PMC
August 2020

Molecular typing, in vitro susceptibility and virulence of Cryptococcus neoformans/Cryptococcus gattii species complex clinical isolates from south-eastern Brazil.

Mycoses 2020 Dec 30;63(12):1341-1351. Epub 2020 Sep 30.

Faculdade de Ciências Farmacêuticas de Ribeirao Preto, Departamento de Analises Clinicas, Toxicologicas e Bromatologicas, Universidade de Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.

Background: Cryptococcus neoformans/ Cryptococcus gattii species complex is composed of encapsulated yeast species that are causative agents of cryptococcosis. The characterisation of pathogenic Cryptococcus species provides useful data for epidemiological studies as well as the clinical diagnosis and treatment of patients.

Objectives: This study aimed to characterise the epidemiology, antifungal susceptibility and virulence of 72 clinical strains isolated from cryptococcosis cases between 2012 and 2017 in a tertiary reference hospital in south-eastern Brazil.

Methods: Species and molecular types were molecularly assessed by PCR and PCR-restriction fragment length polymorphism (RFLP) of the URA5 gene. Antifungal susceptibility testing was performed according to the CLSI protocols. The virulence was studied in a Galleria mellonella infection model.

Results: The most frequently isolated strain was C. neoformans molecular type VNI (61/72; 84.7%), although C. neoformans molecular type VNII (3/72; 4.2%) was also isolated. Additionally, C. deuterogattii molecular type VGII (8/72; 11.1%) was present, but most frequently from non-HIV-infected patients. Non-wild-type phenotype to the antifungals was observed in 26.4% (19/72) of the C. neoformans and C. deuterogattii clinical isolates, and the latter demonstrated higher MIC to fluconazole and itraconazole than C. neoformans clinical isolates. Finally, the virulence of C. neoformans and C. deuterogattii clinical isolates was diverse in G mellonella larvae and uncorrelated with the virulence factors of melanin and capsule.

Conclusions: The assessment of the spread of cryptococcal species and molecular types as well as the pattern of corresponding antifungal susceptibility and virulence aids in surveil the emergence of resistant strains, ensuring more accurate management of the cryptococcal infection.
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http://dx.doi.org/10.1111/myc.13174DOI Listing
December 2020

Phylogenetic Species of spp. Isolated from Clinical and Environmental Samples in a Hyperendemic Area of Paracoccidioidomycosis in Southeastern Brazil.

J Fungi (Basel) 2020 Aug 11;6(3). Epub 2020 Aug 11.

Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Ribeirão Preto 14049-900, Brazil.

complex and are the etiological agents of paracoccidioidomycosis. The geographic distribution of these species in South America is still poorly comprehended. Fifty samples of spp. were genotyped, with 46 clinical isolates predominantly isolated in the geographic area of Ribeirão Preto, SP, and four environmental isolates collected in Ibiá, MG, southeastern Brazil. These isolates were evaluated by PCR-RFLP (Restriction Fragment Length Polymorphism) of the 1 gene and the sequencing of the exon 2 loci. The species was confirmed by sequencing the internal transcribed spacer (ITS) region of the ribosomal DNA. S1b ( = 42) and S1a ( = 5), ( = 1), ( = 1), and ( = 1) were identified among the clinical isolates. All the environmental isolates were characterized as S1b. The patient infection by , (PS2), and one isolate of S1b most likely occurred in a geographic area far from the fungal isolation site. No association was found between the infecting genotype and the disease form. These results expand the knowledge of the species distribution and emphasize that human migration must also be considered to pinpoint the genotypes in the endemic area.
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http://dx.doi.org/10.3390/jof6030132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559761PMC
August 2020

[Collateral damage of COVID-19 pandemic in private healthcare centres of Argentina].

Medicina (B Aires) 2020 ;80 Suppl 3:37-41

Instituto Modelo de Cardiología Privado, Argentina.

To contain the coronavirus pandemic (COVID-19), a strict nationwide lockdown has been enforced and the health systems have been reorganized to deal with this entity. During this period, changes in the care of non-infectious diseases have been observed. Our aim was to describe the impact of the COVID-19 pandemic in the care of non-communicable diseases. A structured retrospective survey was carried out in 31 healthcare centers affiliated with the Asociación de Clínicas, Sanatorios y Hospitales Privados de la República Argentina y Cámara de Entidades de Diagnóstico y Tratamiento. We compared data for April 2019 versus April 2020 regarding emergency room consultations, hospital admissions, invasive procedures and treatments, and bed occupancy. In April 2020, we observed a decrease in emergency room visits (75%) and hospitalizations (48%). A 62% decrease in admissions was noted for angina pectoris and acute coronary syndromes and a 46% decrease in admissions for stroke and transient ischemic attack. A meaningful decrease was found in coronary angioplasties (59%) and total percutaneous interventions (65%), and also a decrease in general surgeries (73%), and cardiac surgeries (58%). Although social distancing measures are a key public health strategy to flatten the infection curve, the observed decrease in medical visits and interventions may impact negatively on cardiovascular, cerebrovascular and cancer related morbidity and mortality. A collective effort is required to avoid the unintended consequences and collateral damage of the COVID-19 pandemic.
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August 2020

Characterization of a Paracoccidioides spp. strain from southeastern Brazil genotyped as Paracoccidioides restrepiensis (PS3) and review of this phylogenetic species.

Genet Mol Biol 2020 29;43(2):e20190201. Epub 2020 May 29.

Universidade de São Paulo (USP), Faculdade de Medicina de Ribeirão Preto (FMRP), Departamento de Clínica Médica, Ribeirão Preto, SP, Brazil.

Phylogenetic species of Paracoccidioides brasiliensis complex (S1a and S1b, PS2, PS3, and PS4) and Paracoccidioides lutzii are agents of paracoccidioidomycosis, an endemic fungal disease in Latin America. P. restrepiensis (PS3 genotype) was classified as monophyletic and geographically restricted to Colombia and neighboring territories. BAT (or Pb-327B) was isolated from a patient living in the southeast region of Brazil but with genotype similar to Colombian Paracoccidioides spp. strains. This study aimed to define the phylogenetic species of BAT isolate by using additional genotyping methods, as well as reviewing the epidemiological and clinical studies related to P. restrepiensis isolates. Genomic DNA of BAT isolate and reference strains of P. brasiliensis sensu stricto (S1b), P. americana (PS2), P. restrepiensis (PS3), and P. lutzii were analyzed by conventional polymerase chain reaction (PCR) of partial gp43 exon 2 loci, by PCR-RFLP technique of tub1 gene, and by sequencing of the whole gp43 exon 2 loci. Here, we show that BAT isolate belongs to P. restrepiensis species, which is an unusual identification in southeastern Brazil, where P. brasiliensis sensu stricto is the prevalent genotype. This identification has relevance for geographical distribution and propagation of the genus Paracoccidioides in South America.
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http://dx.doi.org/10.1590/1678-4685-GMB-2019-0201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268198PMC
May 2020

Improving lifespan automation for Caenorhabditis elegans by using image processing and a post-processing adaptive data filter.

Sci Rep 2020 05 26;10(1):8729. Epub 2020 May 26.

Cell Biology Laboratory/ADM Nutrition/Biopolis SL/Archer Daniels Midland, Paterna, Valencia, Spain.

Automated lifespan determination for C. elegans cultured in standard Petri dishes is challenging. Problems include occlusions of Petri dish edges, aggregation of worms, and accumulation of dirt (dust spots on lids) during assays, etc. This work presents a protocol for a lifespan assay, with two image-processing pipelines applied to different plate zones, and a new data post-processing method to solve the aforementioned problems. Specifically, certain steps in the culture protocol were taken to alleviate aggregation, occlusions, contamination, and condensation problems. This method is based on an active illumination system and facilitates automated image sequence analysis, does not need human threshold adjustments, and simplifies the techniques required to extract lifespan curves. In addition, two image-processing pipelines, applied to different plate zones, were employed for automated lifespan determination. The first image-processing pipeline was applied to a wall zone and used only pixel level information because worm size or shape features were unavailable in this zone. However, the second image-processing pipeline, applied to the plate centre, fused information at worm and pixel levels. Simple death event detection was used to automatically obtain lifespan curves from the image sequences that were captured once daily throughout the assay. Finally, a new post-processing method was applied to the extracted lifespan curves to filter errors. The experimental results showed that the errors in automated counting of live worms followed the Gaussian distribution with a mean of 2.91% and a standard deviation of ±12.73% per Petri plate. Post-processing reduced this error to 0.54 ± 8.18% per plate. The automated survival curve incurred an error of 4.62 ± 2.01%, while the post-process method reduced the lifespan curve error to approximately 2.24 ± 0.55%.
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http://dx.doi.org/10.1038/s41598-020-65619-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251096PMC
May 2020

How to minimize the pain of local anesthetic administration.

J Fam Pract 2020 May;69(4):172-178

Department of Plastic Surgery, University of Virginia, Charlottesville, USA.

Expertise in the delivery of effective local analgesia is critical to the success of in-office procedures. Here's how to optimize patient outcomes and satisfaction.
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May 2020

Clinical outcome following cerebral AVM hemorrhage.

Acta Neurochir (Wien) 2020 07 8;162(7):1759-1766. Epub 2020 May 8.

Department of Surgery, Div. of Neurosurgery, National University Hospital, 5 Lower Kent Ridge Road, Singapore, 119074, Singapore.

Background: A significant difference exists between the published results reporting the clinical outcome following brain arteriovenous malformation (AVM) ruptures. Information about the outcome following hemorrhage in an AVM population treated with radiosurgery could provide additional information to assess the risk of mortality and morbidity following an AVM hemorrhage.

Methods: Clinical outcome was studied in 383 patients, the largest patient population yet studied, who suffered from a symptomatic hemorrhage after Gamma Knife® surgery (GKS) but before confirmed AVM obliteration. The impact of different patient, AVM, and treatment parameters on the clinical outcome was analyzed. The aim was to generate outcome predictions by comparing our data to and combining them with earlier published results.

Results: No relation was found between clinical outcome and treatment parameters, indicating that the results are applicable also on untreated AVMs. Twenty-one percent of the patients died, 45% developed or experienced worsening of neurological sequelae, and 35% recovered completely after the hemorrhage. Old age was a predictor of poor outcome. Sex, AVM location, AVM volume, and history of prior hemorrhage did not influence the outcome. The mortality rate was comparable to earlier published prospective data, but higher than that found in retrospective studies.

Conclusions: The mortality rates in earlier published retrospective series as well as in studies focusing on clinical outcome following AVM hemorrhage significantly underestimate the risk for a mortal outcome following an AVM hemorrhage. Based on our findings, an AVM rupture has around 20% likelihood to result in mortality, 45% likelihood to result in a minor or major deficit, and 35% likelihood of complete recovery. The findings are probably applicable also for AVM ruptures in general. The cumulative mortality and morbidity rates 25 years after diagnosis were estimated to be around 40% in a patient with a patent AVM.
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http://dx.doi.org/10.1007/s00701-020-04380-zDOI Listing
July 2020

Wood Density and Moisture Content Estimation by Drilling Chips Extraction Technique.

Materials (Basel) 2020 Apr 5;13(7). Epub 2020 Apr 5.

Timber Construction Research Group, UPM, 28040 Madrid, Spain.

The novelty of this study is the development of an accurate wood moisture content (MC) estimation method based on a relatively brand-new, non-destructive testing technique (drilling chips extraction). The method is especially important in the assessment of existing timber structures, where non-destructive testing (NDT) results are affected by wood MC and should be adjusted to a reference MC, usually 12%. In the assessment of timber structures, it is not possible to determine MC by oven drying method and this should be estimated. Electrical resistance and capacitance are the conventional methods used for MC estimation. This research work aims to present an accurate MC estimation method based on the drilling chips extraction technique. For that, 99 specimens (90 × 65 × 38 mm) from three softwood and hardwood species covering a wide range of densities (from 355 to 978 kg m) were tested after conditioning at five different MCs (5%, 10%, 15%, 20%, 25%). The Wood Extractor device based on the drilling chips extraction technique was used. The mass of the chips collected (drilling residue) from each drill was recorded. The results show that the MC of the chips extracted was statistically significantly different than the MC of the specimen and cannot be directly used as MC determination. However, the chips MC can be used as an estimator of specimen MC with high determination coefficients (R from 71% to 86%). As the main result, models to estimate density directly adjusted to a reference 12% MC from the wet and dry mass of chips extracted were developed with an R of 98%. In sum, the drilling chips extractor is a dependable and straightforward method to estimate MC and density from only one measurement. Density adjusted to a reference 12% MC can be directly estimated from a single model.
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http://dx.doi.org/10.3390/ma13071699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178678PMC
April 2020

Classification and Staging of Morgellons Disease: Lessons from Syphilis.

Clin Cosmet Investig Dermatol 2020 7;13:145-164. Epub 2020 Feb 7.

Union Square Medical Associates, San Francisco, CA, USA.

Introduction: Morgellons disease (MD) is a contested dermopathy that is associated with spirochetal infection. A simple classification system was previously established to help validate the disease based on clinical features (classes I-IV).

Methods: Drawing on historical and pathological parallels with syphilis, we formulated a more detailed staging system based on clinical features as well as severity of skin lesions and corresponding histopathological infection patterns, as determined by anti- immunohistochemical staining.

Results: Clinical classes I-IV of MD are further categorized as mild, moderate and severe, or stages A, B and C, respectively, based on histopathological findings. Stage A lesions demonstrated little or no immune infiltrates and little or no disorganization of cells; macrophages were not present, and hemorrhage was negligible. Extracellular isolated spirochetes and intracellular staining of keratinocytes in the lower epidermis was occasionally seen. Stage C lesions demonstrated positive staining of keratinocytes in the stratum basale and stratum spinosum and positive intracellular staining of macrophages for . Aggregate colonies were frequently encountered, hemorrhage was frequent, and intracellularly stained fibroblasts were occasionally seen. Stage B lesions demonstrated a pattern intermediate between Stages A and C.

Conclusion: The enhanced staging system provides objective criteria to assess the severity of dermopathy in MD. Further studies are needed to determine the optimal treatment for MD based on this staging system related to infection.
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http://dx.doi.org/10.2147/CCID.S239840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012249PMC
February 2020

Minimum concentration of Amphotericin B in serum according to the formulation, dose, and daily or prolonged intermittent therapeutic regimen.

Rev Soc Bras Med Trop 2020 7;53:e20180463. Epub 2020 Feb 7.

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Ribeirão Preto, SP, Brasil.

Introduction: The therapeutic efficacy of daily amphotericin B infusion is related to its maximum concentration in blood; however, trough levels may be useful in intermittent regimens of this antifungal drug.

Methods: : High performance liquid chromatography (HPLC) was used to determine the minimum concentration (Cmin) of amphotericin B in the serum of patients receiving deoxycholate (D-Amph) or liposomal amphotericin B (L-AmB) for the treatment of cryptococcal meningitis (n=28), histoplasmosis (n=8), paracoccidioidomycosis (n=1), and leishmaniasis (n=1).

Results: Daily use of D-Amph 30 to 50 mg or L-AmB 50 mg resulted in a similar Cmin, but a significant increase ocurred with L-AmB 100 mg/day. The geometric mean Cmin tended to decrease with a reduction in the dose and frequency of intermittent L-AmB infusions: 357 ng/mL (100 mg 4 to 5 times/week) > 263 ng/mL (50 mg 4 to 5 times/week) > 227 ng/mL (50 mg 1 to 3 times/week). The impact on Cmin was variable in patients whose dose or therapeutic scheme was changed, especially when administered the intermittent infusion of amphotericin B. The mean Cmin for each L-AmB schedule of intermittent therapy was equal or higher than the minimum inhibitory concentration of amphotericin B against Cryptococcus isolates from 10/12 patients. The Cmin of amphotericin B in patients with cryptococcal meningitis was comparable between those that survived or died.

Conclusions: By evaluating the Cmin of amphotericin B, we demonstrated the therapeutic potential of its intermittent use including in the consolidation phase of neurocryptococcosis treatment, despite the great variability in serum levels among patients.
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http://dx.doi.org/10.1590/0037-8682-0463-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083383PMC
March 2020

An Amphiphilic Polymer-Supported Strategy Enables Chemical Transformations under Anhydrous Conditions for DNA-Encoded Library Synthesis.

ACS Comb Sci 2020 03 27;22(3):120-128. Epub 2020 Feb 27.

Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, CH-4002, Basel, Switzerland.

The use of DNA-encoded libraries has emerged as a powerful hit generation technology. Combining the power of combinatorial chemistry to enumerate large compound collections with the efficiency of affinity selection in pools, the methodology makes it possible to interrogate vast chemical space against biological targets of pharmaceutical relevance. Thus, the chemical transformations employed for the synthesis of encoded libraries play a crucial role in the identification of diverse and drug-like starting points. Currently established transformations have mostly been limited to water-compatible reactions to accommodate the growing oligonucleotide tag. Herein, we describe the development of a practical catch-and-release methodology utilizing a cationic, amphiphilic PEG-based polymer to perform chemical transformations on immobilized DNA conjugates under anhydrous conditions. We demonstrate the usefulness of our APTAC (amphiphilic polymer-facilitated transformations under anhydrous conditions) approach by performing several challenging transformations on DNA-conjugated small molecules in pure organic solvents: the addition of a carbanion equivalent to a DNA-conjugated ketone in tetrahydrofuran, the synthesis of saturated heterocycles using the tin (Sn) amine protocol (SnAP) in dichloromethane, and the dual-catalytic (Ir/Ni) metallaphotoredox decarboxylative cross-coupling of carboxylic acids to DNA-conjugated aryl halides in DMSO. In addition, we demonstrate the feasibility of the latter in multititer-plate format.
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http://dx.doi.org/10.1021/acscombsci.9b00164DOI Listing
March 2020

First Comprehensive Report of Clinical Strains Isolated in the State of Sao Paulo (Brazil) and Identified by MALDI-TOF MS and Molecular Biology.

Microorganisms 2019 Dec 31;8(1). Epub 2019 Dec 31.

Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP 14040-900, Brazil.

The aim of this study was to compare the performance of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), phenotypic and molecular methods for the identification of species complexes isolated from clinical cases in the State of Sao Paulo (Brazil) between the years 2001 and 2017. Sequencing of ITS region of ribosomal DNA and elongation factor 1 alpha gene (ET1α) were used as reference method in the analysis of a total of 108 spp. clinical strains isolated from human hosts with superficial and systemic infections. Agreement between MALDI-TOF-MS and molecular data was observed for 97 out of 108 clinical isolates (89.8%), whereas five (4.6%) and six (5.5%) clinical isolates were misidentified and were not identified by MALDI-TOF MS, respectively. ITS region sequences and MALDI-TOF MS mass spectra identified and grouped correctly most of clinical isolates at species complex level. This investigation highlights the potential of MALDI-TOF MS technique as a fast and cost-efficient alternative for clinical identification. However, MALDI-TOF MS requires a more accurate and larger database. This work is the first comprehensive report for population, based on phenotypic analyses, proteomic profile by MALDI-TOF and phylogenetic analyses of species complexes isolated from clinical cases in the State of Sao Paulo, Brazil.
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http://dx.doi.org/10.3390/microorganisms8010066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022604PMC
December 2019

Synthesis and antituberculosis activity of new acylthiosemicarbazides designed by structural modification.

Drug Dev Res 2020 05 28;81(3):350-355. Epub 2019 Nov 28.

Universidad Nacional Autónoma de México, Instituto de Química, Ciudad Universitaria, Ciudad de México, México.

Acylthiosemicarbazides 8a-n were designed by structural modification of lead Compound 7. The syntheses of 8a-n involve a five-step procedure starting from carboxylic acids. Compounds 8a-n were tested against three Mycobacterium tuberculosis strains to measure their inhibitory antituberculosis activities. These activities could be explained according to the presence or absence of the chlorine substituent in the aromatic ring of the amide joined to the thiosemicarbazide core. Thiosemicarbazide derivative 8n is a candidate for the development of novel antitubercular agents. Ongoing studies are focused on exploring the mechanism by which these compounds inhibit M. tuberculosis cell growth.
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http://dx.doi.org/10.1002/ddr.21626DOI Listing
May 2020

Oral mucositis as a pathway for fatal outcome among critically ill patients exposed to chlorhexidine: post hoc analysis of a randomized clinical trial.

Crit Care 2019 Nov 27;23(1):382. Epub 2019 Nov 27.

Social Medicine Department, Ribeirão Preto Medical School, University of São Paulo, Campus Universitário, s/n, Monte Alegre, Ribeirão Preto, São Paulo, 14048-900, Brazil.

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http://dx.doi.org/10.1186/s13054-019-2664-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882234PMC
November 2019

Combined assessment of peritumoral Th1/Th2 polarization and peripheral immunity as a new biomarker in the prediction of BCG response in patients with high-risk NMIBC.

Oncoimmunology 2019;8(8):1602460. Epub 2019 Apr 13.

IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute (IGTP) UAB, Badalona, Spain.

Intravesical Bacille Calmette-Guérin (BCG) remains the most effective treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), unfortunately there is no validated biomarker to predict clinical outcome. Here we tried to explore the possibility that a combination of the density of peritumoral infiltrating cells (Th1, Th2 and PD-L1) and the composition of peripheral immune cells (neutrophil and lymphocyte counts) could generate a more reliable prognostic biomarker. Twenty-two patients with high-risk NMIBC treated with BCG (10 BCG nonresponders and 12 BCG responders) were selected. BCG responders had significantly lower level of peritumoral T-bet cells with an associated higher GATA-3/T-bet ratio (p = 0.04, p = 0.02, respectively). Furthermore, the immune polarization in tissue (GATA-3/T-bet ratio) adjusted for the systemic inflammation (neutrophil-to-lymphocyte ratio) showed a significantly higher association with the BCG response (p = 0.004). A survival analysis demonstrated prolonged recurrence-free survival (RFS) in patients with a lower T-bet/Lymphocyte ratio and higher GTR/NLR (p = 0.01). No association was observed between peritumoral PD-L1 expression and the BCG response. In conclusion, alterations in overall immune function, both local and systemic, may influence the therapeutic response to BCG, therefore a combined analysis of tumoral (Th2/Th1 ratio) and peripheral (NLR) immune composition prior to treatment may be a promising approach to predict the BCG response in high-risk NMIBC patients.
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http://dx.doi.org/10.1080/2162402X.2019.1602460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682363PMC
April 2019
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