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1.
Cancer Sci ; 111(10): 3468-3477, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33044028

RESUMO

The effectiveness of current chemotherapies for cancer is gradually progressing; however achieving a complete cure through chemotherapy is still difficult and has been the main goal in treatment of advanced cancer. Drug resistance is an issue in cancer therapy, therefore increasing numbers of investigations into drug resistance have focused on the characteristics of the cancer cells themselves. The interaction between the tumor microenvironment (TME) and cancer cells is also intimately involved in the development of drug resistance. Cancer-associated fibroblasts (CAFs) are a predominant component of the TME and affect tumor progression by secreting soluble factors. This review summarizes the most up-to-date knowledge of CAFs and drug resistance in cancer, with a focus on factors secreted from CAFs including proteins, cytokines, extracellular vesicles, and metabolites. A perspective on the potential role of anti-CAF therapies in overcoming CAF-induced drug resistance is also discussed.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Resistência a Medicamentos , Neoplasias/tratamento farmacológico , Humanos , Neoplasias/patologia , Microambiente Tumoral
2.
S Afr Med J ; 110(7): 678-685, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32880347

RESUMO

BACKGROUND: The outcome and response of idiopathic nephrotic syndrome (NS) to steroids have been linked to race. OBJECTIVES: To determine the age of presentation, sex, race, histopathology, kidney function and disease status at the last hospital visit and correlate these with steroid response in Indian and black African children with idiopathic NS. METHODS: This is a retrospective review of 231 children aged 1 - 14 years, who were seen at Inkosi Albert Luthuli Central Hospital, Durban, South Africa (SA) from 2003 to 2018. RESULTS: The mean (standard deviation (SD)) age of presentation was 6.2 (3.4) years, with the majority of children (n=107; 46.3%) presenting at an early age (1 - 3 years) with a mean (SD) follow-up of 3.0 (2.4) years. One-hundred and twenty-one (52.4%) were males and 110 (47.6%) were females, with a male/female ratio of 1.1:1. There were 166 (71.9%) black African and 65 (28.1%) Indian children. The latter presented at a younger age than black African children (p<0.001). Seventy-six (32.9%) children were steroid sensitive (SS) and 155 (67.1%) were steroid resistant (SR). Black African children were more likely to be SR (odds ratio (OR) 2.0; p=0.02; 95% confidence interval (CI) 1.1 - 3.7). A kidney biopsy was performed in 209 (90.5%) children. Minimal change disease (MCD) was observed in 32 (13.9%) children and 162 (70.1%) had focal segmental glomerulosclerosis (FSGS). Black African children were slightly more likely to have FSGS; this, however, did not reach statistical significance (122/166 (73.5%) v. 40/65 (61.5%); OR 1.73; p=0.08; 95% CI 0.94 - 3.18). On comparing disease status at last hospital visit by race, 49/65 (75.4%) Indian and 94/166 (56.6%) black African children were in remission. At last hospital visit, black African children were less likely to be in remission than Indian children (OR 0.47; p=0.02; 95% CI 0.2 - 0.9), while 15/65 (23.1%) Indian and 47/166 (28.3%) black African children had relapsed, with no significant difference between the two groups. One (1.5%) Indian child and 25 (15.1%) black African children had end-stage kidney disease (ESKD) (OR 9.27; p=0.03; 95% CI 1.2 - 70.4) ‒ the majority had FSGS. Sixteen (61.5%) received renal replacement therapy. CONCLUSIONS: Our study shows a rising incidence of FSGS, with the majority of patients having SRNS, particularly black African children. This highlights the need for alternative efficacious therapy in the management of this disease. Also, a higher percentage of black African children with both MCD and FSGS were SS on histopathological examination, which was in keeping with reports from other regions in SA. There are still major challenges for the inclusion of all children into a chronic dialysis and transplant programme.


Assuntos
Síndrome Nefrótica/epidemiologia , Adolescente , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Criança , Pré-Escolar , Resistência a Medicamentos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Glomerulosclerose Segmentar e Focal/epidemiologia , Glucocorticoides/farmacologia , Humanos , Lactente , Falência Renal Crônica/epidemiologia , Masculino , Nefrose Lipoide/epidemiologia , Terapia de Substituição Renal/estatística & dados numéricos , Estudos Retrospectivos , Distribuição por Sexo , África do Sul/epidemiologia
3.
Pestic Biochem Physiol ; 170: 104677, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980052

RESUMO

Two-spotted spider mite (TSSM) Tetranychus urticae (Koch) is an important agricultural pest that causes considerable yield losses to over 150 field and greenhouse crops. Mitochondrial electron transport inhibitors (METI) acaricides are commonly used to control mite species in commercial Canadian greenhouses. Development of resistance to METIs in TSSM populations have been reported worldwide, but not until recently in Canada. The objectives of this study were to: 1) monitor the acaricide-susceptibility in greenhouse TSSM populations, and 2) investigate the resistance to pyridaben, a METI acaricide, in greenhouse resistant and pyridaben-selected (SRS) mite strains. The increased mortality to the pyridaben sub-lethal concentration (LC30) when SRS mites were exposed to piperonyl butoxide (PBO), a general cytochrome P450 monooxygenase inhibitor, and higher P450 activity compared to the greenhouse strain (RS) mites, indicated that P450s may be at least partially responsible for the resistance. The molecular mechanisms of target site insensitivity-mediated resistance in the pyridaben resistant strain of TSSM were investigated by comparing the DNA sequence of NADH dehydrogenase subunits TYKY and PSST, NADH-ubiquinone oxidoreductase chain 1 and 5 (ND1, ND5) and the NADH-ubiquinone oxidoreductase subunit 49 kDa from SRS to the reference strain (SS) and RS. Despite a number of nucleotide substitutions, none correlated with the pyridaben resistance. Understanding the underlying mechanisms of TSSM adaptation to acaricides is an essential part of resistance management strategy in any IPM program. The findings of this study will encourage growers to apply acaricides with different modes of action to reduce the rate at which acaricide resistance will occur in greenhouse TSSM populations.


Assuntos
Acaricidas/farmacologia , Ácaros/efeitos dos fármacos , Tetranychidae/efeitos dos fármacos , Animais , Canadá , Resistência a Medicamentos , Piridazinas
4.
BMC Infect Dis ; 20(1): 671, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933490

RESUMO

BACKGROUND: The increasing antimalarial drug resistance is a significant hindrance to malaria control and elimination programs. For the last six decades, chloroquine (CQ) plus pyrimethamine remains the first-line treatment for P. vivax malaria. Regions where both P. falciparum and P. vivax co-exist, P. vivax is exposed to antifolate drugs due to either misdiagnosis or improper treatment that causes selective drug pressure to evolve. Therefore, the present study aims to estimate antimalarial drug resistance among the complicated and uncomplicated P. vivax patients. METHODS: A total of 143 P. vivax malaria positive patients were enrolled in this study, and DNA was isolated from their blood samples. Pvcrt-o, Pvmdr-1, Pvdhps, and Pvdhfr genes were PCRs amplified, and drug resistance-associated gene mutations were analyzed. Statistical analysis of the drug resistance genes and population diversity was performed using MEGA vs. 7.0.21 and DnaSP v software. RESULTS: Among the CQ resistance marker gene Pvcrt-o, the prevalence of K10 insertion was 17.5% (7/40) and 9.5% (7/73) of complicated and uncomplicated P vivax group isolates respectively. In Pvmdr-1, double mutant haplotype (M958/L1076) was found in 99% of the clinical isolates. Among the pyrimethamine resistance-associated gene Pvdhfr, the double mutant haplotype I13P33F57R58T61N117I173 was detected in 23% (11/48) in complicated and 20% (17/85) in uncomplicated group isolates. In the sulphadoxine resistance-associated Pvdhps gene, limited polymorphism was observed with the presence of a single mutant (D459A) among 16 and 5% of the clinical isolates in the complicated and uncomplicated group respectively. CONCLUSION: The study presents the situations of polymorphism in the antimalarial drug resistance-associated genes and emphasizes the need for regular surveillance. It is imperative for the development of suitable antimalarial drug policy in India.


Assuntos
Antimaláricos/uso terapêutico , Resistência a Medicamentos/genética , Malária Vivax/tratamento farmacológico , Plasmodium vivax/genética , Proteínas de Protozoários/genética , Adolescente , Criança , Pré-Escolar , Cloroquina/uso terapêutico , DNA de Protozoário/genética , DNA de Protozoário/metabolismo , Feminino , Antagonistas do Ácido Fólico/uso terapêutico , Haplótipos , Humanos , Índia , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium vivax/isolamento & purificação , Polimorfismo de Nucleotídeo Único , Adulto Jovem
5.
Rev Panam Salud Publica ; 44, sept. 2020
Artigo em Espanhol | PAHO-IRIS | ID: phr-52655

RESUMO

El año 2020 será recordado por la pandemia ocasionada por el coronavirus SARS-CoV-2, responsable de más de 10 millones de casos y más de 500 000 muertes solo en la primera mitad del año, que recibió una atención política y social sin precedentes. Esta crisis global de salud pública debe servir para llamar la atención también sobre otras epidemias silenciosas, como la resistencia a los antimicrobianos (RAM), que se considera responsable de 700 000 muertes en todo el mundo anualmente, 230 000 de ellas por tuberculosis multirresistente. En la Región de las Américas, los microorganismos multirresistentes son la causa principal de las infecciones asociadas a la atención de la salud. Los datos de la vigilancia procedentes de la Red de Vigilancia de la Resistencia a los Antimicrobianos (RELAVRA) demuestran una tendencia creciente de la resistencia de patógenos hospitalarios como Klebsiella pneumoniae, cuyo porcentaje de no sensibilidad a los antibióticos carbapenémicos está aumentando significativamente en Latinoamérica desde 2014, hasta alcanzar el 21% en promedio. Las consecuencias en términos de mortalidad, discapacidad y costos económicos son significativas para los sistemas de salud. Por ejemplo, Staphylococcus aureus ocasiona un amplio rango de infecciones y es uno de los microorganismos aislado con mayor frecuencia en infecciones asociadas a la atención de la salud; en Latinoamérica, más del 25% de los aislamientos de S. aureus son resistentes a la meticilina. Las consecuencias son un exceso de mortalidad —atribuible a la resistencia a la meticilina— del 45,2% en comparación con las cepas sensibles, y el aumento de los costos del tratamiento antibiótico y de la hospitalización en veces y en casi 3 veces, respectivamente...


Assuntos
Betacoronavirus , Betacoronavirus , Infecções por Coronavirus , Resistência a Medicamentos , América
6.
Nat Commun ; 11(1): 4813, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968076

RESUMO

Artemisinins have revolutionized the treatment of Plasmodium falciparum malaria; however, resistance threatens to undermine global control efforts. To broadly explore artemisinin susceptibility in apicomplexan parasites, we employ genome-scale CRISPR screens recently developed for Toxoplasma gondii to discover sensitizing and desensitizing mutations. Using a sublethal concentration of dihydroartemisinin (DHA), we uncover the putative transporter Tmem14c whose disruption increases DHA susceptibility. Screens performed under high doses of DHA provide evidence that mitochondrial metabolism can modulate resistance. We show that disrupting a top candidate from the screens, the mitochondrial protease DegP2, lowers porphyrin levels and decreases DHA susceptibility, without significantly altering parasite fitness in culture. Deleting the homologous gene in P. falciparum, PfDegP, similarly lowers heme levels and DHA susceptibility. These results expose the vulnerability of heme metabolism to genetic perturbations that can lead to increased survival in the presence of DHA.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Resistência a Medicamentos/genética , Testes Genéticos/métodos , Heme/genética , Heme/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Técnicas de Inativação de Genes , Humanos , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana Transportadoras/metabolismo , Mutação , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Toxoplasma/efeitos dos fármacos , Toxoplasma/genética
8.
Mikrobiyol Bul ; 54(3): 444-462, 2020 Jul.
Artigo em Turco | MEDLINE | ID: mdl-32755520

RESUMO

World Health Organization reported that approximately one billion people are at risk in endemic areas, one million cases of cutaneous leishmaniasis (CL) and approximately 300,000 cases of visceral leishmaniasis (VL) were reported per year in the last five years. The number of deaths due to VL is reported to be approximately 20,000 per year. Approximately 2500 cases/year have been reported as CL, caused by Leishmania tropica and Leishmania infantum, in Turkey. The significant increase observed in many cities mainly in the provinces of Mediterranean and Aegean regions in cases and foci in recent years, suggests that there may be an increase in this infections in the following years as well. In Turkey, the causative agent of CL is L.tropica and meglumine antimoniate is used in the treatment of CL. We aimed to determine antimony resistance genes specific for L.tropica by comparing the gene and protein expressions of antimony-resistant and non-resistant L.tropica strains. L.tropica isolates obtained from 3 CL patients without antimonate resistance from Aegean, Mediterranean and Southeastern regions of Turkey were provided to transform into 3 resistant isolates against meglumine antimony in the laboratory conditions. Gene expression alterations by microarray method; protein profiles by two-dimensional gel electrophoresis (2D-PAGE) and relevant proteins by MALDI-TOF/TOF MS of these isolates were accomplished and compared. L.tropica isolates from 10 CL patients who did not respond to antimony therapy were analyzed for resistance to antimonial compounds and quantitative real-time polymerase chain reaction was performed to detect the expression of genes responsible for resistance development. Moreover, differences in protein expression levels in isolates with and without antimony resistance were determined by comparing protein profiles and identification of proteins with different expression levels was carried out. Enolase, elongation factor-2, heat shock protein 70, tripanthione reductase, protein kinase C and metallo-peptidase proteins have been shown to play roles in L.tropica isolates developing resistance to antimonial compounds and similar expression changes have also been demonstrated in naturally resistant isolates from patients. In conclusion, it was revealed that L.tropica strains in our country may gain resistance to meglumine antimoniate in a short time. It is foreseen that if the patients living in our country or entering the country are treated inadequately and incompletely, there may be new, resistant leishmaniasis foci that may increase the number of resistant strains and cases rapidly.


Assuntos
Resistência a Medicamentos , Leishmania tropica , Leishmaniose Cutânea , Antimoniato de Meglumina , Resistência a Medicamentos/genética , Humanos , Leishmania tropica/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/farmacologia , Antimoniato de Meglumina/uso terapêutico , Turquia
9.
Lancet Haematol ; 7(8): e613-e623, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32735839

RESUMO

Lifelong anticoagulation with warfarin or alternative vitamin K antagonist is the standard anticoagulant treatment for thrombotic antiphospholipid syndrome. Anticoagulant-refractory thrombotic antiphospholipid syndrome can be broadly defined as breakthrough thrombosis while on standard oral anticoagulation treatment and its management is a major challenge given the serious nature of the thrombotic disease observed, which has become refractory to oral anticoagulation. The factors (genetic and cellular) that cause anticoagulant-refractory thrombotic antiphospholipid syndrome are now better understood. However, efforts to use this greater understanding have not yet transformed the capacity to treat it successfully in many patients. In this Viewpoint, we review the factors that are likely to be contributing to the cause of this syndrome and consider how they might be modified or inhibited. We also discuss management, including general strategies to minimise thrombotic risk, intensification of anticoagulation, addition of an antiplatelet agent, adjunctive treatment for thrombosis, immunomodulatory therapy, complement inhibition, vascular options, and future potential therapeutic targets.


Assuntos
Anticoagulantes/farmacologia , Síndrome Antifosfolipídica/terapia , Resistência a Medicamentos/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Terapia Trombolítica , Trombose/prevenção & controle , Síndrome Antifosfolipídica/patologia , Humanos , Trombose/patologia
10.
Medicine (Baltimore) ; 99(30): e20710, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791665

RESUMO

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder of unknown etiology with systemic symptoms that include fever, night sweats, weight loss, and fatigue. Although tocilizumab (TCZ), which is a recombinant, humanized, anti-human interleukin 6 receptor monoclonal antibody, has been recommended to treat patients with iMCD, 40% of patients with iMCD do not achieve complete remission with TCZ treatment. METHODS/DESIGN: In this phase II, investigator-initiated, multicenter, double-blind, randomized, parallel-group trial, the efficacy and safety of sirolimus will be compared with placebo in patients with TCZ-resistant iMCD. The study will be conducted in 8 centers in Japan. Participants (n = 20) will be randomly assigned to receive 2 mg of oral sirolimus (n = 10) or placebo (n = 10) once daily for 16 weeks. The primary endpoint is a decrease in CHAP score by ≥1 from baseline at 16 weeks. Secondary endpoints include levels of hemoglobin, albumin, and C-reactive protein; change in CHAP score; SF-36 Health Survey Questionnaire; physician global assessment (100 mm visual analog scale); patient global assessment (100 mm visual analog scale) at 2, 4, 8, 12, and 16 weeks; change in lymphadenopathy at 16 weeks; and pharmacodynamic assessment, including the measurement of whole blood sirolimus level. DISCUSSION: This clinical trial will provide evidence of efficacy and safety of sirolimus as a potential new therapeutic agent for patients with TCZ-resistant iMCD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials as jRCT2071190029 on October 8, 2019.


Assuntos
Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Imunossupressores/uso terapêutico , Sirolimo/uso terapêutico , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Resistência a Medicamentos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Medicine (Baltimore) ; 99(34): e21694, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846786

RESUMO

BACKGROUND: We conducted a meta-analysis to summarize all available evidence from randomized controlled trial studies regarding the clinical efficacy and safety of spironolactone in patients with resistant hypertension (RH) and provided a quantitative assessment. METHODS: A systematic search of PubMed, Web of Science, Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) databases through December 8, 2019, was performed. Randomized controlled trials randomized controlled trials meeting inclusion criteria were included to assess the effect of the addition of spironolactone on office blood pressure (BP), 24-hour ambulatory BP or adverse events in RH patients. RESULTS: Twelve trials, which enrolled a total of 1655 patients, were included in this meta-analysis. In comparison with placebo, spironolactone significantly reduced office BP (office SBP, weighted mean difference [WMD] = -20.14, 95% CI = -31.17 to -9.12, P < .001; office DBP WMD = -5.73, 95% CI = -8.13 to -3.33, P < .001) and 24-hour ambulatory BP (ASBP, WMD = -10.31, 95% CI = -12.86 to -7.76, P < .001; ADBP, WMD = -3.94, 95% CI = -5.50 to -2.37, P < .001). Compared with alternative drugs, spironolactone treatment in RH patients significantly decreased 24-hour ambulatory BP (ASBP, WMD = -6.98, 95% CI = -12.66 to -1.30, P < .05; ADBP, WMD = -3.03, 95% CI = -5.21 to -0.85, P < .001). CONCLUSION: This meta-analysis fully evaluated the antihypertensive effect of spironolactone compared with placebo, alternative drugs, renal nerve denervation and no treatment. Spironolactone can result in a substantial BP reduction in patients with RH at 3 months.


Assuntos
Diuréticos/uso terapêutico , Hipertensão/tratamento farmacológico , Espironolactona/uso terapêutico , Diuréticos/efeitos adversos , Resistência a Medicamentos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Espironolactona/efeitos adversos , Resultado do Tratamento
12.
PLoS Negl Trop Dis ; 14(8): e0008506, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745103

RESUMO

Plasmodium vivax has become the predominant malaria parasite and a major challenge for malaria elimination in the Greater Mekong Subregion (GMS). Yet, our knowledge about the evolution of P. vivax populations in the GMS is fragmental. We performed whole genome sequencing on 23 P. vivax samples from the China-Myanmar border (CMB) and used 21 high-coverage samples to compare to over 200 samples from the rest of the GMS. Using genome-wide single nucleotide polymorphisms (SNPs), we analyzed population differentiation, genetic structure, migration and potential selection using an array of methods. The CMB parasites displayed a higher proportion of monoclonal infections, and 52% shared over 90% of their genomes in identity-by-descent segments with at least one other sample from the CMB, suggesting preferential expansion of certain parasite strains in this region, likely resulting from the P. vivax outbreaks occurring during this study period. Principal component, admixture, fixation index and phylogenetic analyses all identified that parasites from the CMB were genetically distinct from parasites from eastern parts of the GMS (Cambodia, Laos, Vietnam, and Thailand), whereas the eastern GMS parasite populations were largely undifferentiated. Such a genetic differentiation pattern of the P. vivax populations from the GMS parasite was largely explainable through geographic distance. Using the genome-wide SNPs, we narrowed down to a set of 36 SNPs for differentiating parasites from different areas of the GMS. Genome-wide scans to determine selection in the genome with two statistical methods identified genes potentially under drug selection, including genes associated with antifolate resistance and genes linked to chloroquine resistance in Plasmodium falciparum.


Assuntos
Malária Vivax/epidemiologia , Malária Vivax/parasitologia , Plasmodium vivax/genética , Polimorfismo de Nucleotídeo Único , Antimaláricos/farmacologia , China , Surtos de Doenças , Resistência a Medicamentos/genética , Antagonistas do Ácido Fólico/farmacologia , Genômica , Humanos , Mianmar , Filogenia , Plasmodium vivax/efeitos dos fármacos
13.
PLoS One ; 15(8): e0237321, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853226

RESUMO

Kawasaki disease is the leading cause of pediatric acquired heart disease. Coronary artery abnormalities are the main complication of Kawasaki disease. Kawasaki disease patients with intravenous immunoglobulin resistance are at a greater risk of developing coronary artery abnormalities. Several scoring models have been established to predict resistance to intravenous immunoglobulin, but clinicians usually do not apply those models in patients because of their poor performance. To find a better model, we retrospectively collected data including 753 observations and 82 variables. A total of 644 observations were included in the analysis, and 124 of the patients observed were intravenous immunoglobulin resistant (19.25%). We considered 7 different linear and nonlinear machine learning algorithms, including logistic regression (L1 and L1 regularized), decision tree, random forest, AdaBoost, gradient boosting machine (GBM), and lightGBM, to predict the class of intravenous immunoglobulin resistance (binary classification). Data from patients who were discharged before Sep 2018 were included in the training set (n = 497), while all the data collected after 9/1/2018 were included in the test set (n = 147). We used the area under the ROC curve, accuracy, sensitivity, and specificity to evaluate the performances of each model. The gradient GBM had the best performance (area under the ROC curve 0.7423, accuracy 0.8844, sensitivity 0.3043, specificity 0.9919). Additionally, the feature importance was evaluated with SHapley Additive exPlanation (SHAP) values, and the clinical utility was assessed with decision curve analysis. We also compared our model with the Kobayashi score, Egami score, Formosa score and Kawamura score. Our machine learning model outperformed all of the aforementioned four scoring models. Our study demonstrates a novel and robust machine learning method to predict intravenous immunoglobulin resistance in Kawasaki disease patients. We believe this approach could be implemented in an electronic health record system as a form of clinical decision support in the near future.


Assuntos
Resistência a Medicamentos , Imunoglobulinas Intravenosas/farmacologia , Aprendizado de Máquina , Modelos Biológicos , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Pré-Escolar , China , Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/prevenção & controle , Estudos de Viabilidade , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Modelos Logísticos , Masculino , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/imunologia , Curva ROC , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
14.
PLoS One ; 15(8): e0237150, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760111

RESUMO

Prevention of canine heartworm disease caused by Dirofilaria immitis relies on chemoprophylaxis with macrocyclic lactone anthelmintics. Alarmingly, there are increased reports of D. immitis isolates with resistance to macrocyclic lactones and the ability to break through prophylaxis. Yet, there is not a well-established laboratory assay that can utilize biochemical phenotypes of microfilariae to predict drug resistance status. In this study we evaluated laboratory assays measuring cell permeability, metabolism, and P-glycoprotein-mediated efflux. Our assays revealed that trypan blue, propidium iodide staining, and resazurin metabolism could detect differences among D. immitis isolates but none of these approaches could accurately predict drug susceptibility status for all resistant isolates tested. P-glycoprotein assays suggested that the repertoire of P-gp expression is likely to vary among isolates, and investigation of pharmacological differences among different P-gp genes is warranted. Further research is needed to investigate and optimize laboratory assays for D. immitis microfilariae, and caution should be applied when adapting cell death assays to drug screening studies for nematode parasites.


Assuntos
Antinematódeos/farmacologia , Dirofilaria immitis/efeitos dos fármacos , Ivermectina/farmacologia , Macrolídeos/farmacologia , Fenótipo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Células Cultivadas , Dirofilaria immitis/metabolismo , Dirofilaria immitis/patogenicidade , Dirofilariose/parasitologia , Cães , Resistência a Medicamentos , Proteínas de Helminto/metabolismo
15.
PLoS One ; 15(8): e0235401, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817665

RESUMO

BACKGROUND: Current malaria control and elimination strategies rely mainly on efficacious antimalarial drugs. However, drug resistance is a major threat facing malaria control programs. Determination of drug resistance molecular markers is useful in the monitoring and surveillance of malaria drug efficacy. This study aimed to determine the mutations and haplotypes frequencies of different genes linked with antimalarial drug resistance in certain areas in Sudan. METHODS: A total of 226 dried blood spots (DBS) of microscopically diagnosed P. falciparum isolates were collected from Khartoum and three other areas in Sudan during 2015-2017. Plasmodium falciparum confirmation and multiplicity of infection was assessed using the Sanger's 101 SNPs-barcode and speciation was confirmed using regions of the parasite mitochondria. Molecular genotyping of drug resistance genes (Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, exonuclease, Pfk13, parasite genetic background (PGB) (Pfarps10, ferredoxin, Pfcrt, Pfmdr2)) was also performed. All genotypes were generated by selective regions amplicon sequencing of the parasite genome using the Illumina MiSeq platform at the Wellcome Sanger Institute, UK then genotypes were translated into drug resistance haplotypes and species determination. FINDINGS: In total 225 samples were confirmed to be P. falciparum. A higher proportion of multiplicity of infection was observed in Gezira (P<0.001) based on the Sanger 101 SNPs -barcode. The overall frequency of mutant haplotype Pfcrt 72-76 CVIET was 71.8%. For Pfmdr1, N86Y was detected in 53.6%, Y184F was observed in 88.1% and D1246Y was detected in 1.5% of the samples. The most frequently observed haplotype was YFD 47.4%. For Pfdhfr (codons 51, 59,108,164), the ICNI haplotype was the most frequent (80.7%) while for Pfdhps (codons 436, 437, 540, 581, 613) the (SGEAA) was most frequent haplotype (41%). The Quadruple mutation (dhfr N51I, S108N + dhps A437G, K540E) was the highest frequent combined mutation (33.9%). In Pfkelch13 gene, 18 non-synonymous mutations were detected, 7 of them were detected in other African countries. The most frequent Pfk13 mutation was E433D detected in four samples. All of the Pfk13 mutant alleles have not been reported to belong to mutations associated with delayed parasite clearance in Southeast Asia. PGB mutations were detected only in Pfcrt N326S\I (46.3%) and Pfcrt I356T (8.2%). The exonuclease mutation was not detected. There was no significant variation in mutant haplotypes between study areas. CONCLUSIONS: There was high frequency of mutations in Pfcrt, Pfdhfr and Pfdhps in this study. These mutations are associated with chloroquine and sulfadoxine-pyrimethamine (SP) resistance. Many SNPs in Pfk13 not linked with delayed parasite clearance were observed. The exonuclease E415G mutation which is linked with piperaquine resistance was not reported.


Assuntos
Resistência a Medicamentos/genética , Malária/parasitologia , Mutação , Plasmodium falciparum/genética , Adolescente , Antimaláricos/farmacologia , Criança , Cloroquina/farmacologia , Feminino , Humanos , Malária/epidemiologia , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Pirimetamina/farmacologia , Sudão , Sulfadoxina/farmacologia , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/metabolismo , Adulto Jovem
16.
Nat Commun ; 11(1): 3922, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764664

RESUMO

The Plasmodium falciparum chloroquine resistance transporter (PfCRT) is a key contributor to multidrug resistance and is also essential for the survival of the malaria parasite, yet its natural function remains unresolved. We identify host-derived peptides of 4-11 residues, varying in both charge and composition, as the substrates of PfCRT in vitro and in situ, and show that PfCRT does not mediate the non-specific transport of other metabolites and/or ions. We find that drug-resistance-conferring mutations reduce both the peptide transport capacity and substrate range of PfCRT, explaining the impaired fitness of drug-resistant parasites. Our results indicate that PfCRT transports peptides from the lumen of the parasite's digestive vacuole to the cytosol, thereby providing a source of amino acids for parasite metabolism and preventing osmotic stress of this organelle. The resolution of PfCRT's native substrates will aid the development of drugs that target PfCRT and/or restore the efficacy of existing antimalarials.


Assuntos
Antimaláricos/farmacologia , Cloroquina/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/metabolismo , Animais , Transporte Biológico Ativo , Resistência a Medicamentos/genética , Feminino , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/fisiologia , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Proteínas de Membrana Transportadoras/genética , Modelos Biológicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Oligopeptídeos/metabolismo , Oócitos/metabolismo , Plasmodium falciparum/genética , Transporte Proteico , Proteínas de Protozoários/genética , Xenopus laevis
17.
Cardiovasc Ther ; 2020: 8157858, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821284

RESUMO

Aim: The present study compared the acute effects of aerobic (AER), resistance (RES), and combined (COM) exercises on blood pressure (BP) levels in people with resistant hypertension (RH) and nonresistant hypertension (NON-RH). Methods: Twenty patients (10 RH and 10 NON-RH) were recruited and randomly performed three exercise sessions and a control session. Ambulatory BP was monitored over 24 hours after each experimental session. Results: Significant reductions on ambulatory BP were found in people with RH after AER, RES, and COM sessions. Notably, ambulatory BP was reduced during awake-time and night-time periods after COM. On the other hand, the effects of AER were more prominent during awake periods, while RES caused greater reductions during the night-time period. In NON-RH, only RES acutely reduced systolic BP, while diastolic BP was reduced after all exercise sessions. However, the longest postexercise ambulatory hypotension was observed after AER (~11 h) in comparison to RES (~8 h) and COM (~4 h) exercises. Conclusion: Findings of the present study indicate that AER, RES, and COM exercises elicit systolic and diastolic postexercise ambulatory hypotension in RH patients. Notably, longer hypotension periods were observed after COM exercise. In addition, NON-RH and RH people showed different changes on BP after exercise sessions, suggesting that postexercise hypotension is influenced by the pathophysiological bases of hypertension.


Assuntos
Pressão Sanguínea , Hipertensão/terapia , Treinamento de Resistência , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial , Brasil , Estudos Cross-Over , Resistência a Medicamentos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
18.
Chem Biol Interact ; 330: 109165, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32771326

RESUMO

The effect of N-geranyl-ethane-1,2-diamine dihydochloride (GIB24), a synthetic diamine, was assayed against different developmental forms of the parasitic protozoan Trypanosoma cruzi (strain Dm28c). The compound was effective against culture epimastigote forms (IC50/24h = 5.64 µM; SI = 16.4) and intracellular amastigotes (IC50/24h = 12.89 µM; SI = 7.18), as detected by the MTT methodology and by cell counting, respectively. Incubation of epimastigotes for 6h with 6 µM GIB24 (IC50/24h value) resulted in significant dissipation of the mitochondrial membrane potential, prior to permeabilization of the plasma membrane. Rounded epimastigotes with cell size reduction were observed by scanning electron microscopy. These morpho-physiological changes induced by GIB24 suggest an incidental death process. Treatment of infected Vero cells did not prevent the intracellular amastigotes from completing the intracellular cycle. However, there was a decrease in the number of released parasites, increasing the ratio amastigotes/trypomastigotes. Proteomic analysis of 15 µM GIB24 resistant epimastigotes indicated that the compound acts mainly on mitochondrial components involved in the Krebs cycle and in maintaining the oxidative homeostasis of the parasites. Our data suggest that GIB24 is active against the main morphological forms of T. cruzi.


Assuntos
Diaminas/farmacologia , Resistência a Medicamentos , Espaço Intracelular/efeitos dos fármacos , Proteômica , Terpenos/química , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/crescimento & desenvolvimento , Animais , Chlorocebus aethiops , Diaminas/química , Espaço Intracelular/parasitologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/metabolismo , Células Vero
19.
Dermatol Online J ; 26(6)2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32815686

RESUMO

Drug rash with eosinophilia and systemic symptoms (DRESS) is a rare delayed drug reaction that often occurs 2-6 weeks after initiation of therapy and may develop into a life-threatening systemic reaction. Besides immediate discontinuation of the suspected inciting drug, initiation of high dose systemic corticosteroids has long been the mainstay of treatment for severe cases. Nevertheless, significant drawbacks associated with systemic corticosteroid therapy, such as the requirement of a long tapering period post resolution and extensive adverse side effects profile, have motivated clinicians to seek alternative treatment options. Over the past decade, an undisputed increasing number of favorable case reports has highlighted cyclosporine as an emerging, safe, and effective alternative despite inconsistent dosing regimens reported. Herein, we report a severe case of vancomycin-induced DRESS syndrome in which the patient failed initial intervention with cyclosporine and needed rescue with methylprednisolone. To the best of our knowledge, this constitutes the first unsuccessful report of cyclosporine treatment for DRESS syndrome.


Assuntos
Ciclosporina/uso terapêutico , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Vancomicina/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/tratamento farmacológico , Síndrome de Hipersensibilidade a Medicamentos/patologia , Resistência a Medicamentos , Eosinofilia/induzido quimicamente , Eosinofilia/patologia , Exantema/induzido quimicamente , Feminino , Antebraço/patologia , Humanos
20.
PLoS One ; 15(8): e0237791, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822392

RESUMO

Artemisinin-based combination therapies (ACTs) have been recommended by the World Health Organization (WHO) as first-line treatment of uncomplicated Plasmodium falciparum (P. falciparum) malaria since 2005 in Democratic Republic of Congo (DRC) and a regular surveillance of the ACT efficacy is required to ensure the treatment effectiveness. Mutations in the propeller domain of the pfk13 gene were identified as molecular markers of artemisinin resistance (ART-R). This study investigated the pfk13-propeller gene polymorphism in clinical isolates of P. falciparum collected in the DRC. In 2017, ten geographical sites across DRC were selected for a cross-sectional study that was conducted first in Kinshasa from January to March, then in the nine other sites from September to December. Dried blood samples were collected from patients attending health centers for fever where diagnosis of Malaria was first made by rapid diagnostic test (RDT) available on site (SD Bioline malaria Ag Pf or CareStart Malaria Pf) or by thick blood smear and then confirmed by a P. falciparum real-time PCR assay. A pfk13-propeller segment containing a fragment that codes for amino acids at positions 427-595 was amplified by conventional PCR before sequencing. In total, 1070 patients were enrolled in the study. Real-time PCR performed confirmed the initial diagnosis of P. falciparum infection in 806 samples (75.3%; 95% CI: 72.6%- 77.9%). Of the 717 successfully sequenced P. falciparum isolates, 710 (99.0%; 95% CI: 97.9% - 99.6) were wild-type genotypes and 7 (1.0%; 95% CI: 0.4% - 2.1%) carried non-synonymous (NS) mutations in pfk13-propeller including 2 mutations (A578S and V534A) previously detected and 2 other (M472I and A569T) not yet detected in the DRC. Mutations associated with ART-R in Southeast Asia were not observed in DRC. However, the presence of other mutations in pfk13-propeller gene calls for further investigations to assess their implication in drug resistance.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Adolescente , Adulto , Idoso , Antimaláricos/farmacologia , Artemisininas/farmacologia , Criança , Pré-Escolar , República Democrática do Congo/epidemiologia , Resistência a Medicamentos , Feminino , Humanos , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético , Adulto Jovem
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