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1.
Mem Inst Oswaldo Cruz ; 114: e190111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31433006

RESUMO

BACKGROUND: In addition to the limited therapeutic arsenal and the side effects of antileishmanial agents, drug resistance hinders disease control. In Brazil, Leishmania braziliensis causes atypical (AT) tegumentary leishmaniasis lesions, frequently refractory to treatment. OBJECTIVES: The main goal of this study was to characterise antimony (Sb)-resistant (SbR) L. braziliensis strains obtained from patients living in Xakriabá indigenous community, Minas Gerais, Brazil. METHODS: The aquaglyceroporin 1-encoding gene (AQP1) from L. braziliensis clinical isolates was sequenced, and its function was evaluated by hypo-osmotic shock. mRNA levels of genes associated with Sb resistance were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Atomic absorption was used to measure Sb uptake. FINDINGS: Although clinical isolates presented delayed recovery time in hypo-osmotic shock, AQP1 function was maintained. Isolate 340 accumulated less Sb than all other isolates, supporting the 65-fold downregulation of AQP1 mRNA levels. Both 330 and 340 isolates upregulated antimony resistance marker (ARM) 56/ARM58 and multidrug resistant protein A (MRPA); however, only ARM58 upregulation was an exclusive feature of SbR field isolates. CA7AE seemed to increase drug uptake in L. braziliensis and represented a tool to study the role of glycoconjugates in Sb transport. MAIN CONCLUSIONS: There is a clear correlation between ARM56/58 upregulation and Sb resistance in AT-harbouring patients, suggesting the use of these markers as potential indicators to help the treatment choice and outcome, preventing therapeutic failure.


Assuntos
Antimônio/farmacologia , Resistência a Medicamentos/genética , Leishmania braziliensis/efeitos dos fármacos , Leishmaniose Cutânea/parasitologia , Proteínas de Protozoários/genética , Tripanossomicidas/farmacologia , Aquagliceroporinas/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Humanos , Leishmania braziliensis/genética , Testes de Sensibilidade Parasitária , Proteínas de Protozoários/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
2.
Arq Gastroenterol ; 56(2): 178-183, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31460583

RESUMO

BACKGROUND: Abdominal tuberculosis is an increasing problem in developing world. OBJECTIVE: The objective of the study was to describe the clinical presentations, drug resistance pattern and treatment outcomes of abdominal tuberculosis in Western India. METHODS: All the cases of abdominal tuberculosis from May 2014 to April 2017, diagnosed on the basis of clinical profile and gross morphological findings at endoscopy, imaging, followed by histology and/or GeneXpert and MGIT culture were included. All patients received antitubercular drug (AKT) therapy according to national protocol. Patients were followed from diagnoses till completion of treatment and various parameters were studied. RESULTS: Out of the 176 patients, 48% were males. Abdominal pain was most common complaint in 83.5%. On colonoscopy terminal ileum and ileocaecal valve were most commonly involved segments. Upper gastrointestinal tract was involved in four patients. Overall ulceronodular lesions were most common followed by ulcerative/nodular lesion. Strictures in bowel were seen in 28 (15.9%) patients with ileocaecal valve being most commonly involved, of which 23 had symptomatic relief with AKT and only three required dilatation. Histopathology showed granuloma in 80.8% cases. MGIT was positive in 43 (35.80%) cases and GeneXpert was positive in 35 (26.1%) cases. Eight patients had multi drug resistant tuberculosis. Only two patients required surgical management. CONCLUSION: Abdominal tuberculosis with wide spectrum of presentation, can still be managed with early diagnosis and treatment even in patients with sub acute intestinal obstruction. Weight gain or resolving symptoms were considered early markers of treatment response. Patients with stricture can become asymptomatic with medical treatment alone.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Gastrointestinal/diagnóstico , Tuberculose Gastrointestinal/tratamento farmacológico , Adolescente , Adulto , Idoso , Criança , Resistência a Medicamentos , Endoscopia Gastrointestinal , Feminino , Seguimentos , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores Socioeconômicos , Resultado do Tratamento , Adulto Jovem
3.
Rev Fac Cien Med Univ Nac Cordoba ; 76(3): 154-158, 2019 08 29.
Artigo em Espanhol | MEDLINE | ID: mdl-31465182

RESUMO

Introduction: Aeromonas is a common cause of gastroenteritis but occasionally it can cause extraintestinal infections. The incidence of bacteremia by this genus is very low and in general the patients have associated base diseases. Materials and methods: Retrospective analysis of episodes of bacteremia by Aeromonas spp. during a period of eight years in the National Hospital of Clinics of the city of Córdoba, emphasizing age, sex, associated comorbidities, clinical presentation, focus, origin of the infection, clinical evolution, species prevalence and antimicrobial sensitivity of the same . Results: 10 episodes of bacteremia were recorded by Aeromonas spp. 60% corresponded to women and 40% to men. The average age was 65 years. In seven patients the origin of the infection was community and in three nosocomial. 70% of the patients presented predisposing base pathologies. The focus of bacteremia was abdominal in two cases. A. hydrophila complex was responsible for 50% of the cases. 80% of bacteremia were monomicrobial. The isolates generally showed high percentages of sensitivity. Conclusion: Bacteremia occurred in elderly patients of both sexes, most of whom had associated comorbidities. The majority of the infections originated in the community. While bacteremia by Aeromonas spp. it is rare, the mortality found in our study was relatively high despite the high percentage of sensitivity to antimicrobials.


Assuntos
Aeromonas/isolamento & purificação , Bacteriemia/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/classificação , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/epidemiologia , Comorbidade , Resistência a Medicamentos , Feminino , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
4.
Gene ; 716: 144016, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377318

RESUMO

Drug resistance of malaria parasites remains a problem affecting antimalarial treatment and control of the disease. We previously synthesized an antimalarial endoperoxide, N-89, having high antimalarial effects in vitro and in vivo. In this study we seek to understand the resistant mechanism against N-89 by establishing a highly N-89-resistant clone, named NRC10H, of the Plasmodium falciparum FCR-3 strain. We describe gene mutations in the parent FCR-3 strain and the NRC10H clone using whole-genome sequencing and subsequently by expression profiling using quantitative real-time PCR. Seven genes related to drug resistance, proteolysis, glycophosphatidylinositol anchor biosynthesis, and phosphatidylethanolamine biosynthesis exhibited a single amino acid substitution in the NRC10H clone. Among these seven genes, the multidrug resistance protein 2 (mdr2) variant A532S was found only in NRC10H. The genetic status of the P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC), a potential target of N-89, was similar between the NRC10H clone and the parent FCR-3 strain. These findings suggest that the genetic alterations of the identified seven genes, in particular mdr2, in NRC10H could give rise to resistance of the antimalarial endoperoxide N-89.


Assuntos
Antimaláricos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Compostos de Espiro/farmacologia , Resistência a Medicamentos/genética , Genômica , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , RNA Mensageiro/metabolismo , Sequenciamento Completo do Genoma
5.
Parasit Vectors ; 12(1): 348, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300064

RESUMO

BACKGROUND: In the last decade, resistance to antimonials has become a serious problem due to the emergence of drug-resistant strains. Therefore, understanding the mechanisms used by Leishmania parasites to survive under drug pressure is essential, particularly for species of medical-veterinary importance such as L. amazonensis. METHODS: Here, we used RNA-seq technology to analyse transcriptome profiles and identify global changes in gene expression between antimony-resistant and -sensitive L. amazonensis promastigotes. RESULTS: A total of 723 differentially expressed genes were identified between resistant and sensitive lines. Comparative transcriptomic analysis revealed that genes encoding proteins involved in metabolism (fatty acids) and stress response, as well as those associated with antimony resistance in other Leishmania species, were upregulated in the antimony-resistant line. Most importantly, we observed upregulation of genes encoding autophagy proteins, suggesting that in the presence of trivalent stibogluconate (SbIII) L. amazonensis can activate these genes either as a survival strategy or to induce cell death, as has been observed in other parasites. CONCLUSIONS: This work identified global transcriptomic changes in an in vitro-adapted strain in response to SbIII. Our results provide relevant information to continue understanding the mechanism used by parasites of the subgenus Leishmania (L. amazonensis) to generate an antimony-resistant phenotype.


Assuntos
Gluconato de Antimônio e Sódio/farmacologia , Antiprotozoários/farmacologia , Resistência a Medicamentos/genética , Leishmania/efeitos dos fármacos , Leishmania/genética , Transcriptoma , DNA de Protozoário/genética , Perfilação da Expressão Gênica , Ontologia Genética , Fenótipo , Análise de Sequência de RNA , Regulação para Cima
6.
Medicine (Baltimore) ; 98(28): e16372, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305435

RESUMO

BACKGROUND: Acute graft-vs-host disease (aGVHD) is a common complication of allogenic hematopoietic stem-cell transplantation (allo-HSCT) and skin is the most common and often the 1st site at which aGVHD develops. Cutaneous aGVHD is usually treated with oral and/or topical corticosteroids as the 1st-line treatment; however, steroid-refractory aGVHD not only impairs patients' quality of life but also causes significant morbidity and mortality after allo-HSCT. Narrow-band ultraviolet B (NB-UVB) phototherapy has been utilized for a wide range of immunologic inflammatory skin diseases, but there is limited information on the efficacy, safety, and biomarkers for response prediction of NB-UVB for cutaneous aGVHD. AIMS: The purpose of this study is to investigate the efficacy and safety of NB-UVB phototherapy for steroid-refractory cutaneous aGVHD. PATIENTS AND METHODS: A total of 40 subjects aged from 16 to 70 years with steroid-refractory cutaneous aGVHD after allo-HSCT will be included in the trial. Patients with worse than stage 2 intestine/liver aGVHD will be excluded. Eligible patients will undergo NB-UVB phototherapy until resolution or further worsening of rash or occurrence of an unmanageable adverse event. The primary endpoint is the overall response rate. The secondary outcomes include rates for complete response, partial response, stable disease, progressive disease, duration of response, sparing effect on calcineurin inhibitors and/or corticosteroids, safety, and predictive biomarkers for treatment response. ETHICS AND DISSEMINATION: The protocol has been approved by the institutional Clinical Research Review Board of Kyoto Prefectural University of Medicine. Written informed consent will be obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. TRIAL REGISTRATION: Trial registration numbers UMIN000032426 and jRCTs052180005.


Assuntos
Ensaios Clínicos Fase II como Assunto , Doença Enxerto-Hospedeiro/terapia , Dermatopatias/terapia , Transplante de Células-Tronco , Terapia Ultravioleta , Doença Aguda , Adolescente , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Resistência a Medicamentos , Humanos , Pessoa de Meia-Idade , Retratamento , Dermatopatias/etiologia , Esteroides/uso terapêutico , Transplante Homólogo , Terapia Ultravioleta/efeitos adversos , Terapia Ultravioleta/métodos , Adulto Jovem
8.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(7): 644-649, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31315762

RESUMO

OBJECTIVE: To study the clinical characteristics, drug sensitivity of isolated strains, and risk factors of drug resistance in children with invasive pneumococcal disease (IPD). METHODS: The clinical characteristics and drug sensitivity of the isolated strains of 246 hospitalized children with IPD in nine grade A tertiary children's hospitals from January 2016 to June 2018 were analyzed. RESULTS: Of the 246 children with IPD, there were 122 males and 124 females. Their ages ranged from 1 day to 14 years, and among them, 68 (27.6%) patients were less than 1 year old, 54 (22.0%) patients were 1 to 2 years old, 97 (39.4%) patients were 2 to 5 years old, and 27 (11.0%) patients were 5 to 14 years old. Pneumonia with sepsis was the most common infection type (58.5%, 144/246), followed by bloodstream infection without focus (19.9%, 49/246) and meningitis (15.0%, 37/246). Forty-nine (19.9%) patients had underlying diseases, and 160 (65.0%) had various risk factors for drug resistance. The isolated Streptococcus pneumoniae strains were 100% sensitive to vancomycin, linezolid, moxifloxacin, and levofloxacin, 90% sensitive to ertapenem, ofloxacin, and ceftriaxone, but had a low sensitivity to erythromycin (4.2%), clindamycin (7.9%), and tetracycline (6.3%). CONCLUSIONS: IPD is more common in children under 5 years old, especially in those under 2 years old. Some children with IPD have underlying diseases, and most of the patients have various risk factors for drug resistance. Pneumonia with sepsis is the most common infection type. The isolated Streptococcus pneumoniae strains are highly sensitive to vancomycin, linezolid, moxifloxacin, levofloxacin, ertapenem, and ceftriaxone in children with IPD.


Assuntos
Infecções Pneumocócicas , Antibacterianos , Ceftriaxona , Criança , Pré-Escolar , Resistência a Medicamentos , Feminino , Humanos , Lactente , Masculino , Testes de Sensibilidade Microbiana , Streptococcus pneumoniae
9.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(7): 724-729, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31315776

RESUMO

Glucocorticoid (GC) is currently the most effective drug for controlling persistent asthma; however, there is a significant difference in the response to GC among patients with asthma. Steroid-resistant asthma is one of the subtypes of asthma and has poor response to high-dose GC treatment. It may affect the quality of life of patients and even threaten their lives. Therefore, it is of great significance to explore the pathogenesis of steroid-resistant asthma and related targeted treatment strategy. In recent years, a variety of pathogeneses have been found to participate in the development and progression of steroid-resistant asthma, including the reduction in the binding between GC receptor and GC, the increase in the expression of GC receptor ß, over-activation of nuclear transcription factor activating protein 1 and nuclear factor-κB, abnormality in histone acetylation, and immune-mediated cytokine dysregulation. In addition, many studies have shown that vitamin D can improve the sensitivity to GC among patients with steroid-resistant asthma. This article reviews the pathogenesis of steroid-resistant asthma and the influence of vitamin D.


Assuntos
Asma , Resistência a Medicamentos , Glucocorticoides , Humanos , Qualidade de Vida , Receptores de Glucocorticoides , Vitamina D
10.
Vet Parasitol ; 271: 31-37, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31303200

RESUMO

The recovery of fenbendazole efficacy against Haemonchus contortus was attempted in a sheep intensive production system, using a strategy of population replacement in which the initial absolute efficacy of fenbendazole was 0%. The strategy was based on managing the parasite populations in refugia. Firstly, the resistant parasite population was reduced by means of anthelmintic treatments with efficacious drugs (Phase I), then a new, susceptible population was introduced in summer by way of artificially infected lambs at weaning, which were left to graze on the experimental pasture for eleven months (Phase II). Lastly, the impact of the replacement strategy, in terms of benzimidazole efficacy, was measured (Phase III). Faecal egg counts from permanent lambs and worm burdens as a measure of pasture infectivity from tracer lambs were determined throughout the study. During Phase I, faecal egg counts diminished from a peak of 2968 (300-7740) epg to 0 epg at the end, while adult worm burdens of H. contortus were reduced from 2625 (800-5100) to 0, which showed that the treatment strategy used in Phase I was effective in reducing the resistant population. These parameters also showed that good levels of pasture contamination and infectivity were achieved in Phase II, as faecal egg counts of up to 7275 (3240-13080) epg and adult worm burdens of 500 (200-800) H. contortus were reached. The absolute benzimidazole efficacy on H. contortus estimated at 16 months post-population replacement (Phase III) was 97.58%. The results lead to the conclusion that the recovery of anthelmintic efficacy of fenbendazole against a resistant population of H. contortus may be achieved by means of a strategy based on management of refugia and a subsequent introduction of a susceptible population. This strategy might be translatable to other resistant nematode genera.


Assuntos
Criação de Animais Domésticos/métodos , Resistência a Medicamentos , Fenbendazol/farmacologia , Hemoncose/veterinária , Haemonchus/efeitos dos fármacos , Criação de Animais Domésticos/normas , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Fenbendazol/uso terapêutico , Hemoncose/tratamento farmacológico , Hemoncose/prevenção & controle , Ovinos
11.
Vet Parasitol ; 271: 7-13, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31303208

RESUMO

In the current study, the egg hatch test (EHT) has been evaluated as an in vitro technique to detect albendazole (ABZ) resistance in Fasciola hepatica. The intra- and inter-assay variations of the EHT were measured by means of the coefficient of variation in different fluke isolates and over time; then, the results of the EHT were compared with the "gold standard" controlled efficacy test, which assesses the in vivo anthelmintic efficacy. The EHT was used later to evaluate the intra-herd variability regarding the level of ABZ resistance in calves infected by the same fluke isolate. Finally, several factors of the initial protocol were modified to improve the simplicity of the assay, including the incubation time of eggs with the drug and the use of eggs collected from faeces. The greatest uniformity between results within the assay and over time until 8 weeks after gallbladder collection (the deadline proposed for egg analysis) was obtained with an ABZ concentration of 0.5 µM. The length of exposure to ABZ was shown to be critical, as prolonged incubation (15 days) led to a change of ovicidal activity. The ABZ concentration of 0.5 µM is suggested as a possible discriminating dose to predict ABZ resistance, due to the close agreement between the results of the EHT at an ABZ concentration of 0.5 µM and those of the in vivo assays.


Assuntos
Albendazol/farmacologia , Doenças dos Bovinos/parasitologia , Fasciola hepatica/efeitos dos fármacos , Fasciolíase/veterinária , Testes de Sensibilidade Parasitária/métodos , Animais , Anti-Helmínticos/farmacologia , Bovinos , Doenças dos Bovinos/diagnóstico , Resistência a Medicamentos , Fasciolíase/diagnóstico , Fasciolíase/parasitologia , Fezes/parasitologia , Óvulo/efeitos dos fármacos , Fatores de Tempo
12.
Niger J Clin Pract ; 22(6): 790-795, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31187763

RESUMO

Background: Earlier studies on childhood nephrotic syndrome (NS) in tropical Africa showed steroid resistance in the majority. More recent studies show a variable picture, necessitating a re-evaluation. This study was aimed at determining the current pattern of steroid response in childhood NS, in an environment known to be dominated by steroid resistance. Patients and Methods: This prospective study of consecutive children who received steroid therapy for primary NS was carried out at the University College Hospital, Ibadan, Nigeria between 2006 and 2013. The outcomes of interest were steroid sensitivity and death. The recruited patients received a 4-6 weeks' course of prednisolone at 60 mg/m2/day followed by alternate day doses of 40 mg/m2 up to total steroid therapy duration of 6 months in steroid sensitive patients. Statistical analysis was carried out using STATA version 12.0. P value <0.05 was considered significant. Results: Of 109 children that received steroids for at least 8 weeks, whose mean (SD) age was 7.9 (3.7) years, 69 (63.3%) were steroid sensitive. Those aged ≥6 years responded as well as those aged <6 years (P = 0.78). Boys were more likely to be steroid-sensitive than girls, 65.2% versus 34.8% (P = 0.039). There was zero mortality among the patients studied. Conclusion: This study has shown a better steroid sensitivity of 63.3% in children with primary NS compared with the previously reported 36.8-42.9% in patients with highly selective proteinuria. This improved steroid response and zero mortality show a remarkable departure from the past.


Assuntos
Glucocorticoides/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Prednisolona/uso terapêutico , Criança , Pré-Escolar , Resistência a Medicamentos , Feminino , Humanos , Masculino , Nigéria , Estudos Prospectivos , Fatores Sexuais , Taxa de Sobrevida , Clima Tropical
13.
Nat Commun ; 10(1): 2665, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209259

RESUMO

Estimates of Plasmodium falciparum migration may inform strategies for malaria elimination. Here we elucidate fine-scale parasite population structure and infer recent migration across Southeast Asia using identity-by-descent (IBD) approaches based on genome-wide single nucleotide polymorphisms called in 1722 samples from 54 districts. IBD estimates are consistent with isolation-by-distance. We observe greater sharing of larger IBD segments between artemisinin-resistant parasites versus sensitive parasites, which is consistent with the recent spread of drug resistance. Our IBD analyses reveal actionable patterns, including isolated parasite populations, which may be prioritized for malaria elimination, as well as asymmetrical migration identifying potential sources and sinks of migrating parasites.


Assuntos
Resistência a Medicamentos/genética , Monitoramento Epidemiológico , Genoma de Protozoário/genética , Malária Falciparum/microbiologia , Plasmodium falciparum/genética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Ásia Sudeste , Biodiversidade , Genótipo , Geografia Médica , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/isolamento & purificação , Polimorfismo de Nucleotídeo Único
14.
Korean J Ophthalmol ; 33(3): 259-266, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31179657

RESUMO

PURPOSE: To evaluate the changes in visual acuity (VA) and central macular thickness (CMT) after intravitreal dexamethasone (IVD) implantation in intravitreal bevacizumab (IVB) treatment-resistant cases with pseudophakic cystoid macular edema (PCME). METHODS: This study included 10 PCME cases who underwent uneventful phacoemulsification and intraocular lens implantation with similar methods and six PCME cases referred to our hospital for treatment of low VA after cataract surgery. Due to the persistence of PCME, both topical steroid and anti-inflammatory medication were administered first, followed by IVB injection. IVD implantation was performed for all IVB treatment-resistant cases. VA and CMT values were compared before and at three months after the first IVD implantation. RESULTS: The mean VA values before and at 3 months after the first IVD implantation were 0.69 ± 0.19 logarithm of the minimum angle of resolution (logMAR) (1.50 to 0.10 logMAR) and 0.26 ± 0.07 logMAR (1.00 to 0.00 logMAR), respectively (p < 0.001). The mean CMT was 476.13 ± 135.13 mm (314 to 750 mm) and 294.06 ± 15.26 mm (222 to 480 mm), respectively (p < 0.001). The mean number of implanted IVD was 1.44 ± 0.89 (1 to 4) and the mean follow-up time was 7.4 ± 4.6 months (6 to 24 months). After IVD implantation therapy, the mean VA and CMT values were 0.19 ± 0.05 logMAR (0.70 to 0.00 logMAR) and 268.38 ± 31.35 mm (217 to 351 mm), respectively. CONCLUSIONS: To the best of our knowledge, this is the first report to show the efficacy of IVD implantation even after repeated IVB injections in treatment-resistant PCME. IVD implantation is both a safe and effective method for decreasing PCME after both uneventful and complicated cataract surgery.


Assuntos
Bevacizumab/administração & dosagem , Dexametasona/administração & dosagem , Resistência a Medicamentos , Macula Lutea/patologia , Edema Macular/tratamento farmacológico , Pseudofacia/complicações , Acuidade Visual , Idoso , Inibidores da Angiogênese/administração & dosagem , Implantes de Medicamento , Feminino , Glucocorticoides/administração & dosagem , Humanos , Injeções Intravítreas , Edema Macular/diagnóstico , Masculino , Pessoa de Meia-Idade , Facoemulsificação , Pseudofacia/diagnóstico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tomografia de Coerência Óptica
15.
Nat Commun ; 10(1): 2680, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213597

RESUMO

Genetic studies of complex traits in animals have been hindered by the need to generate, maintain, and phenotype large panels of recombinant lines. We developed a new method, C. elegans eXtreme Quantitative Trait Locus (ceX-QTL) mapping, that overcomes this obstacle via bulk selection on millions of unique recombinant individuals. We use ceX-QTL to map a drug resistance locus with high resolution. We also map differences in gene expression in live worms and discovered that mutations in the co-chaperone sti-1 upregulate the transcription of HSP-90. Lastly, we use ceX-QTL to map loci that influence fitness genome-wide confirming previously reported causal variants and uncovering new fitness loci. ceX-QTL is fast, powerful and cost-effective, and will accelerate the study of complex traits in animals.


Assuntos
Caenorhabditis elegans/genética , Mapeamento Cromossômico/métodos , Aptidão Genética/genética , Locos de Características Quantitativas/genética , Característica Quantitativa Herdável , Animais , Mapeamento Cromossômico/economia , Resistência a Medicamentos/genética , Feminino , Regulação da Expressão Gênica/genética , Masculino , Fatores de Tempo
16.
Malar J ; 18(1): 192, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185976

RESUMO

BACKGROUND: Mutational analysis of the Plasmodium falciparum kelch 13 (k13) gene is routinely performed to track the emergence and spread of artemisinin resistance. Surveillance of resistance markers has been impeded by the difficulty of extracting sufficient DNA from low parasite density infections common in low-transmission settings, such as Southeast Asia. This problem can be overcome by collecting large volumes of venous blood. Efficient methods for extracting and amplifying k13 from dried blood spots (DBS) would facilitate resistance surveillance. METHODS: Methods for k13 amplification from standard Whatman 3MM DBS (stored for 14 days at 28 °C with 80% relative humidity) were optimized by systematically testing different extraction conditions. Conditions that improved parasite DNA recovery as assessed by quantitative polymerase chain reaction (PCR) of 18S rDNA were then tested for their impact on k13 PCR amplification. RESULTS: The optimized protocol for amplification of k13 from DBS is markedly more sensitive than standard methods using commercial kits. Using this method, k13 was successfully amplified from laboratory-created DBS samples with parasite densities as low as 500 parasites/mL. Importantly, the method recovers both DNA and RNA, making it compatible with RNA-based ultrasensitive techniques currently in use. CONCLUSIONS: The optimized DBS protocol should facilitate drug resistance surveillance, especially in low-transmission settings where clinical malaria infections with high parasite densities are rare.


Assuntos
Artemisininas/farmacologia , Sangue/parasitologia , DNA de Protozoário/isolamento & purificação , Resistência a Medicamentos , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Antimaláricos/farmacologia , Ásia Sudeste , DNA de Protozoário/química , DNA de Protozoário/genética , Dessecação/métodos , Humanos , Plasmodium falciparum/efeitos dos fármacos , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Manejo de Espécimes/métodos
17.
Exp Appl Acarol ; 78(2): 149-172, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31190248

RESUMO

Monitoring acaricide resistance and understanding the underlying mechanisms are critically important in developing strategies for resistance management and tick control. Identification of single nucleotide polymorphisms in the acaricide-resistant associated gene of Rhipicephalus microplus has enabled the development of molecular markers for detection and monitoring of resistance against different types of acaricide. There are many molecular markers developed for resistance monitoring, including mutations on target genes such as sodium channel, acetylcholinesterase, carboxylesterase, ß-adrenergic octopamine receptor, octopamine-tyramine etc. Molecular genotyping through molecular markers can detect the presence of resistance-associated genes in a tick population before it reaches high frequency. This review aims to provide an update on the various molecular markers discovered to date from different regions of the world.


Assuntos
Acaricidas/farmacologia , Proteínas de Artrópodes/genética , Resistência a Medicamentos/genética , Polimorfismo de Nucleotídeo Único/genética , Rhipicephalus/genética , Animais , Proteínas de Artrópodes/metabolismo , Mutação , Rhipicephalus/efeitos dos fármacos , Controle de Ácaros e Carrapatos
18.
Curr Urol Rep ; 20(7): 40, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31168725

RESUMO

PURPOSE OF REVIEW: In this article, we review why patients may fail medical therapy for benign prostatic hyperplasia (BPH) and by doing so, gain a better understanding of the disease process and how to optimize the care of these patients. RECENT FINDINGS: A growing body of literature has attempted to better characterize the various mechanisms by which patients develop BPH as well as identify predictors of disease progression and treatment failure. BPH is a heterogenous disease process. A more personalized approach to treatment, including patient selection for medical or surgical management, would allow us to optimize patient care.


Assuntos
Resistência a Medicamentos , Hiperplasia Prostática/tratamento farmacológico , Falha de Tratamento , Inibidores de 5-alfa Redutase/uso terapêutico , Antagonistas Adrenérgicos alfa/uso terapêutico , Fatores Etários , Ensaios Clínicos como Assunto , Progressão da Doença , Quimioterapia Combinada , Humanos , Masculino , Obesidade/complicações , Inibidores da Fosfodiesterase 5/uso terapêutico , Antígeno Prostático Específico/análise , Prostatite/complicações
19.
BMC Vet Res ; 15(1): 184, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164118

RESUMO

BACKGROUND: Since pastoralists in South Darfur, Sudan, had complained about lack of albendazole (ABZ) efficacy to control nematodes in goats, the frequency of infection with gastrointestinal helminths was studied before in vivo faecal egg count reduction tests (FECRT) were conducted using ABZ orally either at the dose recommended for sheep, 5 mg/kg body weight (bw) or at 10 mg/kg bw. Experiments included goats naturally infected with gastrointestinal nematodes or experimentally infected with local Haemonchus contortus isolates. Three study areas (Nyala, Beleil and Kass) were visited in autumn or winter. RESULTS: Out of 478 screened goats, 82.4% were infected with gastrointestinal helminths and 82% were shedding eggs of strongyle nematodes with 90% of the strongyle larvae representing Haemonchus spp. A FECRT using naturally infected goats (n = 225: 71 untreated, 104 and 50 treated with 5 and 10 mg ABZ/kg bw, respectively) detected reduced ABZ efficacy in Nyala and Kass. Paired and unpaired FECRT calculations detected reductions of 72-92% with samples taken at 8 days post treatment with 5 mg ABZ/kg bw and of 85-94% with 10 mg ABZ/kg bw. The FECRT based on day 14 post treatment samples showed reductions of 69-77% with 5 mg/kg and of 75-87% with 10 mg ABZ/kg bw. In Beleil, ABZ efficacy was 95%. In the egg hatch test EC50 values for Nyala and Kass ranged from 0.12-0.24 µg thiabendazole/ml, corresponding to benzimidazole resistant phenotypes. Only Haemonchus spp. larvae were present after treatments in coprocultures. When the efficacy was evaluated experimentally using isolates of H. contortus from Nyala and Kass, the 5 mg ABZ/kg dose revealed reductions of 76-78% on day 8 and of 62-70% on day 14 with the unpaired method. Using 10 mg ABZ/kg, the FECR was still only 77-82%. CONCLUSIONS: Both, in vivo and in vitro methods detected resistant H. contortus populations in goats from South Darfur State. The time point 14 days post treatment was more sensitive for detection of ABZ resistance than 8 days post treatment. This is the first report on the occurrence of anthelmintic resistance in Sudan confirming that anthelmintic resistance selection is occurring in African subsistence farming systems.


Assuntos
Albendazol/uso terapêutico , Antinematódeos/uso terapêutico , Doenças das Cabras/parasitologia , Hemoncose/epidemiologia , Haemonchus/efeitos dos fármacos , Enteropatias Parasitárias/veterinária , Animais , Resistência a Medicamentos , Feminino , Doenças das Cabras/tratamento farmacológico , Doenças das Cabras/epidemiologia , Cabras , Hemoncose/tratamento farmacológico , Hemoncose/parasitologia , Enteropatias Parasitárias/epidemiologia , Masculino , Contagem de Ovos de Parasitas/veterinária , Prevalência , Sudão/epidemiologia
20.
Expert Opin Investig Drugs ; 28(7): 573-581, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31208237

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease, which affects joints and extra-articular structures. Nowadays, the armamentarium of therapeutic options is progressively expanding and embraces several mechanisms of action: TNF inhibition, B-cell depletion, T-cell co-stimulation inhibition, IL-6 blockade, and JAK-inhibition. Granulocyte-Monocyte-Colony-Stimulating-Factor (GM-CSF) is a mediator acting as a cytokine with a proven pathogenetic role in RA, providing a potential alternative target for the management of the disease. Mavrilimumab is a monoclonal antibody against GM-CSF receptor, which has been successfully tested in RA patients. Areas covered: Beginning with a description of the preclinical evidence and the rationale for GM-CSF blockade in RA, this review will provide a wide overview of mavrilimumab efficacy and safety profile by analyzing phase I/II RCTs conducted in patients with moderate to severe RA. Expert opinion: According to the promising results from phase I-II RCTs, mavrilimumab could be considered as an additional therapeutic option for RA patients multi-resistant to the available targeted drugs. However, the optimal dose and the profile of this new drug should be confirmed in phase III RCTs before the marketing.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Artrite Reumatoide/fisiopatologia , Resistência a Medicamentos , Humanos , Terapia de Alvo Molecular , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Índice de Gravidade de Doença
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