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1.
Rev Med Liege ; 75(5-6): 362-365, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32496680

RESUMO

Malaria is a worldwide public health problem. In Europe, data show an increasing trend of imported cases in the last ten years. Following an alarming observation reporting resistance to anti-malarial drugs, new effective treatments have been developed in early 21st century. These are artemisinin and its derivatives. Artemisinin-based combination therapies (ACT) are now recommended by the World Health Organisation (WHO) since 2006 as the first-line treatment for uncomplicated Plasmodium falciparum malaria. However, resistance phenomena to these new drugs have been described in South-East Asia since 2009. It is thus necessary to use them properly and to monitor their use to preserve their effectiveness in the future.


Assuntos
Antimaláricos , Malária Falciparum , Antimaláricos/uso terapêutico , Resistência a Medicamentos , Europa (Continente) , Humanos , Malária Falciparum/tratamento farmacológico
2.
BMC Infect Dis ; 20(1): 413, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32539801

RESUMO

BACKGROUND: Successful control programs have impeded local malaria transmission in almost all Gulf Cooperation Council (GCC) countries: Qatar, Bahrain, Kuwait, Oman, the United Arab Emirates (UAE) and Saudi Arabia. Nevertheless, a prodigious influx of imported malaria via migrant workers sustains the threat of local transmission. Here we examine the origin of imported malaria in Qatar, assess genetic diversity and the prevalence of drug resistance genes in imported Plasmodium falciparum, and finally, address the potential for the reintroduction of local transmission. METHODS: This study examined imported malaria cases reported in Qatar, between 2013 and 2016. We focused on P. falciparum infections and estimated both total parasite and gametocyte density, using qPCR and qRT-PCR, respectively. We also examined ten neutral microsatellites and four genes associated with drug resistance, Pfmrp1, Pfcrt, Pfmdr1, and Pfkelch13, to assess the genetic diversity of imported P. falciparum strains, and the potential for propagating drug resistance genotypes respectively. RESULTS: The majority of imported malaria cases were P. vivax, while P. falciparum and mixed species infections (P. falciparum / P. vivax) were less frequent. The primary origin of P. vivax infection was the Indian subcontinent, while P. falciparum was mostly presented by African expatriates. Imported P. falciparum strains were highly diverse, carrying multiple genotypes, and infections also presented with early- and late-stage gametocytes. We observed a high prevalence of mutations implicated in drug resistance among these strains, including novel SNPs in Pfkelch13. CONCLUSIONS: The influx of genetically diverse P. falciparum, with multiple drug resistance markers and a high capacity for gametocyte production, represents a threat for the reestablishment of drug-resistant malaria into GCC countries. This scenario highlights the impact of mass international migration on the reintroduction of malaria to areas with absent or limited local transmission.


Assuntos
Doenças Transmissíveis Importadas/transmissão , Resistência a Medicamentos/genética , Malária/transmissão , Plasmodium falciparum/genética , Doenças Transmissíveis Importadas/epidemiologia , Doenças Transmissíveis Importadas/parasitologia , Variação Genética , Genótipo , Humanos , Malária/epidemiologia , Malária/parasitologia , Carga Parasitária , Plasmodium falciparum/isolamento & purificação , Plasmodium vivax/genética , Plasmodium vivax/isolamento & purificação , Prevalência , Catar/epidemiologia
3.
Encephale ; 46(3S): S126-S127, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32475694
4.
Vet Parasitol ; 281: 109121, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32361524

RESUMO

The search of novel strategies for anthelmintic control is a crucial need considering the widespread increase in resistant parasitic populations in livestock. Bioactive phytochemicals may contribute to improve parasite control by enhancing the effect of existing anthelmintic drugs. The aim of the current work was to evaluate the in vivo and in vitro pharmaco-chemical interaction and the in vivo efficacy of the combination of albendazole (ABZ) with thymol (TML) in lambs naturally infected with resistant gastrointestinal nematodes. Thirty (30) lambs were allocated into three experimental groups. Each group was treated orally with either ABZ (5 mg/kg), TML (150 mg/kg, twice every 24 h) or the co-administration of both compounds. Blood samples were collected between 0 and 51 h post-treatment and TML, ABZ and its metabolites were measured by HPLC. Individual faecal samples were collected at days -1 and 14 post-treatment to perform the faecal egg count reduction test. Additionally, the effect of TML on the sulphoreduction and sulphonation of ABZ sulphoxide was assessed in vitro using ruminal content and liver microsomes, respectively. The metabolism of TML in the ruminal content was very low and the monoterpene exhibited a low degree of association with the particulate phase of the ruminal content. No changes in the pharmacokinetic behavior of ABZ sulphoxide were observed in the presence of the natural product (TML). In contrast, the ABZ sulphone Cmax and AUC were lower (P 0.002 and 0.001 respectively) in the co-administered animals (0.16 ±â€¯0.07 µg/mL and 3.63 ±â€¯1.21 µg.h/mL) compared with those that received ABZ alone (0.45 ±â€¯0.15 µg/mL and 9.50 ±â€¯2.84 µg.h/mL). TML was detected in the bloodstream between 1 and 48 h post-treatment, which indicates the time of target nematodes being exposed to the bioactive monoterpene. However, the in vivo efficacy of TML was 0% and the presence of this terpene did not increase the efficacy of ABZ. The presence of TML significantly inhibited the ruminal sulphoreduction (P 0.001) and the hepatic sulphonation (P 0.001) of ABZ sulphoxide. These observations point out that in vivo pharmaco-parasitological studies are relevant to corroborate the adverse kinetic/metabolic interactions and the efficacy of bioactive natural products combined with synthetic anthelmintics.


Assuntos
Albendazol/administração & dosagem , Resistência a Medicamentos/efeitos dos fármacos , Gastroenteropatias/tratamento farmacológico , Helmintíase Animal/tratamento farmacológico , Doenças dos Ovinos/tratamento farmacológico , Timol/administração & dosagem , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/farmacologia , Quimioterapia Combinada , Gastroenteropatias/parasitologia , Helmintíase Animal/parasitologia , Compostos Fitoquímicos/farmacologia , Ovinos , Doenças dos Ovinos/parasitologia , Resultado do Tratamento
5.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 32(2): 174-180, 2020 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-32458607

RESUMO

OBJECTIVE: To detect the chloroquine-resistant molecular marker polymorphisms in Plasmodium falciparum imported into China, investigate the mutation types of P. falciparum chloroquine resistant transporter (Pfcrt) gene at positions 72 to 76, and analyze the specificity of the P. falciparum specimens with different origins. METHODS: A total of 674 filter paper blood samples were collected from the National Malaria Diagnosis Reference Laboratory of China in 2012 and 2018. The amino acid po- sitions 72 to 76 of the Pfcrt gene on chromosome 7 were amplified using nested PCR assay and sequenced, and the sequencing results of the target gene fragment and the geographical region-specific prevalence of the mutations in the Pfcrt gene were analyzed. RESULTS: Among the 674 imported P. falciparum malaria cases in China in 2012 and 2018, 99.5% (644/674) were from Africa, which were predominantly from western and central Africa (80.4%, 518/644), and 4.5% (30/674) from Southeast Asia and Oceania (Papua New Guinea). A total of 4 site mutations (C72S, M74I, N75E and K76T) and 5 haplotypes (CVMNK, CVIET and SVMNT and two mixed types) were identified, with haplotypes CVMNK and CVIET present in parasites of both African and Southeast Asian origins, SVMNT detected in Southeast Asia (Myanmar) and Papua New Guinea isolates, the mixed type of haplo- types CVMNK/CVIET detected in P. falciparum of African and Southeast Asian origins, and the mixed type of haplotypes CVMNK/SVMNT detected only in the Myanmar isolate. Most P. falciparum parasites of the African origin carried the wild-type Pfcrt allele (77.7%, 478/615), and 68.0% (17/25) of the P. falciparum parasites of the Southeast Asian and Papua New Guinea or- igins harbored chloroquine resistant molecular markers (χ2 = 28.5, P < 0.05). The constituent ratio of the wild- and mutant-type Pfcrt allele varied in different geographical regions of Africa (P < 0.01), and the lowest prevalence of the wild-type Pfcrt allele was seen in western Africa. CONCLUSIONS: Among the 674 imported malaria cases in China in 2012 and 2018, the P. falciparum imported from Sotheast Asia habors a higher proportion of resistance to chloroquine and a higher molecular polymophism at ami- no acid positions 72 to 76 of the Pfcrt gene than the parasite of the African origin.


Assuntos
Cloroquina , Doenças Transmissíveis Importadas , Malária Falciparum , Plasmodium falciparum , Polimorfismo Genético , Proteínas de Protozoários , África , Antimaláricos/farmacologia , Ásia , China , Cloroquina/farmacologia , Doenças Transmissíveis Importadas/parasitologia , Resistência a Medicamentos/genética , Haplótipos , Humanos , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Proteínas de Protozoários/genética
6.
Parasitol Res ; 119(6): 1857-1871, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32350589

RESUMO

Antimony is an important drug for the treatment of Leishmania parasite infections. In several countries, the emergence of drug-resistant Leishmania species has reduced the effectiveness of this drug. The mechanism of clinical drug resistance is unclear. The aim of this work was to identify mitochondrial proteome alterations associated with resistance against antimonial. A combination of cell fractionation, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and Label-Free Quantification was used to characterize the mitochondrial protein composition of Leishmania tropica field isolates resistant and sensitive to meglumine antimoniate. LC-MS/MS analysis resulted in the identification of about 1200 proteins of the Leishmania tropica mitochondrial proteome. Various criteria were used to allocate about 40% proteins to mitochondrial proteome. Comparative quantitative proteomic analysis of the sensitive and the resistant strains showed proteins with differential abundance in resistance species are involved in TCA and aerobic respiration enzymes, stress proteins, lipid metabolism enzymes, and translation. These results showed that the mechanism of antimony resistance in Leishmania spp. field isolate may be associated with alteration in enzymes involved in mitochondrial pathways.


Assuntos
Antiprotozoários/farmacologia , Leishmania tropica/efeitos dos fármacos , Antimoniato de Meglumina/farmacologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Animais , Linhagem Celular , Cromatografia Líquida , Resistência a Medicamentos , Leishmania tropica/isolamento & purificação , Leishmania tropica/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Proteoma , Proteômica , Espectrometria de Massas em Tandem
7.
Parasitol Res ; 119(6): 1915-1923, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32405804

RESUMO

Trichomoniasis is the most prevalent curable sexually transmitted infection (STI) worldwide and a risk factor for the acquisition of other STIs and adverse pregnancy outcomes. The objectives of this study were to determine the prevalence of T. vaginalis and related coinfections in women attending a third-level hospital of Madrid (Spain). A retrospective study of 24,173 vaginal exudates from women with suspected vaginitis was conducted between 2013 and 2017. Likewise, among T. vaginalis positive samples, co-occurrence with gonorrhea, chlamydia, syphilis, VIH, Mycoplasma hominis, and Ureaplasma urealyticum was checked. Moreover, seven T. vaginalis isolates from 2017 were randomly collected for endobionts, drug resistance, and microsatellite (MS) instability determinations. The prevalence of T. vaginalis was 0.8% between 2013 and 2017. Less than 20% of patients with trichomoniasis were submitted to a complete screening for other genital pathogens. From that, two patients were coinfected with chlamydia and three with syphilis. Surprisingly, 6.4% of positive samples were diagnosed among pregnant women, showing an alarming increase from 3.2% (2014) to 10% (2017). Among the isolates randomly analyzed, five carried T. vaginalis virus, five harbored mycoplasmas, and one was metronidazole-resistant. The molecular genotyping showed a high variability in the three MS evaluated. To our knowledge, this is the first study in Spain that evaluates the prevalence of trichomoniasis in general and pregnant population and includes biomolecular determinations. These results warn about the increasing prevalence and highlight the importance of including T. vaginalis detection in routine gynecological revisions with special emphasis on childbearing age women and patients with previous STIs.


Assuntos
Metronidazol/farmacologia , Simbiose , Centros de Atenção Terciária , Tricomoníase/epidemiologia , Trichomonas vaginalis , Adulto , Coinfecção , Resistência a Medicamentos , Feminino , Gonorreia/complicações , Humanos , Pessoa de Meia-Idade , Mycoplasma hominis/isolamento & purificação , Gravidez , Complicações Parasitárias na Gravidez/epidemiologia , Taxa de Gravidez , Prevalência , Estudos Retrospectivos , Espanha/epidemiologia , Tricomoníase/complicações , Tricomoníase/tratamento farmacológico
8.
Zhonghua Liu Xing Bing Xue Za Zhi ; 41(5): 770-775, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32447923

RESUMO

Objective: To analyze the resistance mutational profiles of multi-drug resistant Mycobacterium tuberculosis in China and the correlation between major mutation types and genotypes based on the whole-genome sequencing data. Methods: Search and download of the genome-wide sequencing data of M. tuberculosis published in China by August 2019 on NCBI database were conducted. Mutation frequency of drug resistance-related gene loci based on whole-genome sequencing was used to predict the molecular susceptibility of strains, and the correlation between mutation types and genotypes was analyzed. Results: According to the results of molecular resistance and susceptibility profiles, 1 024 MDR strains were identified from 2 019 M. tuberculosis strains. The major mutation types of resistance-related genes to common drugs were katG S315T (73.2%, isoniazid), rpoB S450L (63.1%, rifampicin), rpsL K43R (70.0%, streptomycin), embB M306V (37.4%, ethambutol), pncA_promoter T (-11)C (7.9%, pyrazinamide), gyrA A90V (32.3%, fluoroquinolones), rrs A1401G (67.7%, second-line injection drugs), fabG1_promoter C (-15) T (87.0%, Ethionamide), folC I43T (30.4%, P-aminosalicylic acid). Among them, the frequencies of katG S315T, embB M306V, rpsL K43R, gyrA A90V in lineage 2 were significantly higher than those in lineage 4, and folC I43T was only found in lineage 2. The proportion of katG S315T was significantly higher in the ancient Beijing genotype compared to the modern genotype, in contrast, the proportion of rpsL K43R was significantly higher in modern Beijing genotype, the differences were significant (all P<0.05). Conclusions: The results showed the main mutation types of resistance-related genes of MDR strains to many commonly used anti-tuberculosis drugs in China based on whole-genome sequencing, providing a basis for the development of sensitive and specific rapid molecular detection methods. At the same time, it was also found that the major mutation types of MDR-related genes were related to the genotype of the strains.


Assuntos
Tuberculose Resistente a Múltiplos Medicamentos , Antituberculosos , China , Resistência a Medicamentos , Estudo de Associação Genômica Ampla , Humanos , Testes de Sensibilidade Microbiana , Mutação
9.
J Thromb Thrombolysis ; 50(2): 287-291, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32445064

RESUMO

Patients with COVID-19 have a coagulopathy and high thrombotic risk. In a cohort of 69 intensive care unit (ICU) patients we investigated for evidence of heparin resistance in those that have received therapeutic anticoagulation. 15 of the patients have received therapeutic anticoagulation with either unfractionated heparin (UFH) or low molecular weight heparin (LMWH), of which full information was available on 14 patients. Heparin resistance to UFH was documented in 8/10 (80%) patients and sub-optimal peak anti-Xa following therapeutic LMWH in 5/5 (100%) patients where this was measured (some patients received both anticoagulants sequentially). Spiking plasma from 12 COVID-19 ICU patient samples demonstrated decreased in-vitro recovery of anti-Xa compared to normal pooled plasma. In conclusion, we have found evidence of heparin resistance in critically unwell COVID-19 patients. Further studies investigating this are required to determine the optimal thromboprophylaxis in COVID-19 and management of thrombotic episodes.


Assuntos
Anticoagulantes/uso terapêutico , Betacoronavirus/patogenicidade , Coagulação Sanguínea/efeitos dos fármacos , Infecções por Coronavirus/terapia , Resistência a Medicamentos , Heparina/uso terapêutico , Unidades de Terapia Intensiva , Pneumonia Viral/terapia , Trombose/tratamento farmacológico , Adulto , Idoso , Anticoagulantes/efeitos adversos , Testes de Coagulação Sanguínea , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Monitoramento de Medicamentos , Feminino , Heparina/efeitos adversos , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Estudos Retrospectivos , Trombose/sangue , Trombose/diagnóstico , Trombose/virologia , Resultado do Tratamento
10.
High Blood Press Cardiovasc Prev ; 27(3): 215-223, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32382998

RESUMO

Cardiovascular disease is predicted to be the largest cause of death and disability in India by 2020. Hypertension (HT), one of the main contributing factors, presents a significant public health burden. Inability to achieve adequate blood pressure (BP) control results in uncontrolled hypertension (UHT). The prevalence of UHT is high in India, with only about 9-20% of patients achieving target BP goals. Presently, there are no guidelines specific to UHT, which if left uncontrolled can lead to resistant HT, chronic kidney disease and other complications of HT. A multidisciplinary panel, comprising of specialists in cardiology, nephrology and internal medicine, was convened to address the diagnosis and management of UHT in the Indian population. The panel identified key points concerning UHT and discussed management recommendations in the Indian clinical setting.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/terapia , Comportamento de Redução do Risco , Algoritmos , Anti-Hipertensivos/efeitos adversos , Tomada de Decisão Clínica , Comorbidade , Consenso , Técnicas de Apoio para a Decisão , Progressão da Doença , Resistência a Medicamentos , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Índia/epidemiologia , Prevalência , Fatores de Risco , Resultado do Tratamento
11.
Mem Inst Oswaldo Cruz ; 115: e190408, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32321156

RESUMO

BACKGROUND: The mechanism of resistance to SbIII in Leishmania is complex, multifactorial and involves not only biochemical mechanisms, but also other elements, such as the immune system of the host. OBJECTIVES: In this study, putative changes in the immunological profile of human monocytes infected with wild-type (WT) and antimony (SbIII)-resistant Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum lines were evaluated. METHODS: Susceptibility assays WT and SbIII-resistant L. braziliensis and L. infantum were performed using lines THP-1 human monocytic lineage. Phagocytic capacity, cytokine profile, intracellular nitric oxide (NO) production and surface carbohydrate residues profile were performed in peripheral blood monocytes by flow cytometry. FINDINGS: The phagocytic capacity and intracellular NO production by classical (CD14++CD16-) and proinflammatory (CD14++CD16+) monocytes were higher in the presence of L. infantum lines compared to L. braziliensis lines. The results also highlight proinflammatory monocytes as the cellular subpopulation of major relevance in a phagocytosis event and NO expression. It is important to note that L. infantum induced a proinflammatory cytokine profile characterised by higher levels of TNF-α in culture supernatant than L. braziliensis. Conversely, both Leishmania lines induce high levels of IL-6 in culture supernatant. Analysis of the expression profile of surface carbohydrates showed that L. braziliensis presents 4.3-fold higher expression of galactose(ß1,4)N-acetylglucosamine than L. infantum line. Interestingly, the expression level of α-N-acetylgalactosamine residues was 2-fold lower in the SbIII-resistant L. braziliensis line than its counterpart WT line, indicating differences in surface glycoconjugates between these lines. MAIN CONCLUSIONS: Our results showed that L. braziliensis and L. infantum induce different innate immune responses and a highly inflammatory profile, which is characteristic of infection by L. infantum, the species associated with visceral disease.


Assuntos
Antimônio/farmacologia , Antiprotozoários/farmacologia , Leishmania braziliensis/imunologia , Leishmania infantum/imunologia , Monócitos/parasitologia , Óxido Nítrico/biossíntese , Fagocitose/imunologia , Adulto , Resistência a Medicamentos , Feminino , Citometria de Fluxo , Humanos , Imunidade Inata , Leishmania braziliensis/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Masculino , Monócitos/imunologia , Adulto Jovem
13.
Sheng Wu Gong Cheng Xue Bao ; 36(3): 541-548, 2020 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-32237547

RESUMO

Hyperaccumulators can hyper-accumulate and -tolerate heavy metals, thus are not only an ideal model to explore the mechanisms of ion transport and toxicity tolerance, but also play an irreplaceable role in the development and application of phytoremediation. Sedum plumbizincicola is a recently identified cadmium (Cd)/zinc (Zn) hyperaccumulator in the Crassulaceae family in China. Here we report the construction and screening of its yeast-expressing cDNA library. We identified a metallothionein protein encoding gene SpMT2. SpMT2 is localized in yeast cytoplasm and expression of it in yeast specifically enhanced resistance to Cd. Further analysis showed that SpMT2 did not affect Cd absorption in yeast, but greatly inhibited Cd transport into vacuoles, indicating that SpMT2 may reduce Cd toxicity via chelation in cytoplasm. qRT-PCR analyses indicated that SpMT2 was highly expressed both in roots and shoots, and did not respond to Cd treatment. Taking together the results that SpMT2 was also cytoplasm-localized in plants, we proposed that SpMT2 may chelate/detoxify Cd and retain the complex in cytosol, which renders higher mobility of Cd thus promoting long-distance Cd transport in S. plumbizincicola.


Assuntos
Cádmio , Resistência a Medicamentos , Metaloproteinase 15 da Matriz , Sedum , Poluentes do Solo , Biodegradação Ambiental , Cádmio/toxicidade , China , Resistência a Medicamentos/genética , Metaloproteinase 15 da Matriz/genética , Metais Pesados/toxicidade , Sedum/efeitos dos fármacos , Sedum/genética , Zinco/toxicidade
14.
Cardiovasc Ther ; 2020: 3568608, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256707

RESUMO

Children with Kawasaki disease (KD) resistant to intravenous immunoglobulin (IVIG) have a higher incidence of coronary artery lesions (CAL). Despite the association between Purinergic receptor P2Y12 (P2RY12) polymorphism, KD genetic susceptibility, and CAL complications being proved, few studies have assessed the relationship between P2RY12 polymorphisms and IVIG resistance in patients with KD. We recruited 148 KD patients with IVIG resistance and 611 with IVIG sensitivity and selected five P2RY12 polymorphisms: rs9859538, rs1491974, rs7637803, rs6809699, and rs2046934. A significant difference in the genotype distributions between patients was only observed for the rs6809699 A > C polymorphism (AC vs. AA: adjusted odds ratio (OR) = 0.48, 95% confidence interval (CI) = 0.27-0.84, P=0.011; AC/CC vs. AA: adjusted OR = 0.47, 95% CI = 0.27-0.83, P=0.0084). After adjusting for age and gender, the carriers of the rs6809699 C allele had OR of 0.44 to 0.49 for IVIG sensitivity (AC vs. AA: adjusted OR = 0.48, 95% confidence interval (CI) = 0.27-0.84, P=0.011; AC/CC vs. AA: adjusted OR = 0.47, 95% CI = 0.27-0.83, P=0.0084) compared to the carriers of a rs6809699 AA genotype, suggesting the protective effect of this SNP against IVIG resistance. Moreover, individuals with all five protective polymorphisms experienced a significantly decreased IVIG resistance compared to that of individuals with up to three protective polymorphisms (adjusted OR = 0.27, 95% CI = 0.13-0.57, P=0.0006). Our results suggest that the P2RY12 rs6809699 polymorphism could be used as a biomarker to predict IVIG resistance in KD patients.


Assuntos
Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/prevenção & controle , Resistência a Medicamentos/genética , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Receptores Purinérgicos P2Y12/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Tomada de Decisão Clínica , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/imunologia , Feminino , Frequência do Gene , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/imunologia , Seleção de Pacientes , Testes Farmacogenômicos , Valor Preditivo dos Testes , Fatores de Risco
15.
Environ Sci Pollut Res Int ; 27(20): 24999-25008, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32342417

RESUMO

This study investigated and identified the distribution of drug resistance genes in feces, soil, and water of duck farms in Zhanjiang, China, and analyzed the drug resistance of Salmonella in the duck farm environment. PCR was used to assess the distribution of 25 resistance genes that are common in the duck farm environment. The isolation, biochemical identification, PCR identification of Salmonella, and the minimum inhibitory concentration (MIC) of 22 drugs were measured by micro-broth double dilution. In water, 25 drug resistance genes were detected, 24 in soil, and 23 in feces. Among them, the detection rate of the aadA1 gene in soil reached 100%, 13 drug resistance genes had a detection rate above 80%, and five species had a detection rate below 50%. In water, the detection rate of the floR and aadA1 genes was 100%, 12 drug resistance genes had a detection rate above 80%, and eight genes had a detection rate below 50%. In feces, nine drug resistance genes had a detection rate of 100%, nine genes had a detection rate above 80%, and one gene had a detection rate below 50%. In addition, 92 strains of Salmonella were isolated and identified, and their resistance rate to nine drugs was as high as 100%. All isolated Salmonella can tolerate at least nine drugs, 55.43% (51/92) of the strains can tolerate more than 16 drugs, and 4.35% (4/92) of the strains were resistant to up to 21 drugs. In conclusion, the present experiment suggested that drug resistance genes were ubiquitous in the duck farm environment in Zhanjiang and that these drug resistance genes may spread horizontally between feces, soil, and water. Moreover, drug resistance and multi-drug resistance were found for 92 isolated Salmonella strains from the duck farm environment. The government should consequently strengthen the regulation of antimicrobial drug use in duck farms.


Assuntos
Patos , Salmonella/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , China , Resistência a Medicamentos/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Fazendas , Testes de Sensibilidade Microbiana
16.
Plant Physiol Biochem ; 151: 438-442, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32289637

RESUMO

Acetohydroxyacid synthase (AHAS, E.C. 2.2.1.6) is the target site of several herbicide classes including imidazolinones. Imidazolinone resistance in wheat is conferred by two major genes AhasL-D1 and AhasL-B1. The objective of this work was to evaluate the in vitro and in vivo AHAS activity and plant growth in response to imazamox of nine wheat cultivars. Dose-response curves for two-gene resistant cultivars were significantly different from the single-gene resistant and susceptible cultivars in the in vitro AHAS assay. Resistance levels at the in vivo AHAS and whole-plant assays for resistant cultivars were >10-fold higher than susceptible cultivars. Moreover, in vivo dose-response curves showed differences among cultivars with the same number of resistance genes. It was concluded that in the in vitro AHAS assay cultivar variability was due to differences in target-site sensitivity while the in vivo AHAS assay reflected the resistance at whole-plant level. Both in vitro and in vivo AHAS dose-response curves could be useful tools when exploring mechanisms involved in imidazolinone resistance in different wheat genetic backgrounds and for the selection of higher resistant genotypes.


Assuntos
Acetolactato Sintase , Agricultura , Ensaios Enzimáticos , Resistência a Herbicidas , Imidazóis , Triticum , Acetolactato Sintase/genética , Agricultura/métodos , Resistência a Medicamentos/genética , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Imidazóis/farmacologia , Seleção Genética , Triticum/efeitos dos fármacos , Triticum/enzimologia
17.
Proc Natl Acad Sci U S A ; 117(19): 10246-10253, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32327610

RESUMO

The evolution of insect resistance to pesticides poses a continuing threat to agriculture and human health. While much is known about the proximate molecular and biochemical mechanisms that confer resistance, far less is known about the regulation of the specific genes/gene families involved, particularly by trans-acting factors such as signal-regulated transcription factors. Here we resolve in fine detail the trans-regulation of CYP6CM1, a cytochrome P450 that confers resistance to neonicotinoid insecticides in the whitefly Bemisia tabaci, by the mitogen-activated protein kinase (MAPK)-directed activation of the transcription factor cAMP-response element binding protein (CREB). Reporter gene assays were used to identify the putative promoter of CYP6CM1, but no consistent polymorphisms were observed in the promoter of a resistant strain of B. tabaci (imidacloprid-resistant, IMR), which overexpresses this gene, compared to a susceptible strain (imidacloprid-susceptible, IMS). Investigation of potential trans-acting factors using in vitro and in vivo assays demonstrated that the bZIP transcription factor CREB directly regulates CYP6CM1 expression by binding to a cAMP-response element (CRE)-like site in the promoter of this gene. CREB is overexpressed in the IMR strain, and inhibitor, luciferase, and RNA interference assays revealed that a signaling pathway of MAPKs mediates the activation of CREB, and thus the increased expression of CYP6CM1, by phosphorylation-mediated signal transduction. Collectively, these results provide mechanistic insights into the regulation of xenobiotic responses in insects and implicate both the MAPK-signaling pathway and a transcription factor in the development of pesticide resistance.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Resistência a Medicamentos/genética , Regulação da Expressão Gênica , Hemípteros/crescimento & desenvolvimento , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Sistema Enzimático do Citocromo P-450/genética , Hemípteros/efeitos dos fármacos , Hemípteros/genética , Hemípteros/metabolismo , Inseticidas/farmacologia , Proteínas Quinases Ativadas por Mitógeno/genética , Mutação , Fosforilação , Regiões Promotoras Genéticas
18.
PLoS One ; 15(4): e0232254, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32343723

RESUMO

BACKGROUND: Treatment resistant hypertension(TRH) is detrimental risk of cardiovascular and premature deaths. Globally, the prevalence of resistant hypertension is inclining from time to time and it is yet to be determined in Ethiopia. OBJECTIVE: To assess the prevalence of apparent TRH and its predictors among ambulatory hypertensive patients on follow up in hypertension clinic of Mekelle Hospital, Northern Ethiopia. METHOD: A hospital based cross sectional study was conducted from Nov 25, 2018 to July 20, 2019, among 338 adult ambulatory hypertensive patients on follow up in Mekelle Hospital hypertension clinic. Hypertensive patient aged ≥18 years who were on regular follow up and taking antihypertensive medications for at least 6 months were included in the study. A simple random sampling technique was used to recruit the study patients. RESULTS: A total of 338 adult ambulatory hypertensive patients were analysed. More than half, 182 (53.8%) patients were females and the average age of the patients was 58.9 ±11.5. Three hundred thirty-three (98.5%) patients had no family history of hypertension. Majority, 66.8% of the patients were on monotherapy. The prevalence of apparent TRH was calculated to be 8.6% [Confidence Interval = 0.056-0.116]. Patients with Body Mass Index(BMI) greater than 30[Adjusted Odds Ratio(AOR) = 12.1, 95%CI:2.00-73.19, p = 0.007] and longer duration of hypertension were the predictors of resistant hypertension. CONCLUSION: Even if escalation of antihypertensive medications was not aggressive, apparent TRH was common in the study setting. Obesity (BMI greater than 30) and longer duration of hypertension since diagnosis were the predictors of TRH. Meticulous emphasis should be placed on to detect the prevalence of true hypertension resistance and future studies should discover the impact of aggressive antihypertensive medications scale up on the risks of TRH.


Assuntos
Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Adulto , Idoso , Instituições de Assistência Ambulatorial , Anti-Hipertensivos/uso terapêutico , Comorbidade , Estudos Transversais , Resistência a Medicamentos , Etiópia/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Prevalência , Fatores de Risco
19.
PLoS One ; 15(4): e0232171, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32324826

RESUMO

There is great concern regarding the rapid emergence and spread of drug-resistance in Plasmodium falciparum, the parasite responsible for the most severe form of human malaria. Parasite populations resistant to some or all the currently available antimalarial treatments are present in different world regions. Considering the need for novel and integrated approaches to control malaria, combinations of drugs were tested on P. falciparum. The primary focus was on doxycycline, an antibiotic that specifically targets the apicoplast of the parasite. In combination with doxycycline, three different drugs known to inhibit efflux pumps (verapamil, elacridar and ivermectin) were tested, with the assumption that they could increase the intracellular concentration of the antibiotic and consequently its efficacy against P. falciparum. We emphasize that elacridar is a third-generation ABC transporters inhibitor, never tested before on malaria parasites. In vitro experiments were performed on asexual stages of two strains of P. falciparum, chloroquine-sensitive (D10) and chloroquine-resistant (W2). Incubation times on asynchronous or synchronous cultures were 72h or 96h, respectively. The antiplasmodial effect (i.e. the IC50) was determined by measuring the activity of the parasite lactate dehydrogenase, while the interaction between drugs was determined through combination index (CI) analyses. Elacridar achieved an IC50 concentration comparable to that of ivermectin, approx. 10-fold lower than that of verapamil, the other tested ABC transporter inhibitor. CI results showed synergistic effect of verapamil plus doxycycline, which is coherent with the starting hypothesis, i.e. that ABC transporters represent potential targets, worth of further investigations, towards the development of companion molecules useful to enhance the efficacy of antimalarial drugs. At the same time, the observed antagonistic effect of doxycycline in combination with ivermectin or elacridar highlighted the importance of drug testing, to avoid the de-facto generation of a sub-dosage, a condition that facilitates the development of drug resistance.


Assuntos
Antimaláricos/uso terapêutico , Doxiciclina/uso terapêutico , Ivermectina/uso terapêutico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Cloroquina/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Quimioterapia Combinada/métodos , Humanos , Malária Falciparum/parasitologia
20.
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