Genetic variants in triglyceride metabolism genes among individuals with hypertriglyceridemia in Colombia.

BACKGROUND: The genetic substrate of severe hypertriglyceridemia (sHTG) in Latin America is insufficiently understood. OBJECTIVE: To identify genetic variants in genes related to triglyceride (TG) metabolism among adults with sHTG from Colombia. METHODS: In individuals with plasma TG≥880 mg/dL at least once in their lifetime, we amplified and sequenced all exons and intron/exon boundaries of the genes LPL, APOC2, APOA5, GPIHBP1 and LMF1. For each variant we ascertained its location, zygosity, allelic frequency and pathogenicity classification according to American College of Medical Genetics (ACMG) criteria. RESULTS: The study included 166 participants (62 % male, mean age 50), peak TG levels ranged between 894 and 11,000 mg/dL. We identified 92 variants: 19 in LPL, 7 in APOC2, 11 in GPIHBP1, 38 in LMF1, and 17 in APOA5. Eighteen of these variants had not been reported. We identified a new pathogenic variant in LMF1 (c.41C>A; p.Ser14*), a new likely pathogenic variant in LMF1 (c.1527 C > T; p.Pro509=, also expressed as c.1447C>T; p.Gln483*), and a known pathogenic variant in LMF1 (c.779G>A; p.Trp260*). Four participants were heterozygous for variant c.953A>G; p.Asn318Ser in LPL, a known risk factor for hypertriglyceridemia. Participants with variants of unknown significance (VUS) in LMF1 had significantly higher peak TG than those with VUS in other genes. Peak TG were 4317 mg/dL in participants with a history of pancreatitis, and 1769 mg/dL in those without it (p = 0.001). CONCLUSION: Our study identified variants associated with sHTG among Latinos, and showed that genetic variation in LMF1 may be frequently associated with sHTG in this population.

Resistencia a medicamentos en mycobacterium tuberculosis: contribución de mecanismos constitutivos y adquiridos / Drug resistance in mycobacterium tuberculosis: contribution of constituent and acquired mechanisms

RESUMEN En presencia de aislamientos de Mycobacterium tuberculosis (MTB) multifármaco-resistentes (MTB-MDR) y con resistencia extendida (MTB-XDR) las tasas de fracaso de los esquemas estandarizados de tratamiento son altas, constituyéndose en un verdadero problema de salud pública a nivel mundial. La fármaco-resistencia en MTB se debe principalmente a mutaciones en genes blanco; sin embargo, una proporción de aislamientos fármaco-resistentes no presentan mutaciones en dichos genes, sugiriendo la participación de otros mecanismos, tales como permeabilidad reducida de la pared celular, modificación enzimática y/o bombas de eflujo. La resistencia clínica a los medicamentos anti-tuberculosos (anti-TB) ocurre en gran parte como resultado de la selección de mutantes resistentes durante la falta de adherencia del paciente al tratamiento, inapropiados seguimientos y prescripción médica, dosis subóptimas de fármacos y dificultad de acceso a los servicios de salud y al tratamiento. Los Avances de la biología molecular y la secuenciación del genoma de MTB han contribuido a mejorar el entendimiento de los mecanismos de resistencia a los principales medicamentos anti-TB. Un mejor conocimiento de los mecanismos de fármaco-resistencia en MTB contribuirá a la identificación de nuevos blancos terapéuticos, al diseño de nuevos medicamentos, al desarrollo de nuevos métodos diagnósticos y/o mejorar las técnicas que actualmente están disponibles para la detección rápida de TB fármaco-resistente. Este artículo presenta una revisión actualizada de los mecanismos y las bases moleculares de la resistencia de MTB a medicamentos anti-TB.(AU)

ABSTRACT Due to the emergence of multi-drug resistant (MDR-MTB) and extensively drug-resistant (XDR-MTB) Mycobacterium tuberculosis (MTB) isolates, the failure rates of standard treatment regimens are high, thus becoming a major public health challenge worldwide. Resistance to anti-tuberculous (anti-TB) drugs is attributed mainly to specific mutations in target genes; however, a proportion of drug-resistant MTB isolates do not have mutations in these genes, which suggests the involvement of other mechanisms, such as the low permeability of the mycobacterial cell wall, enzymatic modification and/or efflux pumps. Clinical drug resistance to anti-TB drugs occurs largely as a result of the selection of resistant mutants caused by poor patient adherence to treatment, inappropriate follow-ups and prescriptions, suboptimal doses of drugs and poor access to health services and treatment. Major advances in molecular biology tools and the availability of the complete genome sequences of MTB have contributed to improve understanding of the mechanisms of resistance to the main anti-TB drugs. Better knowledge of the drug-resistance of MTB will contribute to the identification of new therapeutic targets to design new drugs, develop new diagnostic tests and/or improve methods currently available for the rapid detection of drug-resistant TB. This article presents an updated review of the mechanisms and molecular basis of drug resistance in MTB.(AU)

[Drug resistance in Mycobacterium tuberculosis: contribution of constituent and acquired mechanisms]. / Resistencia a Medicamentos en Mycobacterium tuberculosis: contribución de mecanismos constitutivos y adquiridos.

Due to the emergence of multi-drug resistant (MDR-MTB) and extensively drug-resistant (XDR-MTB) Mycobacterium tuberculosis (MTB) isolates, the failure rates of standard treatment regimens are high, thus becoming a major public health challenge worldwide. Resistance to anti-tuberculous (anti-TB) drugs is attributed mainly to specific mutations in target genes; however, a proportion of drug-resistant MTB isolates do not have mutations in these genes, which suggests the involvement of other mechanisms, such as the low permeability of the mycobacterial cell wall, enzymatic modification and/or efflux pumps. Clinical drug resistance to anti-TB drugs occurs largely as a result of the selection of resistant mutants caused by poor patient adherence to treatment, inappropriate follow-ups and prescriptions, suboptimal doses of drugs and poor access to health services and treatment. Major advances in molecular biology tools and the availability of the complete genome sequences of MTB have contributed to improve understanding of the mechanisms of resistance to the main anti-TB drugs. Better knowledge of the drug-resistance of MTB will contribute to the identification of new therapeutic targets to design new drugs, develop new diagnostic tests and/or improve methods currently available for the rapid detection of drug-resistant TB. This article presents an updated review of the mechanisms and molecular basis of drug resistance in MTB.

En presencia de aislamientos de Mycobacterium tuberculosis (MTB) multifármaco-resistentes (MTB-MDR) y con resistencia extendida (MTB-XDR) las tasas de fracaso de los esquemas estandarizados de tratamiento son altas, constituyéndose en un verdadero problema de salud pública a nivel mundial. La fármaco-resistencia en MTB se debe principalmente a mutaciones en genes blanco; sin embargo, una proporción de aislamientos fármaco-resistentes no presentan mutaciones en dichos genes, sugiriendo la participación de otros mecanismos, tales como permeabilidad reducida de la pared celular, modificación enzimática y/o bombas de eflujo. La resistencia clínica a los medicamentos anti-tuberculosos (anti-TB) ocurre en gran parte como resultado de la selección de mutantes resistentes durante la falta de adherencia del paciente al tratamiento, inapropiados seguimientos y prescripción médica, dosis subóptimas de fármacos y dificultad de acceso a los servicios de salud y al tratamiento. Los Avances de la biología molecular y la secuenciación del genoma de MTB han contribuido a mejorar el entendimiento de los mecanismos de resistencia a los principales medicamentos anti-TB. Un mejor conocimiento de los mecanismos de fármaco-resistencia en MTB contribuirá a la identificación de nuevos blancos terapéuticos, al diseño de nuevos medicamentos, al desarrollo de nuevos métodos diagnósticos y/o mejorar las técnicas que actualmente están disponibles para la detección rápida de TB fármaco-resistente. Este artículo presenta una revisión actualizada de los mecanismos y las bases moleculares de la resistencia de MTB a medicamentos anti-TB.

In vitro antifungal activity and cytotoxic effect of essential oils and extracts of medicinal and aromatic plants against Candida krusei and Aspergillus fumigatus / Atividade antifúngica in vitro e os efeitos citotóxicos de óleos essenciais e extratos de plantas medicinais e aromáticas contra Candida krusei e Aspergillus fumigatus

The plants are usually used in traditional medicine as antimicrobial agents and their essential oils and extracts have been known to possess antifungal activity. The aim of this study was to evaluate in vitro the activity of 32 essential oils and 29 extracts against C. krusei and A. fumigatus as well as the cytotoxic effect on Vero cells. Time-kill curve and interaction between antifungals and the most active sample against C. krusei, was also evaluated. The oils from C. ambrosioides and the extract of M. cucullata showed antifungal activity against C. krusei (GM-MIC 7.82 and 31.25 µg/mL, respectively). L. citriodora was actives against C. krusei and A. fumigates (GM-MIC = 99.21 µg/mL and 62.5 µg/mL respectively). Time-kill assays done with C. ambrosioides oil showed fungicidal activity at 4x MIC. The interaction of C. ambrosioides oil with itraconazole and amphotericin B was tested following the chequerboard technique. No interaction was detected for the combination of C. ambrosioides oil with amphotericin B and itraconazole (FICI range = 1.03-1.06 and 1.03-1.00, respectively). Cytotoxicity assays for all samples were carried out with MTT. Only the oil from Hedyosmun sp. and L. dulcis were cytotoxic.

As plantas são geralmente utilizadas na medicina tradicional como agentes antimicrobianos e seus óleos essenciais e extratos foram conhecidos por possuir atividade antifúngica. O objetivo deste estudo foi avaliar in vitro a atividade de 32 óleos essenciais e 29 extratos contra Candida krusei e Aspergillus fumigatus, bem como o efeito citotóxico em células Vero. A curva do tempo-morte e a interação entre antifúngicos e Chenopodium ambrosioidese do extrato de Myrcia cucullata mostraram atividade antifúngica contra C. krusei (geometric means of the minimal inhibitory concentration [GM-MIC] 7,82 e 31,25 µg/mL, respectivamente). Lippia citriodora foi ativa contra C. krusei e A. fumigatus (GM-CIM = 99,21 µg/mL e 62,5 µg/mL, respectivamente). Os testes de tempo-morte feitos com óleo de C. ambrosioides mostraram atividade fungicida em 4x MIC. A interação do óleo C. ambrosioides com itraconazol e anfotericina B foi testada pela técnica de xadrez. Nenhuma interação foi detectada pela combinação do óleo C. ambrosioides com anfotericina B e itraconazol (intervalo fractional inhibitory index [FICI] = 1,03-1,06 e 1,03-1,00, respectivamente). Os ensaios de citotoxicidade para todas as amostras foram realizadas com MTT. Apenas os óleos Hedyosmun sp. e L. dulcis foram citotóxicos.