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1.
Front Med (Lausanne) ; 9: 970408, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36213651

RESUMEN

Tuberculosis (TB) is a lethal disease and remains one of the top ten causes of mortality by an infectious disease worldwide. It can also result in significant morbidity related to persistent inflammation and tissue damage. Pulmonary TB treatment depends on the prolonged use of multiple drugs ranging from 6 months for drug-susceptible TB to 6-20 months in cases of multi-drug resistant disease, with limited patient tolerance resulting from side effects. Treatment success rates remain low and thus represent a barrier to TB control. Adjunct host-directed therapy (HDT) is an emerging strategy in TB treatment that aims to target the host immune response to Mycobacterium tuberculosis in addition to antimycobacterial drugs. Combined multi-drug treatment with HDT could potentially result in more effective therapies by shortening treatment duration, improving cure success rates and reducing residual tissue damage. This review explores the rationale and challenges to the development and implementation of HDTs through a succinct report of the medications that have completed or are currently being evaluated in ongoing clinical trials.

2.
Syst Rev ; 10(1): 174, 2021 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-34108050

RESUMEN

BACKGROUND: Tuberculosis (TB) is still one of the leading causes of death worldwide. Genetic studies have pointed to the relevance of the NOD2 and CD14 polymorphic alleles in association with the risk of diseases caused by Mycobacterium tuberculosis (Mtb) infection. METHODS: A systematic review was performed on PubMed, EMBASE, Scientific Electronic Library Online (SciELO), and Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs) to examine the association between single nucleotide polymorphisms (SNP) and risk of Mtb diseases. Study quality was evaluated using the Newcastle-Ottawa Quality Scale (NOQS), and the linkage disequilibrium was calculated for all SNPs using a webtool (Package LDpop). RESULTS: Thirteen studies matched the selection criteria. Of those, 9 investigated CD14 SNPs, and 6 reported a significant association between the T allele and TT genotypes of the rs2569190 SNP and increased risk of Mtb diseases. The genotype CC was found to be protective against TB disease. Furthermore, in two studies, the CD14 rs2569191 SNP with the G allele was significantly associated with increased risk of Mtb diseases. Four studies reported data uncovering the relationship between NOD2 SNPs and risk of Mtb diseases, with two reporting significant associations of rs1861759 and rs7194886 and higher risk of Mtb diseases in a Chinese Han population. Paradoxically, minor allele carriers (CG or GG) of rs2066842 and rs2066844 NOD2 SNPs were associated with lower risk of Mtb diseases in African Americans. CONCLUSIONS: The CD14 rs2569190 and rs2569191 polymorphisms may influence risk of Mtb diseases depending on the allele. Furthermore, there is significant association between NOD2 SNPs rs1861759 and rs7194886 and augmented risk of Mtb diseases, especially in persons of Chinese ethnicity. The referred polymorphisms of CD14 and NOD2 genes likely play an important role in risk of Mtb diseases and pathology and may be affected by ethnicity. SYSTEMATIC REVIEW REGISTRATION: CRD42020186523.


Asunto(s)
Mycobacterium tuberculosis , Polimorfismo de Nucleótido Simple , Alelos , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Mycobacterium tuberculosis/genética , Proteína Adaptadora de Señalización NOD2/genética
3.
Life (Basel) ; 11(1)2021 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-33477581

RESUMEN

Antiretroviral therapy (ART) has represented a major advancement in the care of people living with HIV (PLWHH), resulting in significant reductions in morbidity and mortality through immune reconstitution and attenuation of homeostatic disruption. Importantly, restoration of immune function in PLWH with opportunistic infections occasionally leads to an intense and uncontrolled cytokine storm following ART initiation known as immune reconstitution inflammatory syndrome (IRIS). IRIS occurrence is associated with the severe and rapid clinical deterioration that results in significant morbidity and mortality. Here, we detail the determinants underlying IRIS development in PLWH, compiling the available knowledge in the field to highlight details of the inflammatory responses in IRIS associated with the most commonly reported opportunistic pathogens. This review also highlights gaps in the understanding of IRIS pathogenesis and summarizes therapeutic strategies that have been used for IRIS.

4.
Sci Rep ; 10(1): 18982, 2020 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-33149225

RESUMEN

Sickle cell anemia (SCA) is the most common inherited hemolytic anemia worldwide. Here, we performed an exploratory study to investigate the systemic oxidative stress in children and adolescents with SCA. Additionally, we evaluated the potential impact of hydroxyurea therapy on the status of oxidative stress in a case-control study from Brazil. To do so, a panel containing 9 oxidative stress markers was measured in plasma samples from a cohort of 47 SCA cases and 40 healthy children and adolescents. Among the SCA patients, 42.5% were undertaking hydroxyurea. Multidimensional analysis was employed to describe disease phenotypes. Our results demonstrated that SCA is associated with increased levels of oxidative stress markers, suggesting the existence of an unbalanced inflammatory response in peripheral blood. Subsequent analyses revealed that hydroxyurea therapy was associated with diminished oxidative imbalance in SCA patients. Our findings reinforce the idea that SCA is associated with a substantial dysregulation of oxidative responses which may be dampened by treatment with hydroxyurea. If validated by larger prospective studies, our observations argue that reduction of oxidative stress may be a main mechanism through which hydroxyurea therapy attenuates the tissue damage and can contribute to improved clinical outcomes in SCA.


Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Biomarcadores/sangre , Hidroxiurea/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Adolescente , Anemia de Células Falciformes/sangre , Brasil , Estudios de Casos y Controles , Niño , Femenino , Humanos , Hidroxiurea/farmacología , Masculino , Análisis de Componente Principal , Estudios Prospectivos , Resultado del Tratamiento
5.
PLoS One ; 15(9): e0239061, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32956382

RESUMEN

Diabetes (DM) has a significant impact on public health. We performed an in silico study of paired datasets of messenger RNA (mRNA) micro-RNA (miRNA) transcripts to delineate potential biosignatures that could distinguish prediabetes (pre-DM), type-1DM (T1DM) and type-2DM (T2DM). Two publicly available datasets containing expression values of mRNA and miRNA obtained from individuals diagnosed with pre-DM, T1DM or T2DM, and normoglycemic controls (NC), were analyzed using systems biology approaches to define combined signatures to distinguish different clinical groups. The mRNA profile of both pre-DM and T2DM was hallmarked by several differentially expressed genes (DEGs) compared to NC. Nevertheless, T1DM was characterized by an overall low number of DEGs. The miRNA signature profiles were composed of a substantially lower number of differentially expressed targets. Gene enrichment analysis revealed several inflammatory pathways in T2DM and fewer in pre-DM, but with shared findings such as Tuberculosis. The integration of mRNA and miRNA datasets improved the identification and discriminated the group composed by pre-DM and T2DM patients from that constituted by normoglycemic and T1DM individuals. The integrated transcriptomic analysis of mRNA and miRNA expression revealed a unique biosignature able to characterize different types of DM.


Asunto(s)
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , MicroARNs/genética , Estado Prediabético/genética , ARN Mensajero/genética , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Estado Prediabético/diagnóstico
6.
PLoS One ; 15(2): e0222552, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32097409

RESUMEN

BACKGROUND: Cigarette smoking is associated with an increased risk of developing respiratory diseases and various types of cancer. Early identification of such unfavorable outcomes in patients who smoke is critical for optimizing personalized medical care. METHODS: Here, we perform a comprehensive analysis using Systems Biology tools of publicly available data from a total of 6 transcriptomic studies, which examined different specimens of lung tissue and/or cells of smokers and nonsmokers to identify potential markers associated with lung cancer. RESULTS: Expression level of 22 genes was capable of classifying smokers from non-smokers. A machine learning algorithm revealed that AKR1B10 was the most informative gene among the 22 differentially expressed genes (DEGs) accounting for the classification of the clinical groups. AKR1B10 expression was higher in smokers compared to non-smokers in datasets examining small and large airway epithelia, but not in the data from a study of sorted alveolar macrophages. Moreover, AKR1B10 expression was relatively higher in lung cancer specimens compared to matched healthy tissue obtained from nonsmoking individuals. Although the overall accuracy of AKR1B10 expression level in distinction between cancer and healthy lung tissue was 76%, with a specificity of 98%, our results indicated that such marker exhibited low sensitivity, hampering its use for cancer screening such specific setting. CONCLUSION: The systematic analysis of transcriptomic studies performed here revealed a potential critical link between AKR1B10 expression, smoking and occurrence of lung cancer.


Asunto(s)
Aldo-Ceto Reductasas/metabolismo , Neoplasias Pulmonares/etiología , Fumar/efectos adversos , Biología de Sistemas/métodos , Transcriptoma , Aldo-Ceto Reductasas/genética , Biomarcadores de Tumor , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Fumar/genética
7.
Int J Infect Dis ; 93: 277-283, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32081776

RESUMEN

BACKGROUND: The present study evaluated factors associated with losses in the latent tuberculosis infection (LTBI) cascade of care in contacts of tuberculosis (TB) patients, in a referral center from a highly endemic region in Brazil. METHODS: Contacts of 1672 TB patients were retrospectively studied between 2009 and 2014. Data on TB screening by clinical investigation, radiographic examination and tuberculin skin test (TST) were extracted from medical records. Losses in the cascade of care and TB incidence within 2-year follow-up were calculated. RESULTS: From a total of 1180 TB contacts initially identified, only 495 were examined (58% loss), and 20 were diagnosed with active TB at this stage. Furthermore, 435 persons returned for TST result interpretation and 351 (∼81%) were TST positive. Among those with positive TST, 249 (73%) were treated with isoniazid for 6 months whereas 51 abandoned therapy early. Three individuals who did not receive LTBI treatment, one with incomplete treatment and another who completed treatment developed active TB. A logistic regression analysis revealed that increases in age were associated with losses in the LTBI cascade independent of other clinical and epidemiological characteristics. CONCLUSIONS: Major losses occur at initial stages and older patients are at higher risk of not completing the LTBI cascade of care.


Asunto(s)
Atención a la Salud , Tuberculosis Latente/terapia , Adulto , Factores de Edad , Antituberculosos/uso terapéutico , Brasil , Estudios de Cohortes , Trazado de Contacto , Femenino , Humanos , Incidencia , Isoniazida/uso terapéutico , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/epidemiología , Tuberculosis Latente/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Prueba de Tuberculina
8.
Sci Rep ; 9(1): 8002, 2019 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-31142816

RESUMEN

Tuberculosis (TB) is a chronic inflammatory disease caused by Mycobacterium tuberculosis infection which causes tremendous morbidity and mortality worldwide. Clinical presentation of TB patients is very diverse and disease heterogeneity is associated with changes in biomarker signatures. Here, we compared at the molecular level the extent of individual inflammatory perturbation of plasma protein and lipid mediators associated with TB in patients in China versus India. We performed a cross-sectional study analyzing the overall degree of inflammatory perturbation in treatment-naïve pulmonary TB patients and uninfected individuals from India (TB: n = 97, healthy: n = 20) and China (TB: n = 100, healthy: n = 11). We employed the molecular degree of perturbation (MDP) adapted to plasma biomarkers to examine the overall changes in inflammation between these countries. M. tuberculosis infection caused a significant degree of molecular perturbation in patients from both countries, with higher perturbation detected in India. Interestingly, there were differences in biomarker perturbation patterns and the overall degree of inflammation. Patients with severe TB exhibited increased MDP values and Indian patients with this condition exhibited even higher degree of perturbation compared to Chinese patients. Network analyses identified IFN-α, IFN-ß, IL-1RI and TNF-α as combined biomarkers that account for the overall molecular perturbation in the entire study population. Our results delineate the magnitude of the systemic inflammatory perturbation in pulmonary TB and reveal qualitative changes in inflammatory profiles between two countries with high disease prevalence.


Asunto(s)
Biomarcadores/sangre , Inflamación/epidemiología , Tuberculosis Latente/epidemiología , Tuberculosis Pulmonar/epidemiología , Adulto , Proteínas Sanguíneas/genética , China/epidemiología , Citocinas/sangre , Femenino , Humanos , India/epidemiología , Inflamación/sangre , Inflamación/microbiología , Inflamación/patología , Interferón gamma/sangre , Tuberculosis Latente/sangre , Tuberculosis Latente/microbiología , Tuberculosis Latente/patología , Lípidos/sangre , Masculino , Mycobacterium tuberculosis/patogenicidad , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patología , Factor de Necrosis Tumoral alfa/sangre
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