CRISPR/Cas9 mutagenesis of the Arabidopsis GROWTH-REGULATING FACTOR (GRF) gene family.

Genome editing in plants typically relies on T-DNA plasmids that are mobilized by Agrobacterium-mediated transformation to deliver the CRISPR/Cas machinery. Here, we introduce a series of CRISPR/Cas9 T-DNA vectors for minimal settings, such as teaching labs. Gene-specific targeting sequences can be inserted as annealed short oligonucleotides in a single straightforward cloning step. Fluorescent markers expressed in mature seeds enable reliable selection of transgenic or transgene-free individuals using a combination of inexpensive LED lamps and colored-glass alternative filters. Testing these tools on the Arabidopsis GROWTH-REGULATING FACTOR (GRF) genes, we were able to create a collection of predicted null mutations in all nine family members with little effort. We then explored the effects of simultaneously targeting two, four and eight GRF genes on the rate of induced mutations at each target locus. In our hands, multiplexing was associated with pronounced disparities: while mutation rates at some loci remained consistently high, mutation rates at other loci dropped dramatically with increasing number of single guide RNA species, thereby preventing a systematic mutagenesis of the family.

Reparación del eje carotídeo con injerto autólogo por sangrado recurrente posamigdalectomía en edad pediátrica / Carotid axis repair with autologous vein graft due to recurrent post-tonsillectomy bleeding in a child

Introducción: el sangrado es una complicación común después de una amigdalectomía y habitualmente se tratacon cauterización del lecho quirúrgico. Sin embargo, en algunos pacientes, cuando el sangrado es secundario auna lesión vascular, es necesaria la ligadura o la embolización del vaso lesionado.Caso clínico: presentamos el caso de un paciente de 7 años de edad que requirió reparación y revascularizacióndel eje carotídeo izquierdo con injerto autólogo debido a sangrado recurrente y refractario a embolización de laarteria carótida externa izquierda posamigdalectomía.(AU)

Background: bleeding is a very common complication after tonsillectomy and is often treated through cauter-ization of the tonsillar bed. However, in some cases ligation or embolization of the source of the bleeding due tovascular injury is deemed necessary.Case report: this is the case of a 7-year-old boy that underwent repair and revascularization of his left carotid axiswith an autologous vascular graft due to recurrent bleeding postonsillectomy refractory to previous embolizationof the left external carotid artery.(AU)

Entropic and Complexity Measures in Atomic and Molecular Systems.

Both entropy and complexity are central concepts for the understanding and development of Information Theory, playing an essential role in the increasingly numerous applications in a huge diversity of fields [...].

Evolución y protetización de las amputaciones mayores en pacientes con enfermedadarterial periférica de nuestro centro / Outcomes and prosthesis procedure of major amputations in patients with peripheral arterial disease in our center

Introducción: las amputaciones mayores han disminuido en los últimos años, hasta aproximadamente el 7 % de los pacientes con enfermedad arterial periférica crónica (EAPC). La protetización es un procedimiento complejo e importante para la calidad de vida de los pacientes. Las series publicadas comunican datos muy variables entre ellas. Objetivo: describir la evolución de los pacientes sometidos a una amputación mayor por EAPC en nuestro centro y su protetización en relación a su estado basal. Materiales y métodos: estudio descriptivo, retrospectivo y unicéntrico. Recogimos las amputaciones mayores realizadas por nuestro servicio entre 2013 y 2019. Realizamos una búsqueda del registro de pacientes protetizados. Se recogieron las variables sociodemográficas, clínicas, de la intervención, del posoperatorio y de la rehabilitación. Analizamos las variables cualitativas en forma de frecuencias absolutas y porcentajes, los datos cuantitativos mediante la media, la inferencia estadística con el χ2 y la supervivencia con análisis actuarial. Resultados: realizamos 282 amputaciones mayores, de las que el 65,95 % fue en hombres, con una edad media de 71,23 años. El 82,68 % fueron supracondíleas y el 17,32 %, infracondíleas. El 30,85 % tuvieron una amputación menor previa. El 51,06 % habían sido revascularizados previamente. Solo el 37,9 % contaba con una red social adecuada de apoyo. La mediana de supervivencia fue de 24 meses. La mortalidad al año fue del 35 %.El 29,32 % de los pacientes tenía una marcha independiente previa, el 21,22 % no deambulaba y el resto requería ayuda para la marcha. El 28 % (79) de los pacientes fue protetizado, con un uso medio de la prótesis de 15,34 horas al día. El estado de marcha previa se relacionó de manera significativa con la protetización, que consiguió el 49,9 % de los que tenían una marcha independiente frente al 1,69 % de los que no deambulaban (p < 0,001).

Introduction: a decrease in rate of mayor amputation has been reported over the last years; approximately 7 % of patients with chronic peripheral arterial disease (PAD). Implant a prosthesis is a complex and important procedure for the patients ́ quality of life. The journals shown different data between them. Objective: to describe the evolution of patients undergoing a major amputation due to PAD in our center andtheir prosthesis procedure in relation to their baseline status. Materials and methods: descriptive, retrospective and single center study. We collected all major amputations performed by our department between 2013 to 2019. We searched the registry of patients with prosthesis. Socio-demographic, clinical, intervention, postoperative and rehabilitation variables were collected. We analyzed the qualitative variables in the form of absolute frequencies and percentages, the quantitative data through the mean, the statistical inference with the chi2 and the survival with actuarial analysis. Results: we performed 282 major amputations, 65.95 % in men, with a mean age of 71.23 years. 82.68 % were above the knee and 17.32 % below the knee. 30.85 % had a previous minor amputation. 51.06 % had been previously revascularized. Only 37.9 % had an adequate social support. Median survival was 24 months. Mortality at one year was 35 %. 29.32 % of the patients had a previous independent walk, 21.22 % did not walk and the rest required assistance for walking. 28 % (79) of the patients received a prosthesis, with an average use of the prosthesis of 15.34 hours per day. Previous gait status was significantly related to wearing prosthesis, achieved by 49.9 % of those who walked independently versus 1.69 % of those who did not walk (p < 0.001). Of the rest of the factors analyzed, the following had a statistically significant relationship with prosthetic fitting: male gender (p < 0.028), younger than 70 years (p < 0.001),.(AU)

Host-directed therapies in pulmonary tuberculosis: Updates on anti-inflammatory drugs.

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.

Evolución de los accesos vasculares para hemodiálisis trombosados tras su reparación quirúrgica urgente / Outcomes after surgical thrombectomy in occluded vascular access used for hemodialysis

Resumen: Introducción: un acceso vascular (AV) que funcione bien es esencial para los pacientes en hemodiálisis. La trombosis es la principal causa de fallo de un AV. La trombectomía y la reparación del AV permiten mantenerlo funcional y prolongar su permeabilidad. Por lo tanto, este enfoque sigue siendo el objetivo principal para el rescate del acceso y la prolongación de la tasa de permeabilidad. Objetivo: describir la evolución natural del AV trombosado para HD tras reparación urgente. Métodos: estudio retrospectivo, observacional y unicéntrico. Se incluyeron todos los pacientes sometidos a cirugía urgente por trombosis AV para HD, nativa y protésica, entre 2013 y 2019. Análisis estadístico: en las variables categóricas se obtuvieron proporciones y razones de prevalencia, y en las variables cuantitativas, medias, medianas y desviación estándar. Se realizaron correlaciones de variables, análisis de supervivencia sin falla (SWF) del AV y log rank. Resultados: durante el periodo de estudio rescatamos 54 trombosados e incluimos 48 pacientes. Rescatamos 22 nativos (45,8 %) y 26 protésicos AV (54,2 %) mediante trombectomía urgente. Después de la reparación urgente, el SWF fue del 49 % a los 110 días (ES 0,07), del 25 % a los 478 días (ES 0,07) y del 15 % a los 659 días. Conclusiones: existe un porcentaje nada despreciable de AV que permanece en uso a medio plazo tras ser rescatados, lo que permite una HD eficaz.(AU)

Introduction: a well-functioning vascular access(VA) is essential for patients undergoing hemodialysis. Thrombosis is the leading cause of VA failure. Thrombectomy and the repair of the VA allow maintaining it functional and prolong its permeability. Thus, this approach remains the major goal toward access salvage and prolongation of patency rate. Objective: to describe the natural history of thrombosed VA for HD after urgent repair.Methods: retrospective, observational and single center study. All patients undergoing urgent surgery for VA thrombosis for HD, native and prosthetic, between 2013 and 2019, were included. Statistical analysis: in categorical variables, proportions and prevalence ratios were obtained; and in numerical variables, means, medians and standard deviation. Variable correlations, analysis of survival without failure (SWF) of the VA and log rank were performed. Results: during the study period we rescued 54 thrombosed, we included 48 patients. We rescued 22 native (45.8 %) and 26 prosthetic VA (54.2 %) by urgent thrombectomy. After urgent repair, the SWF was 49 % at 110 days (ES 0.07), 25 % at 478 days (ES 0.07) and 15 % at 659 days. Conclusions: there is a non-negligible percentage of VA that remain in use in the medium term after being rescued, allowing effective HD.(AU)

Resultados obtenidos en el tratamiento de embolización endovascular de varices pélvicas / Treatment outcomes of pelvic varicose veins endovascular embolization

Introducción:el síndrome de congestión pélvica se presenta con un dolor de más de 6 meses de evolución, varices pélvicas e insuficiencia venosa pélvica. El diagnóstico diferencial incluye distintas patologías. Existen diferentes opciones terapéuticas, de las que la terapia endovascular con embolización es la más utilizada, la misma que ha sido significativamente más eficaz que la terapia quirúrgica.Objetivo:analizar la efectividad de la embolización endovascular de varices pélvicas.Materiales y métodos:estudio unicéntrico, observacional descriptivo y ambispectivo. Se han seguidi las recomendaciones STROBE para su redacción. Se incluyeron todos los pacientes a los que se les realizó una embolización de varices pélvicas que cumplían los criterios de inclusión. Se realizó un análisis de las variables cualitativas en forma de frecuencias absolutas y porcentajes y los datos cuantitativos mediante la media. Se describió el éxito terapéutico percibido por las pacientes, las complicaciones, la necesidad de reintervención y la supervivencia libre de reintervenciones.Resultados:se incluyeron 46 pacientes con una edad media de 32,54 años. 22 casos (47,82 %) tenían un peso adecuado, 29 (63,04 %) refirieron una clara mejoría sintomática después del procedimiento de embolización y en ninguno se presentaron complicaciones asociadas al procedimiento. Sin embargo, de este grupo de pacientes 11 tuvieron una intervención subsecuente asociada a las varices de miembros inferiores. El tiempo de supervivencia libre de nuevas embolizaciones fue de 54,37 meses, con un ES de 2,64 meses.Conclusiones:la embolización endovascular de varices pélvicas es una técnica efectiva y segura.(AU)

Introduction:pelvic congestion syndrome presents pain that lasts at least 6 months, pelvic varices and pelvic venous insufficiency. The differential diagnosis includes different pathologies. There are different therapeutic options, being endovascular therapy with embolization the most used, the same one that has been significantly more effective than surgical therapy.Objective:to analyze the effectiveness of endovascular embolization of pelvic varices.Materials and methods:single-center, descriptive and ambispective observational study. Following the STROBE recommendations for writing it. All patients who underwent embolization of pelvic varices who met the inclusion criteria were included. An analysis of the qualitative variables was showed like absolute frequencies and percentages; and quantitative data using the mean. The therapeutic success perceived by the patients, the complications, the need for reoperation, and reoperation-free survival are described.Results:46 patients with a mean age of 32.54 years were included, 22 cases (47.82 %) who had an adequate weight. In 29 cases (63.04 %) reported a clear symptomatic improvement after the embolization procedure, they were not complications associated with the procedure. However, of this group of patients, 11 had a subsequent intervention associated with varicose veins of the lower limbs. The survival time free of new embolizations was 54.37 months with a SE of 2.64 months.Conclusions:embolization is the most widely used treatment for pelvic varicose veins. In this review, symptomatic improvement was found in 63.04 % of the cases, being below the results reported in the bibliography where they report a therapeutic success of 75 % of the cases. Endovascular embolization of pelvic varices is an eective and safe technique for their treatment.(AU)

Mutual Information in Conjugate Spaces for Neutral Atoms and Ions.

The discrepancy among one-electron and two-electron densities for diverse N-electron atomss, enclosing neutral systems (with nuclear charge Z=N) and charge-one ions (|N-Z|=1), is quantified by means of mutual information, I, and Quantum Similarity Index, QSI, in the conjugate spaces position/momentum. These differences can be interpreted as a measure of the electron correlation of the system. The analysis is carried out by considering systems with a nuclear charge up to Z=103 and singly charged ions (cations and anions) as far as N=54. The interelectronic correlation, for any given system, is quantified through the comparison of its double-variable electron pair density and the product of the respective one-particle densities. An in-depth study along the Periodic Table reveals the importance, far beyond the weight of the systems considered, of their shell structure.

Inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection: a prospective cohort study and immunological network analysis.

BACKGROUND: HIV-1 mediated dysregulation of the immune response to tuberculosis and its effect on the response to antitubercular therapy (ATT) is incompletely understood. We aimed to analyse the inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection undergoing ATT, with specific focus on the effect of ART and HIV-1 viraemia in those co-infected with HIV-1. METHODS: In this prospective cohort study and immunological network analysis, a panel of 38 inflammatory markers were measured in the plasma of a prospective patient cohort undergoing ATT at Khayelitsha Site B clinic, Cape Town, South Africa. We recruited patients with sputum Xpert MTB/RIF-positive rifampicin-susceptible pulmonary tuberculosis. Patients were excluded from the primary discovery cohort if they were younger than 18 years, unable to commence ATT for any reason, pregnant, had unknown HIV-1 status, were unable to consent to study participation, were unable to provide baseline sputum samples, had more than three doses of ATT, or were being re-treated for tuberculosis within 6 months of their previous ATT regimen. Plasma samples were collected at baseline (1-5 days after commencing ATT), week 8, and week 20 of ATT. We applied network and multivariate analysis to investigate the dynamic inflammatory profile of these patients in relation to ATT and by HIV status. In addition to the discovery cohort, a validation cohort of patients with HIV-1 admitted to hospital with CD4 counts less than 350 cells per µL and a high clinical suspicion of new tuberculosis were recruited. FINDINGS: Between March 1, 2013, and July 31, 2014, we assessed a cohort of 129 participants (55 [43%] female and 74 [57%] male, median age 35·1 years [IQR 30·1-43·7]) and 76 were co-infected with HIV-1. HIV-1 status markedly influenced the inflammatory profile regardless of ATT duration. HIV-1 viral load emerged as a major factor driving differential inflammatory marker expression and having a strong effect on correlation profiles observed in the HIV-1 co-infected group. Interleukin (IL)-17A emerged as a key correlate of HIV-1-induced inflammation during HIV-tuberculosis co-infection. INTERPRETATION: Our findings show the effect of HIV-1 co-infection on the complexity of plasma inflammatory profiles in patients with tuberculosis. Through network analysis we identified IL-17A as an important node in HIV-tuberculosis co-infection, thus implicating this cytokine's capacity to correlate with, and regulate, other inflammatory markers. Further mechanistic studies are required to identify specific IL-17A-related inflammatory pathways mediating immunopathology in HIV-tuberculosis co-infection, which could illuminate targets for future host-directed therapies. FUNDING: National Institutes of Health, The Wellcome Trust, UK Research and Innovation, Cancer Research UK, European and Developing Countries Clinical Trials Partnership, and South African Medical Research Council.

The influence of single nucleotide polymorphisms of NOD2 or CD14 on the risk of Mycobacterium tuberculosis diseases: a systematic review.

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.

Association between neurofibromatosis type 1 and cerebrovascular diseases in children: A systematic review.

BACKGROUND: Neurofibromatosis type 1 (NF-1) is an autosomal dominant disease that affects one in every 3000 individuals. This disease can present a wide range of clinical manifestations, ranging from skin abnormalities to severe vascular damage. Although not commonly recognized in the context of NF-1, cerebrovascular disease (CVD), can be often present since childhood and diagnosed just later in life. When present, NF-1-associated CVD clinical manifestations may include headache, cognitive deficits and ultimately aneurysm rupture, causing death. Thus, CVD plays an important role in the clinical manifestations, disease severity and prognosis of patients with NF-1. This systematic review aims to summarize the body of evidence linking NF-1 and CVD in children. METHODS: Two independent investigators performed a systematic review on the PubMed and EMBASE search platforms, using the following key terms: "neurofibromatosis type 1", "Von Recklinghausen's disease", "children", "adolescents", "stroke", "Moyamoya disease", "vascular diseases", "cerebrovascular disorders", "aneurysm" and "congenital abnormalities". Studies focused on assessing the development of CVD in children with NF-1 were included. RESULTS: Seven studies met the inclusion criteria. Twelve different clinical manifestations have been associated with cerebrovascular changes in children with NF-1; 44,5% of diagnosed patients were asymptomatic. CONCLUSION: The available evidence suggests that CVDs are related with the progression of NF-1, even in the absence of a clear clinical manifestation. In addition, improved prognosis was observed when imaging tests were performed to screen for cerebrovascular alterations early during the clinical investigation. Early diagnosis of CVD in NF-1 patients foster implementation of timely interventions, directly impacting clinical outcomes.

Systemic Inflammation Associated with Immune Reconstitution Inflammatory Syndrome in Persons Living with HIV.

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.

Inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection: a prospective cohort study and immunological network analysis.

BACKGROUND: HIV-1 mediated dysregulation of the immune response to tuberculosis and its effect on the response to antitubercular therapy (ATT) is incompletely understood. We aimed to analyse the inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection undergoing ATT, with specific focus on the effect of ART and HIV-1 viraemia in those co-infected with HIV-1. METHODS: In this prospective cohort study and immunological network analysis, a panel of 38 inflammatory markers were measured in the plasma of a prospective patient cohort undergoing ATT at Khayelitsha Site B clinic, Cape Town, South Africa. We recruited patients with sputum Xpert MTB/RIF-positive rifampicin-susceptible pulmonary tuberculosis. Patients were excluded from the primary discovery cohort if they were younger than 18 years, unable to commence ATT for any reason, pregnant, had unknown HIV-1 status, were unable to consent to study participation, were unable to provide baseline sputum samples, had more than three doses of ATT, or were being re-treated for tuberculosis within 6 months of their previous ATT regimen. Plasma samples were collected at baseline (1-5 days after commencing ATT), week 8, and week 20 of ATT. We applied network and multivariate analysis to investigate the dynamic inflammatory profile of these patients in relation to ATT and by HIV status. In addition to the discovery cohort, a validation cohort of patients with HIV-1 admitted to hospital with CD4 counts less than 350 cells per µL and a high clinical suspicion of new tuberculosis were recruited. FINDINGS: Between March 1, 2013, and July 31, 2014, we assessed a cohort of 129 participants (55 [43%] female and 74 [57%] male, median age 35·1 years [IQR 30·1-43·7]) and 76 were co-infected with HIV-1. HIV-1 status markedly influenced the inflammatory profile regardless of ATT duration. HIV-1 viral load emerged as a major factor driving differential inflammatory marker expression and having a strong effect on correlation profiles observed in the HIV-1 co-infected group. Interleukin (IL)-17A emerged as a key correlate of HIV-1-induced inflammation during HIV-tuberculosis co-infection. INTERPRETATION: Our findings show the effect of HIV-1 co-infection on the complexity of plasma inflammatory profiles in patients with tuberculosis. Through network analysis we identified IL-17A as an important node in HIV-tuberculosis co-infection, thus implicating this cytokine's capacity to correlate with, and regulate, other inflammatory markers. Further mechanistic studies are required to identify specific IL-17A-related inflammatory pathways mediating immunopathology in HIV-tuberculosis co-infection, which could illuminate targets for future host-directed therapies. FUNDING: National Institutes of Health, The Wellcome Trust, UK Research and Innovation, Cancer Research UK, European and Developing Countries Clinical Trials Partnership, and South African Medical Research Council.

Hydroxyurea treatment is associated with reduced degree of oxidative perturbation in children and adolescents with sickle cell anemia.

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.

In silico transcriptional analysis of mRNA and miRNA reveals unique biosignatures that characterizes different types of diabetes.

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.

Determinants of losses in the latent tuberculosis cascade of care in Brazil: A retrospective cohort study.

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.

Systems biology analysis of publicly available transcriptomic data reveals a critical link between AKR1B10 gene expression, smoking and occurrence of lung cancer.

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.

Polymorphisms in interferon pathway genes and risk of Mycobacterium tuberculosis infection in contacts of tuberculosis cases in Brazil.

BACKGROUND: Host genetic polymorphisms may be important in determining susceptibility to Mycobacterium tuberculosis (Mtb) infection, but their role is not fully understood. Detection of microbial DNA and activation of type I interferon (IFN) pathways regulate macrophage responses to Mtb infection. METHODS: We examined whether seven candidate gene SNPs were associated with tuberculin skin test (TST) positivity in close contacts of microbiologically confirmed pulmonary TB patients in Brazil. Independent associations with TST positivity were tested using multivariable logistic regression (using genotypes and clinical variables) and genetic models. RESULTS: Among 482 contacts of 145 TB index cases, 296 contacts were TST positive. Multivariable regression analysis adjusted for population admixture, age, family relatedness, sex and clinical variables related to increased TB risk demonstrated that SNPs in PYHIN1-IFI16-AIM2 rs1101998 (adjusted OR [aOR]: 3.72; 95%CI=1.15-12.0; p=0.028) and in PYHIN1-IFI16-AIM2 rs1633256 (aOR=24.84; 95%CI=2.26-272.95; p=0.009) were associated with TST positivity in a recessive model. Furthermore, an IRF7 polymorphism (rs11246213) was associated with reduced odds of TST positivity in a dominant model (aOR: 0.50, 95%CI: 0.26-0.93; p=0.029). CONCLUSIONS: Polymorphisms in PYHIN1-IFI16-AIM2 rs1633256, rs1101998 and in IRF7 rs11246213 were associated with altered susceptibility to Mtb infection in this Brazilian cohort.

HLA-B*14 allele predicts HIV-1 mother-to-child-transmission, in Salvador, Brazil.

BACKGROUND: Class I human leukocyte antigens, especially the molecules encoded at the B locus (HLA-B), are associated with AIDS progression risk. Different groups of HLA-B alleles have been associated to a protective effect or increasing susceptibility to HIV infection and are expressed from the earliest stages of gestation. OBJECTIVE: The aim of this study was to evaluate which variants of HLA-B are associated with the risk of HIV vertical transmission in infected pregnant women and in their offspring, in a referral center in Salvador Bahia. METHODS: We performed HLA-B genotyping in 52 HIV-infected mothers and their children exposed to HIV-1 during pregnancy (N=65) in Salvador, Brazil. We compared the HLA-B alleles frequency in mothers, uninfected and infected children, according to the use of antiretroviral prophylaxis. RESULTS: Absence of antiretroviral antenatal and postnatal prophylaxis was significantly associated with vertical transmission of HIV-1 (p=<0.01, and p=<0.01 respectively). Frequency of HLA-B*14 (29.2%, p=0.002), HLA-B*18 (16.7%, p=0.04) or HLA-B*14:1 (20.8%, p=0.01) alleles subgroups were significantly higher in HIV-1 infected children and persisted (HLA-B*14, p=0.04) even after adjusting for use of antiretroviral prophylaxis. No significant difference in expression of HLA-B alleles was observed among mothers who transmitted the virus compared to those who did not. CONCLUSIONS: Expression of HLA-B*14 allele in children exposed to HIV-1 is predictive of vertical transmission and reinforces the important role of genetics in mother-to-child transmission.