Mtb-Selective 5-Aminomethyl Oxazolidinone Prodrugs: Robust Potency and Potential Liabilities.

Linezolid is a drug with proven human antitubercular activity whose use is limited to highly drug-resistant patients because of its toxicity. This toxicity is related to its mechanism of action─linezolid inhibits protein synthesis in both bacteria and eukaryotic mitochondria. A highly selective and potent series of oxazolidinones, bearing a 5-aminomethyl moiety (in place of the typical 5-acetamidomethyl moiety of linezolid), was identified. Linezolid-resistant mutants were cross-resistant to these molecules but not vice versa. Resistance to the 5-aminomethyl molecules mapped to an N-acetyl transferase (Rv0133) and these mutants remained fully linezolid susceptible. Purified Rv0133 was shown to catalyze the transformation of the 5-aminomethyl oxazolidinones to their corresponding N-acetylated metabolites, and this transformation was also observed in live cells of Mycobacterium tuberculosis. Mammalian mitochondria, which lack an appropriate N-acetyltransferase to activate these prodrugs, were not susceptible to inhibition with the 5-aminomethyl analogues. Several compounds that were more potent than linezolid were taken into C3HeB/FeJ mice and were shown to be highly efficacious, and one of these (9) was additionally taken into marmosets and found to be highly active. Penetration of these 5-aminomethyl oxazolidinone prodrugs into caseum was excellent. Unfortunately, these compounds were rapidly converted into the corresponding 5-alcohols by mammalian metabolism which retained antimycobacterial activity but resulted in substantial mitotoxicity.

Two orthogonal differentiation gradients locally coordinate fruit morphogenesis.

Morphogenesis requires the coordination of cellular behaviors along developmental axes. In plants, gradients of growth and differentiation are typically established along a single longitudinal primordium axis to control global organ shape. Yet, it remains unclear how these gradients are locally adjusted to regulate the formation of complex organs that consist of diverse tissue types. Here we combine quantitative live imaging at cellular resolution with genetics, and chemical treatments to understand the formation of Arabidopsis thaliana female reproductive organ (gynoecium). We show that, contrary to other aerial organs, gynoecium shape is determined by two orthogonal, time-shifted differentiation gradients. An early mediolateral gradient controls valve morphogenesis while a late, longitudinal gradient regulates style differentiation. Local, tissue-dependent action of these gradients serves to fine-tune the common developmental program governing organ morphogenesis to ensure the specialized function of the gynoecium.

Exploring the effects of competition and predation on the success of biological invasion through mathematical modeling.

Biological invasions are a major cause of species extinction and biodiversity loss. Exotic predators are the type of introduced species that have the greatest negative impact, causing the extinction of hundreds of native species. Despite this, they continue to be intentionally introduced by humans. Understanding the causes that determine the success of these invasions is a challenge within the field of invasion biology. Mathematical models play a crucial role in understanding and predicting the behavior of exotic species in different ecosystems. This study examines the effect of predation and competition on the invasion success of an exotic generalist predator in a native predator-prey system. Considering that the exotic predator both consumes the native prey and competes with the native predator, it is necessary to study the interplay between predation and competition, as one of these interspecific interactions may either counteract or contribute to the impact of the other on the success of a biological invasion. Through a mathematical model, represented by a system of ordinary differential equations, it is possible to describe four different scenarios upon the arrival of the exotic predator in a native predator-prey system. The conditions for each of these scenarios are described analytically and numerically. The numerical simulations are performed considering the American mink (Mustela vison), an invasive generalist predator. The results highlight the importance of considering the interplay between interspecific interactions for understanding biological invasion success.

Shotgun Metagenomics-Guided Prediction Reveals the Metal Tolerance and Antibiotic Resistance of Microbes in Poly-Extreme Environments in the Danakil Depression, Afar Region.

The occurrence and spread of antibiotic resistance genes (ARGs) in environmental microorganisms, particularly in poly-extremophilic bacteria, remain underexplored and have received limited attention. This study aims to investigate the prevalence of ARGs and metal resistance genes (MRGs) in shotgun metagenome sequences obtained from water and salt crust samples collected from Lake Afdera and the Assale salt plain in the Danakil Depression, northern Ethiopia. Potential ARGs were characterized by the comprehensive antibiotic research database (CARD), while MRGs were identified by using BacMetScan V.1.0. A total of 81 ARGs and 39 MRGs were identified at the sampling sites. We found a copA resistance gene for copper and the ß-lactam encoding resistance genes were the most abundant the MRG and ARG in the study area. The abundance of MRGs is positively correlated with mercury (Hg) concentration, highlighting the importance of Hg in the selection of MRGs. Significant correlations also exist between heavy metals, Zn and Cd, and ARGs, which suggests that MRGs and ARGs can be co-selected in the environment contaminated by heavy metals. A network analysis revealed that MRGs formed a complex network with ARGs, primarily associated with ß-lactams, aminoglycosides, and tetracyclines. This suggests potential co-selection mechanisms, posing concerns for both public health and ecological balance.

Asociación entre condición física y fase angular en el adulto mayor: Un estudio piloto

El diagnóstico por bioimpedancia (BIA) y el ángulo de fase (AnF), como indicador, permiten monitorear el estado físico, de salud y nutricional en adultos mayores. El objetivo de este estudio fue establecer la relación entre la condición física y valores de fase angular por bioimpedancia en un grupo de adultos mayores sedentarios. Participaron voluntariamente 24 adultos mayores sedentarios (21 mujeres y 3 hombres). A cada participante se les midió bioimpedancia, fuerza de presión manual y test de 6 minutos del Senior Fitness Test (SFT). Posteriormente se analizaron los resultados, correlacionando el ángulo de fase (AnF) y condición física cardiorrespiratoria según sexo y el AnF con la fuerza de presión manual. El 71% presentó una media de AnF por debajo de la referencia (4,5º ± 0,4), específicamente, el 67% de los hombres y el 62% de las mujeres. La correlación entre AnF y capacidad física cardiorrespiratoria arrojó un valor de R2= 0,50; p<0,0001. La asociación entre AnF y fuerza de presión manual fue de R2=0,35; p=0,0023. Se encontró una relación significativa entre una prueba de condición física cardiorrespiratoria y AnF y entre la fuerza de presión manual y AnF. Es de importancia clínica incluir parámetros objetivos de valoración celular en adultos mayores como el AnF.

The diagnosis by bioimpedance (BIA) and the phase angle (PhA) are indicators, that allow monitoring of the physical health and nutritional status of older adults. The objective of this study was to establish the relationship between physical fitness and phase angle values by bioimpedance in a group of sedentary older adults. 24 elderly sedentary volunteers participated (21 women and 3 men). Each participant underwent bioimpedance, manual dynamometry, and the 6-minute Senior Fitness Test (SFT). Subsequently, the results were analyzed, making a correlation between PhA and cardiorespiratory physical condition, another between PhA and cardiorespiratory physical condition according to sex and finally an association between PhA and handgrip strength. R71% presented a PhA mean below the reference (4.5º ± 0.4), specifically 67% of men and 62% of women. The correlation between PhA and cardiorespiratory fitness showed a value of R2= 0.50; p<0.0001. The association between PhA and handgrip strength was R2=0.35; p=0.0023. A significant relationship was found between a cardiorespiratory fitness test and PhA and between handgrip strength and PhA. It is of clinical importance to include objective cellular assessment parameters in older adults such as PhA.

O diagnóstico por bioimpedância (BIA) e ângulo de fase (AnF), como indicador, permitem monitorar o estado físico, de saúde e nutricional de idosos. O objetivo deste estudo foi estabelecer a relação entre a condição física e os valores da fase angular por bioimpedância em um grupo de idosos sedentários. Participaram voluntariamente 24 idosos sedentários (21 mulheres e 3 homens). Cada participante foi medido bioimpedância, força de pressão manual e teste de 6 minutos do Senior Fitness Test (SFT). Posteriormente, os resultados foram analisados, correlacionando o ângulo de fase (AnF) e a condição física cardiorrespiratória de acordo com o sexo e o AnF com a força de pressão manual. 71% apresentaram média do LAn abaixo da referência (4,5º ± 0,4), sendo 67% dos homens e 62% das mulheres. A correlação entre o LAn e a aptidão cardiorrespiratória deu um valor de R2= 0,50; p<0,0001. A associação entre LAn e força de pressão manual foi R2=0,35; p=0,0023. Encontrou-se relação significativa entre teste de aptidão cardiorrespiratória e NF e entre força de pressão manual e NF. É de importância clínica incluir parâmetros objetivos de avaliação celular em adultos mais velhos, como AnF.

[Comparative analysis of bleed volume with visual technique]. / Análisis comparativo de volumen de sangrado mediante técnica visual.

Background: Blood loss estimation in a surgery is made by anesthesiologists by means of visual technique, which is not reliable because it can change depending on the judgement of every person, or his/her work experience, which is why it is considered something subjective. Therefore, the results obtained could lead to make mistakes with the exact amount of bleeding, mismanaging unnecessary hemoderived transfusions or administering unnecessary drugs. Objective: To compare the blood volume and its visual calculation between Anesthesiology residents and anesthesiologists. Material and methods: Prolective cross-sectional study which included 85 Anesthesiology residents and anesthesiologists. Diverse scenarios of bleeding were set, divided into gauze pads, compresses and jars, and each participant was asked to answer the poll. Results: There is no significant difference in the estimate of bleeding between the estimation made by residents and anesthesiologists. Conclusions: The grade of studies or experience is not significant for the exact estimation of bleeding with visual technique.

Introducción: la estimación de sangrado en las cirugías se realiza por medio de la técnica de cálculo visual, que es llevada a cabo por parte del servicio de anestesiología. Se trata de una técnica poco confiable, que puede variar dependiendo del juicio de cada persona y de su experiencia laboral, por lo que es considerada algo subjetivo. Por lo tanto, los datos arrojados hacen que se cometan errores en la cantidad exacta del sangrado y llevan a transfusiones de paquetes globulares o a la administración probablemente innecesaria de medicamentos. Objetivo: comparar la cantidad de un volumen de sangrado determinado y su cálculo visual realizada por residentes de Anestesiología y anestesiólogos. Material y métodos: estudio transversal prolectivo en el cual se incluyeron 85 médicos residentes de Anestesiología y anestesiólogos. Se dispusieron diversos escenarios con sangrado, los cuales se dividieron en gasas, compresas y frascos, y se le pidió a cada médico que contestara la encuesta correspondiente según su criterio. Resultados: de acuerdo con los resultados, no hay diferencia significativa en la estimación realizada del sangrado entre residentes y anestesiólogos para las muestras estudiadas. Conclusiones: el grado de estudios o experiencia no es significativo para la exacta estimación de sangrado con técnica visual.

[Chemotherapy at the end of life is compatible with dignified death and palliative care] / Quimioterapia al final de la vida es compatible con muerte digna y cuidados paliativos.

Introduction: Cancer treatment is increasingly aggressive. The aim was to estimate who died due to cancer, to report use of chemotherapy (CT) in the last 3 months of life, and to describe clinical-epidemiological characteristics of these patients. Methods: We included a consecutive sample of deceased during 2017, affiliated to Hospital Italiano de Buenos Aires. Through manual review of medical helath records, they were classified according to the cause of death (cancer or other cause), validating diagnosis and baseline stage, performance status (PS). Prevalences with 95% CI are reported and descriptive statistics were used. Results: A total of 2293 adults died, 59% women with a median age of 84 years old. There were a total of 736 deaths from cancer, representing 32% (95%CI 30-34). This last subgroup were 54% women, with a median age of 75 years, and only one patient had advance directives. Regarding the place of death, 80% were hospitalized (65% general ward and 15% intensive care units). The most frequent tumors were: lung, colorectal-gastric, hematological, and breast. A total of 390 patients received CT at the end of life (53%; 95%CI 49-57), 53% being women and with a mean age of 68 years. Regarding the underlying oncological disease: 81% had a solid tumor, 75% advanced stage, and mostly with poor/regular ability to perform daily activities (25% PS3 and 32% PS4, respectively). Conclusion: There is a high frequency of CT at the end of life and deaths continue to be mainly in-hospital.

Introducción: El tratamiento oncológico es cada vez más agresivo. El objetivo de este trabajo fue estimar las personas fallecidas por causa oncológica, reportar la frecuencia de uso de quimioterapia (QT) en los últimos 3 meses de vida, y describir las características clínicas-epidemiológicas de estos pacientes. Métodos: Se incluyó una muestra consecutiva de fallecidos durante el 2017, afiliados a prepaga del Hospital Italiano de Buenos Aires. Mediante revisión de historias clínicas, se los clasificó según la causa de muerte (oncológico u otra causa), validando diagnóstico y estadio de base, performance status (PS). Se reportan prevalencias con IC95% y se utilizó estadística descriptiva. Resultados: Fallecieron 2293 personas, 59% mujeres con mediana de 84 años. Hubo un total de 736 fallecidos por cáncer, representando el 32% (IC95% 30-34). Este último subgrupo presentó una mediana de 75 años, 54% eran mujeres y sólo una paciente tenía directivas anticipadas. En cuanto al lugar de fallecimiento, 80% ocurrió hospitalizado (65% sala general y 15% unidad cerrada). Los tumores más frecuentes fueron: pulmón, colorrectal-gástrico, hematológico, y mama. Un total de 390 pacientes recibieron QT al final de la vida (53%; IC95% 49-57), siendo 53% mujeres y con promedio de 68 años. En cuanto a la enfermedad oncológica de base: 81% tenían tumor sólido, 75% estadío avanzado, y mayoritariamente con mala/regular capacidad para realizar actividades cotidianas (25% PS3 y 32% PS4 respectivamente). Conclusión: Existe una frecuencia preocupante del uso de QT en el fin de vida y los fallecimientos siguen siendo principalmente intrahospitalarios.

Distributable, Metabolic PET Reporting of Tuberculosis.

Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [18F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian Mtb disaccharide trehalose - 2-[18F]fluoro-2-deoxytrehalose ([18F]FDT) - can act as a mechanism-based enzyme reporter in vivo. Use of [18F]FDT in the imaging of Mtb in diverse models of disease, including non-human primates, successfully co-opts Mtb-specific processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [18F]FDT from the most globally-abundant organic 18F-containing molecule, [18F]FDG. The full, pre-clinical validation of both production method and [18F]FDT now creates a new, bacterium-specific, clinical diagnostic candidate. We anticipate that this distributable technology to generate clinical-grade [18F]FDT directly from the widely-available clinical reagent [18F]FDG, without need for either bespoke radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer.

Synthesis and antitubercular activity of novel 4-arylalkyl substituted thio-, oxy- and sulfoxy-quinoline analogues targeting the cytochrome bc1 complex.

A library of 4-substituted quinolines was synthesised based on the structural features of the privileged 4-(benzylthio)-6-methoxy-2-methylquinoline scaffold. Quinoline-based chemical probes have proven to be effective anti-tuberculosis agents with the ability of inhibiting components of Mycobacterium tuberculosis (MTB) respiratory chain including the b subunit of the cytochrome bc1 complex. Novel 4-(arylalkyl)-thio, -oxy and sulfoxy-quinoline analogues were tested for their ability to inhibit the growth of MTB H37Rv and QcrB mutant strains, and the compounds mode of action was investigated. Members of the 4-subtituted thio- and sulfoxyquinoline series exhibited significant growth inhibitory activity in the high nanomolar range against wild-type MTB and induced depletion of intracellular ATP. These probes also showed reduced potency in the QcrB T313I mutant strain, thus indicating the cytochrome bc1 oxidase complex as the molecular target. Interestingly, new 4-(quinolin-2-yl)oxy-quinoline 4i was more selective for the QcrB T313I strain compared to the wild-type strain.

Concurrent dilution and amplification effects in an intraguild predation eco-epidemiological model.

The dilution and amplification effects are important concepts in the field of zoonotic diseases. While the dilution effect predicts that pathogen prevalence is negatively correlated with increased species diversity, the opposite trend is observed when the amplification effect occurs. Understanding how interspecific interactions such as predation and competition within a community influence disease transmission is highly relevant. We explore the conditions under which the dilution and amplification effects arise, using compartmental models that integrate ecological and epidemiological interactions. We formulate an intraguild predation model where each species is divided into two compartments: susceptible and infected individuals. We obtained that increasing predation increases the disease transmission potential of the predator and the density of infected individuals, but decreases the disease transmission potential of the prey, as well as their density. Also, we found that interspecific competition always helps to decrease the number of infected individuals in the population of the two species. Therefore, dilution and amplification effects can be observed simultaneously but depending on different types of cological interactions.

Editorial: Anaerobic Microorganisms on Mars 2.0.

Recent space missions (MSL-Curiosity, Mars2020-Perseverance) have confirmed the historic presence of water on early Mars [...].

Continuous relative phases of walking with an articulated passive ankle-foot prosthesis in individuals with a unilateral transfemoral and transtibial amputation: an explorative case-control study.

BACKGROUND: A mechanical ankle-foot prosthesis (Talaris Demonstrator) was developed to improve prosthetic gait in people with a lower-limb amputation. This study aims to evaluate the Talaris Demonstrator (TD) during level walking by mapping coordination patterns based on the sagittal continuous relative phase (CRP). METHODS: Individuals with a unilateral transtibial amputation, transfemoral amputation and able-bodied individuals completed 6 minutes of treadmill walking in consecutive blocks of 2 minutes at self-selected (SS) speed, 75% SS speed and 125% SS speed. Lower extremity kinematics were captured and hip-knee and knee-ankle CRPs were calculated. Statistical non-parametric mapping was applied and statistical significance was set at 0.05. RESULTS: The hip-knee CRP at 75% SS walking speed with the TD was larger in the amputated limb of participants with a transfemoral amputation compared to able-bodied individuals at the beginning and end of the gait cycle (p = 0.009). In people with a transtibial amputation, the knee-ankle CRP at SS and 125% SS walking speeds with the TD were smaller in the amputated limb at the beginning of the gait cycle compared to able-bodied individuals (p = 0.014 and p = 0.014, respectively). Additionally, no significant differences were found between both prostheses. However, visual interpretation indicates a potential advantage of the TD over the individual's current prosthesis. CONCLUSION: This study provides lower-limb coordination patterns in people with a lower-limb amputation and reveals a possible beneficial effect of the TD over the individuals' current prosthesis. Future research should include a well-sampled investigation of the adaptation process combined with the prolonged effects of the TD.

Coupled C, H, N, S and Fe biogeochemical cycles operating in the continental deep subsurface of the Iberian Pyrite Belt.

Microbial activity is a major contributor to the biogeochemical cycles that make up the life support system of planet Earth. A 613 m deep geomicrobiological perforation and a systematic multi-analytical characterization revealed an unexpected diversity associated with the rock matrix microbiome that operates in the subsurface of the Iberian Pyrite Belt (IPB). Members of 1 class and 16 genera were deemed the most representative microorganisms of the IPB deep subsurface and selected for a deeper analysis. The use of fluorescence in situ hybridization allowed not only the identification of microorganisms but also the detection of novel activities in the subsurface such as anaerobic ammonium oxidation (ANAMMOX) and anaerobic methane oxidation, the co-occurrence of microorganisms able to maintain complementary metabolic activities and the existence of biofilms. The use of enrichment cultures sensed the presence of five different complementary metabolic activities along the length of the borehole and isolated 29 bacterial species. Genomic analysis of nine isolates identified the genes involved in the complete operation of the light-independent coupled C, H, N, S and Fe biogeochemical cycles. This study revealed the importance of nitrate reduction microorganisms in the oxidation of iron in the anoxic conditions existing in the subsurface of the IPB.

IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques.

The pro- and anti-inflammatory pathways that determine the balance of inflammation and viral control during SARS-CoV-2 infection are not well understood. Here we examine the roles of IFNγ and IL-10 in regulating inflammation, immune cell responses and viral replication during SARS-CoV-2 infection of rhesus macaques. IFNγ blockade tended to decrease lung inflammation based on 18 FDG-PET/CT imaging but had no major impact on innate lymphocytes, neutralizing antibodies, or antigen-specific T cells. In contrast, IL-10 blockade transiently increased lung inflammation and enhanced accumulation of virus-specific T cells in the lower airways. However, IL-10 blockade also inhibited the differentiation of virus-specific T cells into airway CD69 + CD103 + T RM cells. While virus-specific T cells were undetectable in the nasal mucosa of all groups, IL-10 blockade similarly reduced the frequency of total T RM cells in the nasal mucosa. Neither cytokine blockade substantially affected viral load and infection ultimately resolved. Thus, in the macaque model of mild COVID-19, the pro- and anti-inflammatory effects of IFNγ and IL-10 have no major role in control of viral replication. However, IL-10 has a key role in suppressing the accumulation of SARS-CoV-2-specific T cells in the lower airways, while also promoting T RM at respiratory mucosal surfaces.

Idiopathic left fascicular ventricular tachycardia in children and adolescents.

BACKGROUND: Idiopathic ventricular tachycardia (VT) in children with structurally normal hearts is generally unrelated to the risk of sudden arrhythmic death. Still, it may be associated with deterioration in the quality of life. VT involving the fascicular conduction system is the most typical form of idiopathic left VT. In this retrospective study, we describe the experience of the clinical presentation, catheter ablation, and long-term follow-up of left fascicular VT in children. METHODS: An electrophysiological study was performed on consecutive children at a single tertiary center. Clinical fascicular left VT was induced by programmed stimulation, and catheter ablation was guided searching for Purkinje potentials. RESULTS: We included 18 patients (0.8 patients/year): 14 (77.8%) males and four females. The mean age of the first VT episode was 8.5 ± 5 years. Intravenous verapamil administration was effective for paroxysmal fascicular VT but not for prevention of recurrences. The mean age at the time of catheter ablation was 11.1 ± 3.8 years (8 months-16 years). The mean weight was 36.8 ± 16.4 kg (8.7-58 kg). A 100% success rate was observed with catheter ablation after repeated procedures without major complications. Mean follow-up was 2.0 ± 1.2 years (1.0-4.0 years, median 1.5), with permanent success in all patients and no antiarrhythmic drug administration. CONCLUSIONS: Fascicular VT has an adverse clinical course in children. In most cases, this condition is drug refractory. Catheter ablation is successful and safe treatment and should represent the first-line approach in symptomatic children.

INTRODUCCIÓN: La taquicardia ventricular (TV) idiopática en niños con corazón estructuralmente normal generalmente no se relaciona con el riesgo de muerte súbita arrítmica, pero puede asociarse con deterioro de la calidad de vida. La TV que involucra el sistema de conducción fascicular es la forma más común de TV izquierda idiopática. En este estudio retrospectivo se describe la experiencia de presentación clínica, ablación con catéter y seguimiento a largo plazo de TV fascicular en niños. MÉTODOS: Se llevó a cabo un estudio electrofisiológico en niños consecutivos en un centro terciario. La TV fascicular clínica se indujo mediante la estimulación programada y la ablación con catéter fue guiada buscando el registro de potenciales de Purkinje. RESULTADOS: Se incluyeron 18 pacientes (0.8 pacientes/año): 14 (77.8%) de sexo masculino y cuatro de sexo femenino. La media de edad a la cual ocurrió el primer episodio fue de 8.5 ± 5 años. La administración intravenosa de verapamilo fue eficaz para la TV fascicular paroxística, pero no para prevención de recurrencias. La media de edad de la ablación con catéter fue de 11.1 ± 3.8 años (8 meses-16 años). La media del peso fue 36.8 ± 16.4 kg (8.7-58 kg). Se observó el 100% de éxito con la ablación con catéter después de procedimientos repetidos sin complicaciones mayores. La media de seguimiento fue de 2.0 ± 1.2 años (1.0-4.0, mediana de 1.5 años) con éxito permanente en todos los pacientes y sin administración de fármacos antiarrítmicos. CONCLUSIONES: En niños, el curso clínico de la TV fascicular es adverso. Además, en la mayoría de los casos, esta condición es refractaria a fármacos. La ablación con catéter resulta exitosa y segura y debe representar el abordaje de primera línea en niños sintomáticos.

Idiopathic left fascicular ventricular tachycardia in children and adolescents / Taquicardia ventricular fascicular izquierda idiopática en niños y adolescentes

Abstract Background: Idiopathic ventricular tachycardia (VT) in children with structurally normal hearts is generally unrelated to the risk of sudden arrhythmic death. Still, it may be associated with deterioration in the quality of life. VT involving the fascicular conduction system is the most typical form of idiopathic left VT. In this retrospective study, we describe the experience of the clinical presentation, catheter ablation, and long-term follow-up of left fascicular VT in children. Methods: An electrophysiological study was performed on consecutive children at a single tertiary center. Clinical fascicular left VT was induced by programmed stimulation, and catheter ablation was guided searching for Purkinje potentials. Results: We included 18 patients (0.8 patients/year): 14 (77.8%) males and four females. The mean age of the first VT episode was 8.5 ± 5 years. Intravenous verapamil administration was effective for paroxysmal fascicular VT but not for prevention of recurrences. The mean age at the time of catheter ablation was 11.1 ± 3.8 years (8 months-16 years). The mean weight was 36.8 ± 16.4 kg (8.7-58 kg). A 100% success rate was observed with catheter ablation after repeated procedures without major complications. Mean follow-up was 2.0 ± 1.2 years (1.0-4.0 years, median 1.5), with permanent success in all patients and no antiarrhythmic drug administration. Conclusions: Fascicular VT has an adverse clinical course in children. In most cases, this condition is drug refractory. Catheter ablation is successful and safe treatment and should represent the first-line approach in symptomatic children.

Resumen Introducción: La taquicardia ventricular (TV) idiopática en niños con corazón estructuralmente normal generalmente no se relaciona con el riesgo de muerte súbita arrítmica, pero puede asociarse con deterioro de la calidad de vida. La TV que involucra el sistema de conducción fascicular es la forma más común de TV izquierda idiopática. En este estudio retrospectivo se describe la experiencia de presentación clínica, ablación con catéter y seguimiento a largo plazo de TV fascicular en niños. Métodos: Se llevó a cabo un estudio electrofisiológico en niños consecutivos en un centro terciario. La TV fascicular clínica se indujo mediante la estimulación programada y la ablación con catéter fue guiada buscando el registro de potenciales de Purkinje. Resultados: Se incluyeron 18 pacientes (0.8 pacientes/año): 14 (77.8%) de sexo masculino y cuatro de sexo femenino. La media de edad a la cual ocurrió el primer episodio fue de 8.5 ± 5 años. La administración intravenosa de verapamilo fue eficaz para la TV fascicular paroxística, pero no para prevención de recurrencias. La media de edad de la ablación con catéter fue de 11.1 ± 3.8 años (8 meses-16 años). La media del peso fue 36.8 ± 16.4 kg (8.7-58 kg). Se observó el 100% de éxito con la ablación con catéter después de procedimientos repetidos sin complicaciones mayores. La media de seguimiento fue de 2.0 ± 1.2 años (1.0-4.0, mediana de 1.5 años) con éxito permanente en todos los pacientes y sin administración de fármacos antiarrítmicos. Conclusiones: En niños, el curso clínico de la TV fascicular es adverso. Además, en la mayoría de los casos, esta condición es refractaria a fármacos. La ablación con catéter resulta exitosa y segura y debe representar el abordaje de primera línea en niños sintomáticos.

CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection.

HIV/Mycobacterium tuberculosis (Mtb) co-infected individuals have an increased risk of tuberculosis prior to loss of peripheral CD4 T cells, raising the possibility that HIV co-infection leads to CD4 T cell depletion in lung tissue before it is evident in blood. Here, we use rhesus macaques to study the early effects of simian immunodeficiency virus (SIV) co-infection on pulmonary granulomas. Two weeks after SIV inoculation of Mtb-infected macaques, Mtb-specific CD4 T cells are dramatically depleted from granulomas, before CD4 T cell loss in blood, airways, and lymph nodes, or increases in bacterial loads or radiographic evidence of disease. Spatially, CD4 T cells are preferentially depleted from the granuloma core and cuff relative to B cell-rich regions. Moreover, live imaging of granuloma explants show that intralesional CD4 T cell motility is reduced after SIV co-infection. Thus, granuloma CD4 T cells may be decimated before many co-infected individuals experience the first symptoms of acute HIV infection.

Phot0, a plausible primeval pigment on Earth and rocky exoplanets.

In view of the existing controversy around the origin of the photosynthesis and, therefore, the first photosynthetic pigments, our work focuses on the theoretical study of a hypothetical first pigment, simpler than those existing today, that collects energy from solar radiation on Earth-like exoplanets. Our theoretical results show that there could exist geochemical conditions that allow the abiotic formation of a primeval pigment that might become sufficiently abundant in the early stages of habitable rocky exoplanets. These conditions would place this pigment before the appearance of life in a very young planet, thanks to chemical routes instead of biochemical transformations. Thus, our results may refute the currently accepted hypothesis that the complex biomolecules that allowed the photosynthesis to be carried out were synthesized through complex and evolved metabolic pathways. In addition, we show that the proposed primeval pigment, which we call Phot0, is also a precursor of the more evolved pigments known today on Earth and demonstrate, for the first time, an abiotic chemical route leading to tetrapyrroles not involving pyrrole derivatives. Our proposal places simple and very abundant raw materials in never-before-proposed geochemical conditions that lead to the formation of biomolecules of biological interest.

The dynamic atmospheric and aeolian environment of Jezero crater, Mars.

Despite the importance of sand and dust to Mars geomorphology, weather, and exploration, the processes that move sand and that raise dust to maintain Mars' ubiquitous dust haze and to produce dust storms have not been well quantified in situ, with missions lacking either the necessary sensors or a sufficiently active aeolian environment. Perseverance rover's novel environmental sensors and Jezero crater's dusty environment remedy this. In Perseverance's first 216 sols, four convective vortices raised dust locally, while, on average, four passed the rover daily, over 25% of which were significantly dusty ("dust devils"). More rarely, dust lifting by nonvortex wind gusts was produced by daytime convection cells advected over the crater by strong regional daytime upslope winds, which also control aeolian surface features. One such event covered 10 times more area than the largest dust devil, suggesting that dust devils and wind gusts could raise equal amounts of dust under nonstorm conditions.