Progression of Type 2 Helper T Cell-Type Inflammation and Airway Remodeling in a Rodent Model of Naturally Acquired Subclinical Primary Pneumocystis Infection.

Subclinical primary Pneumocystis infection is the most common pulmonary infection in early infancy, making it important to determine whether it damages the lung. Pneumocystis peaks at 2 to 5 months of age, when respiratory morbidity coincidently increases. We have documented that Pneumocystis increases mucus production in infant lungs, and animal models reveal lung lesions that warrant characterization. Herein, immunocompetent rats infected at birth with Pneumocystis by cohabitation, to resemble community-acquired infection, underwent lung assessments at 45, 60, and 75 days of age. Lungs fixed by vascular perfusion to prevent collapse during necropsy were used for morphometry evaluations of mucus production, airway epithelial thickening, perivascular and peribronchiolar inflammation, and structural airway remodeling. Changes in these histologic features indicate lung disease. Selected immune markers were assessed in parallel using fresh-frozen lung tissue from sibling rats of the same cages. Sequential activation of NF-κB and an increased Gata3/T-bet mRNA level ratio, consistent with a type 2 helper T-cell-type inflammatory response, and subacute fibrosis were recognized. Therefore, documenting subclinical Pneumocystis infection induces lung disease in the immunocompetent host. Taken together with the peak age of primary Pneumocystis infection, results warrant investigating the clinical impact of this often subclinical infection on the severity of respiratory diseases in early infancy. This model can also be used to assess the effects of airway insults, including coinfections by recognized respiratory pathogens.

Quality of Life is an Independent Predictor of Mortality in Patients with Heart Failure: A Prospective Cohort Study from the Colombian Heart Failure Registry (RECOLFACA).

AIM: Patients with Heart Failure (HF) commonly have poor quality of life (QoL), secondary to the persistence and severity of HF symptoms. We aimed to evaluate the prognostic value of QoL measures on all-cause mortality in patients with HF from the Colombian registry of heart failure (RECOLFACA). METHODS AND RESULTS: We analyzed data from patients registered in RECOLFACA during 2017-2019. QoL was measured using the EuroQol-5D questionnaire (EQ-5D). From the questionnaire, two independent predictors of mortality were obtained, the visual analogue scale (VAS) and the utility score (US). Primary outcome was all-cause mortality, and secondary variables evaluated were demographic factors, comorbidities, NYHA classification, medications used and laboratory test results. To analyze survival among patients, the Kaplan-Meier method and the hierarchical Cox proportional-hazards regression model were used. This study included 2514 patients from RECOLFACA. Most patients were male (57.6%), and mean age was 67.8 years. Mean value and standard deviation (SD) of the VAS score was 78.8 ± 20.1 points, while the mean and SD of the US score was 0.81 ± 0.20. As the Kaplan-Meier curve illustrated, patients in the lower quartiles of both VAS and US scores had a significantly higher probability of mortality (log-rank test: p<0.001 for both scores). CONCLUSION: QoL, as calculated by the EQ-5D questionnaire, served as an independent predictor of mortality in patients from RECOLFACA. Further studies may be needed to evaluate whether provision of optimizing therapies and follow-up care based on patients' perceived QoL reduces short- and long-term mortality rates in this population.

Expansion microscopy of the chick embryo neural tube to overcome molecular crowding at the centrosomes-cilia.

We describe an optimized protocol for application of expansion microscopy (ExM) on chick neural tube (NT) which enables different oriented nanoscale resolution imaging of the centrosomes/cilia. We explain embryo NT transversal sections and open-book preparations, immunohistochemistry for labeling, and sample preparation for 5-fold tissue expansion. Further, we detail sample orientation and Fast Airyscan confocal acquisition and show that NT-ExM retains fluorescence signals and overcomes biomolecules crowding in structural features that to date were only imaged with electron microscopy on tissues.

Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders.

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.

Registro colombiano de falla cardiaca (RECOLFACA): resultados / Colombian registry of heart failure (RECOLFACA): results

Resumen Introducción: La falla cardiaca (FC) es un problema de salud pública mundial. En Latinoamérica, la incidencia es de 199/100.000 personas-año y la prevalencia de ≈1%. En Colombia, pocos estudios han descrito el comportamiento sociodemográfico y clínico de los pacientes con FC agudamente descompensada (FCAD) y FC crónica (FCC). Método: Se implementó un registro multicéntrico para identificar características que puedan ayudar en la planeación y desarrollo de estrategias de prevención secundaria y tratamiento de esta población. Resultados: Se incluyeron 2528 pacientes. 57.59% hombres, edad promedio 69 años. La principal comorbilidad fue hipertensión arterial (72.04%). Las principales causas de descompensación de la FC fueron la progresión de la enfermedad (35.00%) y el tratamiento insuficiente (19.09%). La etiología más frecuente fue isquémica (43.99%). Al momento del ingreso, 86.95% de pacientes recibían betabloqueador, 67.25% recibían diuréticos, 55.66% recibían ARM, 42.41% recibían ARA-II, 33.66% recibían IECA y 9.73% recibían ARNI. Conclusiones: Los pacientes con FC en Colombia son similares a los descritos por otros registros de FC en el mundo occidental, destacando el uso de terapias basadas en la evidencia. Se documentó una proporción menor de fibrilación auricular, con mayor frecuencia de disfunción sistólica moderada-grave y un aparente uso subóptimo de dispositivos implantables.

Abstract Introduction: Heart failure (HF) is a public health problem worldwide. In Latin America, incidence is 199 / 100,000 person-year and prevalence is ≈1%. In Colombia, few studies have described the sociodemographic and clinical behavior of patients with acutely decompensated HF (ADHF) and chronic HF (CHF). Method: A multicenter registry was implemented to identify characteristics that can help in the planning and development of secondary prevention and treatment strategies for this population. Results: 2528 patients were included. 57.59% men, average age 69 years. The main comorbidity was arterial hypertension (72.04%). The main causes of HF decompensation were disease progression (35.00%) and insufficient treatment (19.09%). The most frequent etiology was ischemic (43.99%). At the time of admission, 86.95% of patients received beta-blocker, 67.25% received diuretics, 55.66% received MRA, 42.41% received ARB-II, 33.66% received ACEI, and 9.73% received ARNI. Conclusions: Patients with HF in Colombia are similar to those described by other HF registries in the western world, highlighting the use of evidence-based therapies. A lower proportion of atrial fibrillation was documented, with a higher frequency of moderate-severe systolic dysfunction and an apparent suboptimal use of implantable devices.