Temporal dynamics of TNF-mediated changes in hematopoietic stem cell function and recovery.

While tumor necrosis factor (TNF) is a critical mediator of appropriate immune response and tissue repair, its misregulation is linked to cancer, autoimmunity, bone marrow failure, and aging. Understanding the context-dependent roles of TNF is essential for elucidating normal and pathogenic conditions and to guide clinical therapy advancements. Prior studies suggested that TNF restricts the self-renewal capacity of hematopoietic stem cells (HSCs), but its long-term effect on HSCs remains unclear. Here, we demonstrate that in vivo TNF administration results in a transient exit of HSCs from quiescence, which coincides with a compromised repopulation capacity. These functional changes are; however, fully reversible even following prolonged/chronic transient exposure to TNF. Notably, antagonizing TNF signaling in transplantation recipients enhances donor HSC reconstitution. Our findings provide molecular and functional insight into HSC regulation, with implications for both acute and chronic inflammatory conditions.

A somatic mutation in moesin drives progression into acute myeloid leukemia.

Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event. Upon clonal transformation, we identified and extensively verified a recurrent codon-changing mutation (Arg295Cys) in the ERM protein moesin that markedly accelerated leukemogenesis. Human cancer-associated moesin mutations at the conserved arginine-295 residue similarly enhanced MLL-ENL-driven leukemogenesis. Mechanistically, the mutation interrupted the stability of moesin and conferred a neomorphic activity to the protein, which converged on enhanced extracellular signal-regulated kinase activity. Thereby, our studies demonstrate a critical role of ERM proteins in AML, with implications also for human cancer.

Bmi1 induction protects hematopoietic stem cells against pronounced long-term hematopoietic stress.

The Polycomb complex protein Bmi1 is regarded as a master regulator of hematopoietic stem cells (HSCs). In the blood system, HSCs express Bmi1 most abundantly, and Bmi1 expression wanes as cells differentiate. Furthermore, Bmi1 has been found to be overexpressed in several hematologic cancers. Most studies exploring the normal role of Bmi1 in HSC biology have used loss-of-function models, which have established Bmi1 as an important regulator for HSC maintenance. Additionally, gain-of-function studies using retroviral and lentiviral approaches have observed increased self-renewal of Bmi1-transduced HSCs. However, the clinical and biological relevance of such studies is typically hampered by uncontrolled transgenic integration and supraphysiological expression levels. Here, we describe how we developed a novel tetracycline-inducible gain-of-function Bmi1 (iBmi1) transgenic mouse model. We found that Bmi1 induction had minor, if any, effects on steady-state hematopoiesis or after 5-fluorouracil-induced cytostatic stress. On the contrary, secondary transplantation of iBmi1 HSCs into wild-type recipients resulted in marked increases in the number and chimerism of HSCs. These data, in concert with previous loss-of-function studies, suggest that although endogenous Bmi1 levels are required and sufficient for normal HSC maintenance, the stabilization of these levels over time protects HSCs from transplantation-associated stress.

Is it possible to treat nonalcoholic liver disease using a flavanol-based nutraceutical approach? Basic and clinical data.

Nonalcoholic fatty liver disease (NAFLD) is characterized by a spectrum of diseases, ranging from simple steatosis to hepatocellular carcinoma. The main factors for NAFLD are closely related to obesity, insulin resistance, intestinal microbiota alterations, hyperinsulinism, low-grade systemic inflammation, nitroxidative stress, lipid peroxidation, and mitochondrial dysfunction. Currently, the treatment of NAFLD is based on diet and exercise because, to date, there is no specific pharmacological agent, already approved, that raises the need for new therapeutic strategies. Nutraceuticals, such as polyphenols, have potential beneficial effects for health. In this article, the beneficial effects of epigallocatechin-3-gallate (EGCG) and (-)-epicatechin (EC) are discussed. EGCG is the main catechin in green tea, which has shown in various studies its potential effect preventing and treating NAFLD since it has shown antihyperlipidemic, anti-inflammatory, antifibrotic, antioxidant, and improvement of liver lipid metabolism. However, it has been found that excessive consumption may cause hepatotoxicity. EC is widely distributed in nature (fruits and vegetables). This flavanol has shown many beneficial effects, including antihypertensive, anti-inflammatory, anti-hyperglycemic, antithrombotic, and antifibrotic properties. It increases mitochondrial biogenesis, and it also has effects on the regulation of synthesis and metabolism of lipids. This flavanol is a nontoxic substance; it has been classified by the United States Food and Drug Administration as harmless. The EC-induced effects can be useful for the prevention and/or treatment of NAFLD.

The human bone marrow harbors a CD45- CD11B+ cell progenitor permitting rapid microglia-like cell derivative approaches.

Microglia, the immune sentinel of the central nervous system (CNS), are generated from yolk sac erythromyeloid progenitors that populate the developing CNS. Interestingly, a specific type of bone marrow-derived monocyte is able to express a yolk sac microglial signature and populate CNS in disease. Here we have examined human bone marrow (hBM) in an attempt to identify novel cell sources for generating microglia-like cells to use in cell-based therapies and in vitro modeling. We demonstrate that hBM stroma harbors a progenitor cell that we name stromal microglial progenitor (STR-MP). STR-MP single-cell gene analysis revealed the expression of the consensus genetic microglial signature and microglial-specific genes present in development and CNS pathologies. STR-MPs can be expanded and generate microglia-like cells in vitro, which we name stromal microglia (STR-M). STR-M cells show phagocytic ability, classically activate, and survive and phagocyte in human brain tissue. Thus, our results reveal that hBM harbors a source of microglia-like precursors that can be used in patient-centered fast derivative approaches.

Clinical and Nutritional Evolution of 24 Patients with Glutaric Aciduria Type 1 in Follow-up at a Center Specialized in Inborn Errors of Metabolism in Chile

Abstract Introduction: Glutaric Aciduria Type 1 (GA-1) is produced by the enzymatic deficiency of glutaryl-CoA-dehydrogenase (GCDH), leading to the accumulation of glutaric acid (GA). 90% of patients without early treatment present acute encephalopathic crisis (AEC), followed by disabling neurological symptoms. The treatment consists of a low lysine (Lys) diet, protein substitute lys-free, tryptophan-reduced (PS) and L-carnitine. Objectives: Describe the clinical and nutritional evolution of a cohort of GA-1 patients at a national referral center in Chile. Methodology: Retrospective study of 24 patients diagnosed with GA-1 between 1998-2020 and referred to the Institute of Nutrition and Food Technology (INTA) of University of Chile. Results: Age at diagnosis was 19±27 months; 10/24 presented AEC and neurological sequelae. The cases without AEC (14/24) 8 presented neurological compromise: psychomotor development delay, abnormal movements and pyramidal syndrome. Nutritional evaluation: 12/24 were malnourished by deficiency, <6 years old group (12/24): 11 cases were found to have Lys and PS, ≥6 years old (12/24): 9/12 did not receive PS. All had normal free carnitine levels. Conclusion: GA-1 has variable symptoms with neurological involvement AEC or insidious start. Is essential to maintain a long-term follow-up and consider its inclusion in neonatal screening programs.

Intervalo de nacimiento entre gemelos como determinante del resultado neonatal precoz / Inter-twin delivery interval as a determinant of early neonatal outcome

INTRODUCCIÓN Y OBJETIVOS: La mayoría de las sociedades científicas recomiendan el parto vaginal del segundo gemelo siempre que el primer gemelo esté en presentación cefálica. En estos casos existe controversia cuánto tiempo transcurrido entre el parto de ambos es determinante en el resultado adverso del segundo gemelo. El objetivo de este estudio es examinar cómo influye dicho intervalo en el resultado perinatal precoz en nuestro Centro y el coste de las estancias neonatales y maternas. MÉTODOS: Estudio de cohortes retrospectivo entre mayo de 2014 y diciembre de 2018. Se comparó el resultado neonatal adverso estableciendo puntos de corte de intervalo entre el nacimiento de 10 y 30 minutos. Así mismo, se examinó la relación de otras variables del parto con el desenlace neonatal y se calcularon los costes de las estancias neonatales y maternas. RESULTADOS: Se incluyeron 128 partos gemelares vaginales asistidos en el Hospital Universitario Nuestra Señora de la Candelaria. Se evidenció triple tasa de resultado neonatal adverso en el grupo de más de 10 minutos (p=0,026 y OR 2,4) y tres veces peor en el de más de 30 minutos (p=0,013 y OR 6,4). Se obtuvo una correlación lineal negativa significativa entre el intervalo intergemelar y el pH umbilical. La prematuridad y el bajo peso al nacer fueron predictores de un mal desenlace neonatal. CONCLUSIONES: No parece recomendable que el intervalo intergemelar se prolongue más allá de los 30 minutos. Es seguro recomendar el parto vía vaginal en gestaciones gemelares siempre que el primero esté en presentación cefálica.

INTRODUCTION AND OBJECTIVES: Most scientific societies recommend vaginal delivery of the second twin when the first twin is in cephalic presentation. In these cases, there is controversy over how much inter-twin interval is decisive in the adverse outcome of the second twin. The aim of this study is to examine whether inter-twin delivery interval affects immediate perinatal outcome and the cost of neonatal and maternal stays. METHODS: Retrospective cohort study including 128 twin vaginal births attended in the Hospital Universitario Nuestra Señora de la Candelaria between May 2014 and December 2018. We compared the presence of composite adverse neonatal outcome by establishing interval cut-off points between birth of 10 and 30 minutes. Likewise, the relationship of other delivery associated variables with neonatal outcome was examined. Health care costs were calculated. RESULTS: There was a higher rate of composite adverse neonatal outcome in the 10 minute-group (p = 0.026, OR 2.4) and three times higher in the 30 minute-group (p = 0.013, OR 6.4). A significant negative linear correlation was obtained between birth interval and umbilical artery pH. Prematurity and low birth weight were predictors of a poor neonatal outcome. CONCLUSION: Our data suggests that inter-twin delivery interval shouldn't be prolonged beyond 30 minutes. Vaginal delivery is a safe option in twin gestations providing the first twin is in a cephalic presentation, regardless of the second twin presentation.

Introducing olive-oil tourism as a special interest tourism.

Olive-oil tourism is an emerging tourism typology that is especially developing in the Mediterranean basin, though successful cases also exist in other regions of the world. The main motivation underlying olive-oil tourism demand is the desire to learn about and enjoy the world of olives and olive oil. The objective of this article is to characterise this new tourism typology and identify its main activities. Based on a thorough bibliographical review and an expert panel, we show that this tourism typology corresponds to special interest tourism, and derives from three types of general interest tourism (rural, nature and cultural) with connections to other specific types of tourism. Furthermore, we demonstrate its links to an increasingly broad range of activities and services, thus revealing how complex this type of tourism can be, a feature proper to so-called special interest tourism.

High Flavonoid Cocoa Supplement Ameliorates Plasma Oxidative Stress and Inflammation Levels While Improving Mobility and Quality of Life in Older Subjects: A Double-Blind Randomized Clinical Trial.

BACKGROUND: The age-related decline in mass, strength, and performance of skeletal muscle is associated with loss of independence, falls risk, disability, institutionalization, and death. METHODS: To determine whether a cocoa supplement enriched in flavonoids can improve plasma markers of oxidative stress and inflammation, physical performance and frailty in middle-aged and older subjects, we conducted a two-phase, randomized, double-blind, clinical trial. The initial study included 60 subjects (55- to 70-year-old) allocated into placebo (P), highly alkalinized (no-flavonoid; NF), or flavonoid-rich natural cocoa (F) beverage groups. The follow-up study included 74 older subjects (65- to 90-year-old) randomly distributed into NF or F groups. Subjects were instructed to consume the beverages once/day for up to 12-weeks. A comprehensive (aging relevant) set of end points were assessed, which included mean change in blood plasma metabolic and oxidative stress indicators, in physical performance tests and quality of life (QoL). RESULTS: In the initial study, the F group showed improved glycemia, triglyceridemia, High-density lipoprotein cholesterol, Low-density lipoprotein cholesterol, triglyceridemia/HDL index, and oxidative markers. Performance on the Up and Go test, skeletal muscle index, and quality of life also improved. In the follow-up study, F treatment was associated with significant improvements in metabolic, oxidative stress, and inflammatory endpoints and positive effects on physical performance, frailty indicators, and quality of life (F vs. NF group). CONCLUSIONS: Regular flavonoids consumption positively affects blood oxidative stress and inflammation end points, cardiometabolic risk markers, physical performance, and quality of life. The sum of such effects may help to mitigate the extent of frailty development in the elderly people. TRIAL REGISTRATION: NCT03585868.

Hif-1α Deletion May Lead to Adverse Treatment Effect in a Mouse Model of MLL-AF9-Driven AML.

Relapse of acute myeloid leukemia (AML) remains a significant clinical challenge due to limited therapeutic options and poor prognosis. Leukemic stem cells (LSCs) are the cellular units responsible for relapse in AML, and strategies that target LSCs are thus critical. One proposed potential strategy to this end is to break the quiescent state of LSCs, thereby sensitizing LSCs to conventional cytostatics. The hypoxia-inducible factor (HIF) pathway is a main driver of cellular quiescence and a potential therapeutic target, with precedence from both solid cancers and leukemias. Here, we used a conditional knockout Hif-1α mouse model together with a standard chemotherapy regimen to evaluate LSC targeting in AML. Contrary to expectation, our studies revealed that Hif-1α-deleted-leukemias displayed a faster disease progression after chemotherapy. Our studies thereby challenge the general notion of cancer stem cell sensitization by inhibition of the HIF pathway, and warrant caution when applying HIF inhibition in combination with chemotherapy in AML.

Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor.

A gradual restriction in lineage potential of multipotent stem/progenitor cells is a hallmark of adult hematopoiesis, but the underlying molecular events governing these processes remain incompletely understood. Here, we identified robust expression of the leukemia-associated transcription factor hepatic leukemia factor (Hlf) in normal multipotent hematopoietic progenitors, which was rapidly downregulated upon differentiation. Interference with its normal downregulation revealed Hlf as a strong negative regulator of lymphoid development, while remaining compatible with myeloid fates. Reciprocally, we observed rapid lymphoid commitment upon reduced Hlf activity. The arising phenotypes resulted from Hlf binding to active enhancers of myeloid-competent cells, transcriptional induction of myeloid, and ablation of lymphoid gene programs, with Hlf induction of nuclear factor I C (Nfic) as a functionally relevant target gene. Thereby, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis.

Use of adenosine in the treatment of supraventricular tachycardia in a pediatric emergency department.

OBJECTIVE: Supraventricular tachycardia (SVT) is the most frequent arrhythmia requiring treatment in childhood, with an estimated incidence of 1/100 to 1/250 children. The treatment of choice of the acute event is intravenous adenosine. This study aimed to determine if doses of adenosine higher than previously described are needed to successfully revert SVT in children. METHODS: This is a retrospective study of SVT cases in a tertiary hospital from January 2007 to December 2011. RESULTS: A total of 44 episodes of SVT were recorded in 26 patients. Mean age was 3.1 years. In 39 patients (89%), adenosine was administered, reverting to stable sinus rhythm in 29 episodes, which represents an effectiveness of 75%. In relation to the number of doses administered, 12 patients (30%) received a single dose, with a mean (SD) response dose of 112 (35) µg/kg; 16 (41%) received 2 doses, with a mean (SD) response dose of 188 (55) µg/kg; and 9 (24%) received 3 doses, with a mean (SD) response dose of 249 (108) µg/kg. Finally, in 2 patients (4%), 4 doses of adenosine were administered, with only 1 of them responding to a dose of 300 µg/kg. The mean (SD) dose that reverted the SVT to normal sinus rhythm was 173 (84) µg/kg, and the mean (SD) number of doses administered was 1.7 (0.8) (range, 1-4). Sixty-six percent were discharged home, without the need to be transferred to pediatric intensive care unit or pediatric ward. CONCLUSIONS: Most of the patients with SVT episodes require treatment with more than 1 dose of adenosine. Doses higher than the usually described in the guidelines are necessary to revert SVT. Most patients can be discharged home from the emergency department, without the need of hospital admission.

Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest.

Polycomb group (PcG) proteins are key epigenetic regulators of hematopietic stem cell (HSC) fate. The PcG members Ezh2 and Ezh1 are important determinants of embryonic stem cell identity, and the transcript levels of these histone methyltransferases are inversely correlated during development. However, the role of Ezh1 in somatic stem cells is largely unknown. Here we show that Ezh1 maintains repopulating HSCs in a slow-cycling, undifferentiated state, protecting them from senescence. Ezh1 ablation induces significant loss of adult HSCs, with concomitant impairment of their self-renewal capacity due to a potent senescence response. Epigenomic and gene expression changes induced by Ezh1 deletion in senesced HSCs demonstrated that Ezh1-mediated PRC2 activity catalyzes monomethylation and dimethylation of H3K27. Deletion of Cdkn2a on the Ezh1 null background rescued HSC proliferation and survival. Our results suggest that Ezh1 is an important histone methyltransferase for HSC maintenance.

Políticas de Salud de Nicaragua dirigidas a las (os) adolescentes

El propósito de este documento es realizar un análisis sobre el desarrollo de las políticas de salud dirigidas a las (os) adolescentes en Nicaragua, conocer la situación actual, perspectivas, fortalezas y debilidades que enfrenta el programa de Atención Integral a la Adolescencia. Este análisis permitirá identificar cuales son los problemas de los adolescentes, además plantear recomendaciones para mejorar el programa de Atención Integral al Adolescente y por consiguiente mejorar la calidad de atención de servicios dirigidos a ellos