Infrequent Presentations of Chronic NPM1-Mutated Myeloid Neoplasms: Clinicopathological Features of Eight Cases from a Single Institution and Review of the Literature.

Non-acute myeloid neoplasms (MNs) with NPM1 mutations (NPM1mut-MNs) pose a diagnostic and therapeutic dilemma, primarily manifesting as chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS). The classification and treatment approach for these conditions as acute myeloid leukemia (AML) are debated. We describe eight cases of atypical NPM1mut-MNs from our institution and review the literature. We include a rare case of concurrent prostate carcinoma and MN consistent with chronic eosinophilic leukemia, progressing to myeloid sarcoma of the skin. Of the remaining seven cases, five were CMML and two were MDS. NPM1 mutations occur in 3-5% of CMML and 1-6% of MDS, with an increased likelihood of rapid evolution to AML. Their influence on disease progression varies, and their prognostic significance in non-acute MNs is less established than in AML. Non-acute MNs with NPM1 mutations may display an aggressive clinical course, emphasizing the need for a comprehensive diagnosis integrating clinical and biological data. Tailoring patient management on an individualized basis, favoring intensive treatment aligned with AML protocols, is crucial, regardless of blast percentage. Research on the impact of NPM1 mutations in non-acute myeloid neoplasms is ongoing, requiring challenging prospective studies with substantial patient cohorts and extended follow-up periods for validation.

Survival Outcomes and Health-Related Quality of Life in Older Adults Diagnosed with Acute Myeloid Leukemia Receiving Frontline Therapy in Daily Practice.

Acute myeloid leukemia has a poor prognosis in older adults, and its management is often unclear due to its underrepresentation in clinical trials. Both overall survival (OS) and health-related quality-of-life (HRQoL) are key outcomes in this population, and patient-reported outcomes may contribute to patient stratification and treatment assignment. This prospective study included 138 consecutive patients treated in daily practice with the currently available non-targeted therapies (intensive chemotherapy [IC], attenuated chemotherapy [AC], hypomethylating agents [HMA], or palliative care [PC]). We evaluated patients' condition at diagnosis (Life expectancy [Lee Index for Older Adults], Geriatric Assessment in Hematology [GAH scale], HRQoL [EQ-5D-5L questionnaire], and fatigue [fatigue items of the QLQ-C30 scale]), OS, early death (ED), treatment tolerability (TT) and change in HRQoL over 12 months follow-up. The median OS was 7.1 months (IC not reached, AC 5.9, HMA 8.8, and PC 1.0). Poor risk AML category and receiving just palliative care, as well as a higher Lee index score in the patients receiving active therapy, independently predicted a shorter OS. The Lee Index and GAH scale were not useful for predicting TT. The white blood cell count was a valid predictor for ED. Patients' HRQoL remained stable during follow-up.

Association of periodontitis with cognitive decline and its progression: Contribution of blood-based biomarkers of Alzheimer's disease to this relationship.

AIM: To assess whether periodontitis is associated with cognitive decline and its progression as well as with certain blood-based markers of Alzheimer's disease. MATERIALS AND METHODS: Data from a 2-year follow-up prospective cohort study (n = 101) was analysed. Participants with a previous history of hypertension and aged ≥60 years were included in the analysis. All of them received a full-mouth periodontal examination and cognitive function assessments (Addenbrooke's Cognitive Examination (ACE) and Mini-Mental State Examination [MMSE]). Plasma levels of amyloid beta (Aß)1-40 , Aß1-42 , phosphorylated and total Tau (p-Tau and t-Tau) were determined at baseline, 12 and 24 months. RESULTS: Periodontitis was associated with poor cognitive performance (MMSE: ß = -1.5 [0.6]) and progression of cognitive impairment (hazard ratio [HR] = 1.8; 95% confidence interval: 1.0-3.1). Subjects with periodontitis showed greater baseline levels of p-Tau (1.6 [0.7] vs. 1.2 [0.2] pg/mL, p < .001) and Aß1-40 (242.1 [77.3] vs. 208.2 [73.8] pg/mL, p = .036) compared with those without periodontitis. Concentrations of the latter protein also increased over time only in the periodontitis group (p = .005). CONCLUSIONS: Periodontitis is associated with cognitive decline and its progression in elderly patients with a previous history of hypertension. Overexpression of p-Tau and Aß1-40 may play a role in this association.

Periodontal inflammation is associated with increased circulating levels of endothelial progenitor cells: a retrospective cohort study in a high vascular risk population.

Background: One of the main biological mechanisms behind the link between periodontitis and atherosclerotic vascular diseases is vascular endothelial dysfunction. Particularly, circulating endothelial progenitor cells (EPCs) have been considered a biomarker of altered vascular endothelial function. Objectives: The aim of this study was to investigate relationship between periodontal inflammation and increased number of circulating EPCs. Design: This is retrospective cohort study. Methods: In this study, 85 elderly patients with a previous history of hypertension were followed up to 12 months. A baseline full-mouth periodontal assessment was carried out, and the amount of periodontal tissue inflamed per subject was calculated as a proxy of periodontal inflammation [periodontal inflamed surface area (PISA)]. The number of circulating EPCs (CD34+/CD133+/KDR+) was determined by flow cytometry from peripheral blood samples collected at baseline and 12 months. Results: Mean concentrations of CD34+/CD133+/KDR+ progenitor cells were higher in periodontitis patients than in those without periodontitis at baseline [55.4, 95% confidence interval (CI) = 20.8 to 90.0 versus 27.2, 95% CI = 13.6 to 40.8, p = 0.008] and 12 months (114.6, 95% CI = 53.5 to 175.7 versus 19.1, 95% CI = 10.8 to 27.4, p = 0.003). A significant increase over the follow-up was noticed in the group of subjects with periodontitis (p = 0.049) but not in the nonperiodontitis group (p = 0.819). PISA was independently associated with CD34+/CD133+/KDR+ EPCs at baseline (B coefficient = 0.031, 95% CI = 0.005 to 0.058; p = 0.021). The relationship between PISA and CD34+/CD133+/KDR+ EPCs at 12 months was confounded by increased baseline body mass index (B coefficient = 0.064, 95% CI = -0.005 to 0.132; p = 0.066). Conclusion: Periodontal inflammation is associated with high number of CD34+/CD133+/KDR+ EPCs, thus supporting a potential link between periodontitis and endothelial dysfunction.

Biomarkers Assessing Endothelial Dysfunction in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common degenerative disorder in the elderly in developed countries. Currently, growing evidence is pointing at endothelial dysfunction as a key player in the cognitive decline course of AD. As a main component of the blood-brain barrier (BBB), the dysfunction of endothelial cells driven by vascular risk factors associated with AD allows the passage of toxic substances to the cerebral parenchyma, producing chronic hypoperfusion that eventually causes an inflammatory and neurotoxic response. In this process, the levels of several biomarkers are disrupted, such as an increase in adhesion molecules that allow the passage of leukocytes to the cerebral parenchyma, increasing the permeability of the BBB; moreover, other vascular players, including endothelin-1, also mediate artery inflammation. As a consequence of the disruption of the BBB, a progressive neuroinflammatory response is produced that, added to the astrogliosis, eventually triggers neuronal degeneration (possibly responsible for cognitive deterioration). Recently, new molecules have been proposed as early biomarkers for endothelial dysfunction that can constitute new therapeutic targets as well as early diagnostic and prognostic markers for AD.

Effectiveness and Safety of Balloon Pulmonary Angioplasty for the Treatment of Patients with Persistent Pulmonary Hypertension after Pulmonary Endarterectomy.

(1) Background: Pulmonary endarterectomy (PEA) is the "gold standard" treatment for operable patients with chronic thromboembolic pulmonary hypertension (CTEPH). Persistent pulmonary hypertension (PH) after PEA confers a worse prognosis. Balloon pulmonary angioplasty (BPA) could represent a useful therapy in this setting, but evidence about its effectiveness and safety in patients with previous PEA is limited. (2) Methods: A total of 14 patients with persistent PH after PEA were treated with BPA in a single PH center. Hemodynamic and clinical effects of BPA and complications of the procedure were retrospectively collected. (3) Results: After BPA, the mean pulmonary arterial pressure fell from 50.7 ± 15.3 mmHg to 38.0 ± 7.9 mmHg (25.0% decrease; 95% confidence interval (CI) 14.0-35.5%; p = 0.01). Pulmonary vascular resistances were reduced from 8.5 ± 3.6 WU to 5.3 ± 2.2 WU (37.6% decrease; 95% CI 18.8-56.5%; p = 0.01). WHO functional class was also improved with BPA. Severe BPA-related complications were infrequent and no periprocedural deaths were observed. (4) Conclusions: BPA is an effective and safe therapy for patients with CTEPH and persistent PH after PEA.

Usefulness of genetics for clinical reclassification and refinement of prognostic stratification in pulmonary arterial hypertension.

INTRODUCTION AND OBJECTIVES: Risk stratification in pulmonary arterial hypertension (PAH) is essential to provide more aggressive treatment for patients at higher risk. Nevertheless, recently introduced simplified prognostic tools neglect the genetic background. Additionally, pulmonary veno-oclusive disease (PVOD) has never been considered in risk assessment strategies. METHODS: We analyzed consecutive patients in the Spanish registry of PAH (REHAP) genetically tested, between 2011 and 2022. We applied the 4-strata COMPERA 2.0 model, comparing these results with an amplified score including genetics. Cox regression models were compared using Harrel c-statistics. The application of the model was specifically tested in PVOD before inclusion. RESULTS: We identified 298 patients tested genetically among the group of idiopathic, familial, drug-induced PAH and PVOD patients in the REHAP registry. When we analyzed only patients with all available variables of interest at baseline (World Health Organization functional class, 6-minute walk test, B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide) and included in the 4-strata model (n=142), after a median follow-up of 58.2 months, 17.6% of patients died and 11.3% underwent lung transplant. The application of the 4-strata model in our population demonstrated a good prognostic capacity (Harrel c of 0.689), which was not improved by the introduction of genetics (c-index 0.690). This last model showed a tendency for a better identification of patients at intermediate-low and intermediate-high risk, and no differences between intermediate-high and high-risk strata. CONCLUSIONS: In this work, the addition of genetics to the COMPERA 4-strata model achieved a similar global prognostic capacity but changed the identification of different risk strata in a cohort of young genetically tested patients.

Association between periodontitis and peripheral markers of innate immunity activation and inflammation.

BACKGROUND: Immune response leading to increased systemic inflammation is one of the mechanisms linking periodontitis to chronic inflammatory diseases. The aim of this study was to compare the expression of toll-like receptors 2 and 4 in monocytes and neutrophils (TLR2M, TLR2N, TLR4M, and TLR4N) and its endogenous ligands (cellular fibronectin [cFN] and heat shock protein 60 [HSP60]) in patients with and without periodontitis. Additionally, the relationship between cFN and HSP60 expression with innate immunity activation and systemic inflammatory response (interleukin 6 [IL-6]) was also evaluated. METHODS: A case-controlled study was designed in which 30 patients with periodontitis (cases) and 30 age- and sex-matched participants without periodontitis (controls) were included. Fasting blood samples were collected to determine: (1) expression of TLR2N, TLR2M, TLR4N, and TLR4M by flow cytometry; and (2) serum concentrations of cFN, HSP60, and IL-6 by ELISA technique. RESULTS: Expression of TLR2M (411.5 [314.2, 460.0] vs. 236.5 [204.0, 333.0] AFU), TLR2N (387.0 [332.0, 545.5] vs 230.0 [166.2, 277.7] AFU), TLR4M (2478.5 [1762.2, 2828.0] vs 1705.0 [1274.5, 1951.2] AFU), and TLR4N (2791.0 [2306.7, 3226.2] vs. 1866.0 [1547.5, 2687.2] AFU) as well as serum levels of cFN (301.1 [222.2, 410.9] vs. 156.4 [115.3, 194.0] ng/ml) and IL-6 (10.4 [6.5, 11.5] vs. 3.5 [2.6, 4.9] pg/ml) were significantly higher in periodontitis patients than those without periodontitis. A positive association was found between periodontitis and cFN (odds ratio [OR] = 1.028, p < 0.001), TLR2N (OR = 1.026, p < 0.001), TLR4M (OR = 1.001, p = 0.002), and IL-6 (OR = 1.774, p < 0.001). CONCLUSIONS: Periodontitis patients exhibited high expression of TLRs, cFN, and IL-6.

The Differences by Sex and Gender in the Relationship Between Urban Greenness and Cardiometabolic Health: A Systematic Review.

In an increasingly urbanized world, where cardiometabolic issues in cities have raised public health concerns, urban greenness is known to be beneficial for some of the most common health issues. However, the examination of the contribution of sex and gender regarding the benefits of urban greenness for people's cardiometabolic health is lacking. For that reason, we conducted a systematic review of previous literature on the topic following the PRISMA methodology. Additionally, we assessed the quality of the included articles, which we found satisfactory as most papers were of very good or good quality. We explored the relationship between urban greenness exposure and cardiovascular risk factors, cardiovascular diseases, and mortality from cardiovascular diseases. Results suggest that urban greenness is protective against cardiovascular risk factors, diseases, and mortality. When stratifying results by sex and gender, findings point to urban greenness being more beneficial for women and females in stroke and cardiovascular risk factors, except for hypertension and lipid accumulation product. On the other hand, males were more protected by urban greenness in terms of cardiovascular diseases and CVD-related mortality, thus proving that sex and gender health inequalities exist. Furthermore, looking towards the future, research needs to use the proper terminology for sex and gender and policy makers should design urban greenness with a gender perspective.

Unraveling the potential of endothelial progenitor cells as a treatment following ischemic stroke.

Ischemic stroke is becoming one of the most common causes of death and disability in developed countries. Since current therapeutic options are quite limited, focused on acute reperfusion therapies that are hampered by a very narrow therapeutic time window, it is essential to discover novel treatments that not only stop the progression of the ischemic cascade during the acute phase, but also improve the recovery of stroke patients during the sub-acute or chronic phase. In this regard, several studies have shown that endothelial progenitor cells (EPCs) can repair damaged vessels as well as generate new ones following cerebrovascular damage. EPCs are circulating cells with characteristics of both endothelial cells and adult stem cells presenting the ability to differentiate into mature endothelial cells and self-renew, respectively. Moreover, EPCs have the advantage of being already present in healthy conditions as circulating cells that participate in the maintenance of the endothelium in a direct and paracrine way. In this scenario, EPCs appear as a promising target to tackle stroke by self-promoting re-endothelization, angiogenesis and vasculogenesis. Based on clinical data showing a better neurological and functional outcome in ischemic stroke patients with higher levels of circulating EPCs, novel and promising therapeutic approaches would be pharmacological treatment promoting EPCs-generation as well as EPCs-based therapies. Here, we will review the latest advances in preclinical as well as clinical research on EPCs application following stroke, not only as a single treatment but also in combination with new therapeutic approaches.

Guía para la vivienda adecuada en la respuesta a refugiados y migrantes de venezuela en Latino América y el Caribe / Guide for adequate housing in the response to refugees and migrants from Venezuela in Latin America and the Caribbean

Desde el Sector de Alojamiento bajo la Plataforma de Coordinación Interagencial para Refugiados y Migrantes de Venezuela (R4V), en coordinación con otros sectores regionales y organizaciones humanitarias en la región, entendemos el acceso a la vivienda adecuada como algo más que la provisión de un techo y cuatro paredes en momentos de crisis, sino como la oportunidad de reconstruir la palabra "hogar" a través del ejercicio del derecho a vivir con dignidad, protección y seguridad en un entorno saludable que permita a las personas reconstruir lo cotidiano y reactivar sus actividades económicas y sociales; compartiendo así las definiciones de "Vivienda Adecuada" de ONU-Derechos Humanos (ADNUDH) y ONU-Hábitat 1 o las recogidas en el Manual Esfera de 2018 2 . Aquellas poblaciones en situación de movilidad, como son refugiados y migrantes, se encuentran en una situación de mayor vulnerabilidad al dejar sus hogares atrás y ante la violación de sus derechos humanos fundamentales, en particular, el de acceso a la vivienda, exacerbado por situaciones de discriminación, racismo y/o xenofobia; que impiden lograr unas condiciones de vida adecuadas y sostenibles. La vivienda adecuada no provee exclusivamente protección dentro del espacio construido, sino que es un medio para acceder a un mejor nivel de vida. En particular, y dado que en la actualidad las situaciones de desplazamiento tienen una duración mayor que en periodos anteriores, llegando incluso a durar décadas, la ausencia de una vivienda adecuada acrecienta los niveles de pobreza, aumentando la brecha de desigualdad para lograr la integración socioeconómica de las personas refugiadas y migrantes a través del acceso a un trabajo digno, y, en consecuencia, a tener una sensación de seguridad física y económica y a la lograr un sentimiento de comunidad y cohesión social.

Ceramide/Sphingosine 1-Phosphate Axis as a Key Target for Diagnosis and Treatment in Alzheimer's Disease and Other Neurodegenerative Diseases.

Alzheimer's disease (AD) is considered the most prevalent neurodegenerative disease and the leading cause of dementia worldwide. Sphingolipids, such as ceramide or sphingosine 1-phosphate, are bioactive molecules implicated in structural and signaling functions. Metabolic dysfunction in the highly conserved pathways to produce sphingolipids may lead to or be a consequence of an underlying disease. Recent studies on transcriptomics and sphingolipidomics have observed alterations in sphingolipid metabolism of both enzymes and metabolites involved in their synthesis in several neurodegenerative diseases, including AD. In this review, we highlight the most relevant findings related to ceramide and neurodegeneration, with a special focus on AD.

Involvement of Ceramide Metabolism in Cerebral Ischemia.

Ischemic stroke, caused by the interruption of blood flow to the brain and subsequent neuronal death, represents one of the main causes of disability in worldwide. Although reperfusion therapies have shown efficacy in a limited number of patients with acute ischemic stroke, neuroprotective drugs and recovery strategies have been widely assessed, but none of them have been successful in clinical practice. Therefore, the search for new therapeutic approaches is still necessary. Sphingolipids consist of a family of lipidic molecules with both structural and cell signaling functions. Regulation of sphingolipid metabolism is crucial for cell fate and homeostasis in the body. Different works have emphasized the implication of its metabolism in different pathologies, such as diabetes, cancer, neurodegeneration, or atherosclerosis. Other studies have shown its implication in the risk of suffering a stroke and its progression. This review will highlight the implications of sphingolipid metabolism enzymes in acute ischemic stroke.

Stress Granules and Acute Ischemic Stroke: Beyond mRNA Translation.

Ischemic stroke is a leading cause of death and disability worldwide. Following an ischemic insult, cells undergo endoplasmic reticulum (ER) stress, which increases the ER's protein-folding and degradative capacities and blocks the global synthesis of proteins by phosphorylating the eukaryotic translation initiation factor 2-alpha (eIF2α). Phosphorylation of eIF2α is directly related to the dynamics of stress granules (SGs), which are membraneless organelles composed of RNA-binding proteins and mRNA. SGs play a critical role in mRNA metabolism and translational control. Other translation factors are also linked to cellular pathways, including SG dynamics following a stroke. Because the formation of SGs is closely connected to mRNA translation, it is interesting to study the relationship between SG dynamics and cellular outcome in cases of ischemic damage. Therefore, in this review, we focus on the role of SG dynamics during cerebral ischemia.

Predator Group Composition Indirectly Influences Food Web Dynamics through Predator Growth Rates.

AbstractConsiderable theoretical work predicts that intraspecific trait variation can have profound ecological consequences by altering species interactions. Because of their high flexibility, behavioral traits may be especially relevant in mediating how species respond to one another, thus affecting food web dynamics and ecosystem functioning. However, empirical evidence supporting this idea is limited. Here, we generated predator groups where we manipulated the composition of behavioral types within the groups to assess effects on predator growth rates, prey communities, basal resources, and ecosystem functioning in replicated outdoor ponds. Using European perch (Perca fluviatilis), we created three types of predator populations: two where all individuals expressed either bold or shy phenotypes and one that contained a mix of individuals of the two behavioral types. Bold perch grew faster in mixed populations, indicating that predator growth depends on each individual's behavioral type and that of its group members. However, there was no evidence that the behavioral composition of the perch population directly altered the dynamics of lower trophic levels. Instead, final perch biomass, not behavioral composition, had the strongest influence on lower trophic levels. Thus, the central question may not be whether predator behavior matters at all for trophic dynamics but rather when behavioral effects will predominate over effects of other influences, such as predator biomass variation.

Ceramide Metabolism Enzymes-Therapeutic Targets against Cancer.

Sphingolipids are both structural molecules that are essential for cell architecture and second messengers that are involved in numerous cell functions. Ceramide is the central hub of sphingolipid metabolism. In addition to being the precursor of complex sphingolipids, ceramides induce cell cycle arrest and promote cell death and inflammation. At least some of the enzymes involved in the regulation of sphingolipid metabolism are altered in carcinogenesis, and some are targets for anticancer drugs. A number of scientific reports have shown how alterations in sphingolipid pools can affect cell proliferation, survival and migration. Determination of sphingolipid levels and the regulation of the enzymes that are implicated in their metabolism is a key factor for developing novel therapeutic strategies or improving conventional therapies. The present review highlights the importance of bioactive sphingolipids and their regulatory enzymes as targets for therapeutic interventions with especial emphasis in carcinogenesis and cancer dissemination.

Ceramide Metabolism and Parkinson's Disease-Therapeutic Targets.

Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or be a consequence of an underlying disease. Recent reports on transcriptomics and electrospray ionization mass spectrometry analysis have demonstrated the variation of specific levels of sphingolipids and enzymes involved in their metabolism in different neurodegenerative diseases. In the present review, we highlight the most relevant discoveries related to ceramide and neurodegeneration, with a special focus on Parkinson's disease.

Radiological Findings in Multidetector Computed Tomography (MDCT) of Hereditary and Sporadic Pulmonary Veno-Occlusive Disease: Certainties and Uncertainties.

Pulmonary veno-occlusive disease (PVOD) is a very infrequent form of pulmonary arterial hypertension with an aggressive clinical course, poor response to specific vasodilator treatment, and low survival. Confirming a definitive diagnosis is essential to guide treatment and assess lung transplantation. However, in the absence of histological or genetic confirmation, the diagnosis is complex, requiring a clinical suspicion. Multidetector computed tomography (MDCT) is an essential part of the non-invasive diagnostic tools of PVOD. We retrospectively reviewed the MDCT findings from a consecutive series of 25 patients diagnosed with PVOD, 9 with the sporadic form and 16 with the hereditary form of the disease. The presence and extent of typical findings of the diagnostic triad were assessed in all patients (ground glass parenchymal involvement, septal lines, and lymphadenopathy). In our series, 92% of patients showed at least two of the radiological findings described as typical of the disease. All patients presented at least one typical radiological characteristic. The incidence of radiological findings considered typical is very high, however was not associated with greater hemodynamic severity nor to the development of acute lung edema. No significant differences were found between the two groups. A poorly expressive MDCT does not exclude the disease.

Feasibility of a Noninvasive Operability Assessment in Chronic Thromboembolic Pulmonary Hypertension under Real-World Practice.

This study aimed to evaluate the feasibility of a noninvasive operability assessment of chronic thromboembolic pulmonary hypertension (CTEPH) based on multidetector computed tomographic angiography (MCTA). Up to 176 patients were evaluated from January 2016 to April 2018. Throughout the first phase, the initial surgical decision was made based on MCTA with further analysis of pulmonary angiography (PA) in order to evaluate in which cases the initial decision was not modified by PA. During the second phase, PA was limited to patients judged inoperable based on MCTA or those whose assessment was not possible. Patients deemed operable (50%) based on MCTA along the first phase had been adequately classified, as PA did not modify the initial decision in all but one patient. Comparable results were obtained throughout the implementation phase. Regarding operated patients, the decision of operability was based solely on MCTA in 94% of those with level I disease, in 75% with level II, and 54% with level III. This approach enabled shorter periods of time to complete surgical assessment and the avoidance of PA-related morbidity. Baseline parameters, postoperative measures, and survival rates at 1 year after surgery were comparable in both phases. Noninvasive operability assessment is feasible in a subset of CTEPH patients and optimizes surgical candidacy evaluation.