Calidad de vida en adultos mayores con trastorno neurocognitivo mayor moderado a grave institucionalizados: efecto de la Doll Therapy / Quality of life in institutionalized older adults with moderate to severe major neurocognitive disorder: Effect of Doll therapy

Antecedentes y objetivos El trastorno neurocognitivo mayor se caracteriza por el deterioro cognitivo progresivo, la disminución de la capacidad de la persona para realizar actividades de la vida diaria y la aparición de síntomas psicológicos y conductuales, que suponen un deterioro de la calidad de vida y la progresión hacia la institucionalización. El manejo más frecuente del trastorno neurocognitivo mayor es la terapia farmacológica, que mitiga o lentifica el deterioro progresivo y el control de los síntomas. El objetivo de este estudio fue establecer el efecto de una intervención de enfermería basada en la Doll Therapy comparada con el cuidado convencional sobre la calidad de vida de los adultos mayores con trastorno neurocognitivo mayor moderado a grave, institucionalizados en centros de bienestar para adultos mayores de la ciudad de Medellín (Colombia). Método Estudio piloto experimental pretest post-test con dos grupos. La muestra estuvo conformada por 26 adultos mayores con trastorno neurocognitivo mayor moderado a grave, institucionalizados, asignados aleatoriamente a cada grupo. El grupo experimental recibió la terapia de enfermería basada en la Doll Therapy, mientras que el grupo control continuó recibiendo el protocolo de la institución. Se utilizó el instrumento QUALID, el cual fue evaluado por profesionales externos a los centros de atención. Resultados La comparación de los grupos, antes y después de la intervención, señala que el grupo experimental mostró un efecto positivo sobre la calidad de vida, apoyado en la significación estadística de los datos, con un tamaño del efecto moderado. Conclusiones La Doll Therapy, como una terapia no farmacológica, tiene un efecto positivo en la calidad de vida de los pacientes con trastorno neurocognitivo mayor moderado a grave, lo cual constituye un aporte para fortalecer el conocimiento asociado a los efectos de esta intervención (AU)

Background and objectives Major neurocognitive disorder is characterized by progressive cognitive impairment, a decrease in the person's ability to perform activities of daily living and the appearance of psychological and behavioral symptoms that lead to a deterioration in the quality of life and progression towards institutionalization. The most common management of major neurocognitive disorder is pharmacological therapy that mitigates or slow progressive deterioration and symptom control. The objective of this study was to establish the effect of a nursing intervention based on Doll therapy, compared to conventional care on the quality of life of older adults with moderate to severe major neurocognitive disorder institutionalized in nursing homes in the city of Medellín, Colombia. Methods Pilot experimental study with two groups and pretest post-test measurement. The sample consisted of 26 institutionalized elderly adults with advanced-stage major neurocognitive disorder, randomly assigned to each group. The experimental group received Doll therapy, based nursing therapy, while the comparison group continued to receive conventional therapy according to the institution's protocol. The QUALID instrument was used, which was evaluated by professionals external to the care centers. Results The comparison of the groups, before and after the intervention, indicates that the experimental group showed a positive effect on quality of life, supported by the statistical significance of the data, with a moderate effect. Conclusions The Doll therapy as a non-pharmacological therapy has a positive effect on the quality of life of patients with moderate to severe major neurocognitive disorder, which constitutes a contribution to strengthen the knowledge associated with the effects or this intervention (AU)

[Quality of life in institutionalized older adults with moderate to severe major neurocognitive disorder: Effect of Doll therapy]. / Calidad de vida en adultos mayores con trastorno neurocognitivo mayor moderado a grave institucionalizados: efecto de la Doll Therapy.

BACKGROUND AND OBJECTIVES: Major neurocognitive disorder is characterized by progressive cognitive impairment, a decrease in the person's ability to perform activities of daily living and the appearance of psychological and behavioral symptoms that lead to a deterioration in the quality of life and progression towards institutionalization. The most common management of major neurocognitive disorder is pharmacological therapy that mitigates or slow progressive deterioration and symptom control. The objective of this study was to establish the effect of a nursing intervention based on Doll therapy, compared to conventional care on the quality of life of older adults with moderate to severe major neurocognitive disorder institutionalized in nursing homes in the city of Medellín, Colombia. METHODS: Pilot experimental study with two groups and pretest post-test measurement. The sample consisted of 26 institutionalized elderly adults with advanced-stage major neurocognitive disorder, randomly assigned to each group. The experimental group received Doll therapy, based nursing therapy, while the comparison group continued to receive conventional therapy according to the institution's protocol. The QUALID instrument was used, which was evaluated by professionals external to the care centers. RESULTS: The comparison of the groups, before and after the intervention, indicates that the experimental group showed a positive effect on quality of life, supported by the statistical significance of the data, with a moderate effect. CONCLUSIONS: The Doll therapy as a non-pharmacological therapy has a positive effect on the quality of life of patients with moderate to severe major neurocognitive disorder, which constitutes a contribution to strengthen the knowledge associated with the effects or this intervention.

Nutritional Care for Institutionalized Persons with Dementia: An Integrative Review.

BACKGROUND: Older people are at risk of malnutrition, especially when they suffer from cognitive impairment. Guidelines that orient nursing care in this regard need to be updated. The aim of this review is to address the best available evidence on interventions that can benefit nutritional nursing care for institutionalized older adults with dementia. METHODS: Integrative review using the Dimensions and Eureka search engines, and the PubMed, Embase, Scielo, CINAHL, and ScienceDirect databases. We searched from the year 2015 through to 2021. We employed the MMAT guidelines for mixed, qualitative, and quantitative studies, and the PRISMA, CASP, and JBI guidelines to value the reviews. RESULTS: A total of 55 studies met the inclusion criteria. The best available evidence to support nutritional nursing care for institutionalized older adults with dementia highlights several aspects related to the assessment and caring interventions that are focused on people with dementia, their caregivers, and their context. CONCLUSIONS: Both the assessment and nutritional care interventions for older people with dementia should consider the patient-caregiver dyad as the subject of care and understand the context as a fundamental part of it. The analysis of the context should look further than the immediate environment.

Automanejo de la diabetes en personas socioeconómicamente vulnerables: estudio de factibilidad / Diabetes self-management in socioeconomically vulnerable people: A feasibility study

Introducción: La diabetes mellitus tipo 2 es una de las principales causas de morbimortalidad en el mundo, su prevalencia es aún mayor en países de medianos y bajos ingresos. El automanejo es una estrategia que ha demostrado controlar las enfermedades crónicas. Objetivo: Determinar la factibilidad y eficacia preliminar de la intervención educativa AMAS + Vida enfocada en el automanejo de la salud dirigida a personas adultas con diabetes tipo 2 en una Institución de salud de primer nivel en Neiva, Colombia. Materiales y Métodos: Estudio de factibilidad, pre test ­ post test con un solo grupo, para establecer la eficacia preliminar de la intervención. Muestra intencional de 36 adultos con diabetes tipo 2. Los instrumentos empleados fueron ficha de caracterización y escala Partners in Health para medir automanejo. Resultados: 31 adultos con diabetes completaron el seguimiento de 3 meses, mayoría eran mujeres, con bajo nivel socioeconómico y educativo, hubo buena factibilidad de la intervención. Los participantes mejoraron significativamente los conocimientos de la enfermedad (p < 0,001); además hábitos alimenticios (p = 0,001), comportamientos de automanejo de la salud (p < 0,001) y disminución del índice de masa corporal (p = 0,01). No hubo cambios significativos en la actividad física (p = 0,125). Discusión: Las intervenciones basadas en el automanejo estructuradas bajo la teoría de adaptación a las enfermedades crónicas logran cambios en la promoción de la salud en personas con diabetes. Conclusiones: La intervención tuvo eficacia preliminar en el grupo estudiado con buena factibilidad. Se recomienda continuar desarrollando estudios de tipo experimental.

Introduction: Type 2 diabetes mellitus is a leading cause of morbidity and mortality worldwide, and its prevalence is even higher in middle- and low-income countries. Self-management is a strategy that has been shown to control chronic diseases. Objective: To determine the feasibility and preliminary efficacy of the AMAS + Vida educational intervention focused on health self-management in adults with type 2 diabetes in a primary health care facility in Neiva, Colombia. Materials and Methods: Feasibility study using a one-group pretest-posttest design to determine the preliminary efficacy of the intervention. Purposive sample of 36 adults with type 2 diabetes. The instruments used were a characterization form and the Partners in Health scale to measure self-management. Results: Thirty-one adults with diabetes completed the 3-month follow-up, most of whom were women with low socioeconomic and educational levels. The feasibility of the intervention was good. Participants significantly improved disease knowledge (p < 0.001), eating habits (p = 0.001), health self-management behaviors (p < 0.001), and decreased body mass index (p = 0.01). There were no significant changes in physical activity (p = 0.125). Discussion: Self-management-based interventions, structured according to the theory of adaptation to chronic illness, achieve health-promoting changes in people with diabetes. Conclusions: The intervention showed preliminary efficacy in the study group with good feasibility. Further experimental studies are recommended.

Introdução: O diabetes mellitus tipo 2 é uma das principais causas de morbidade e mortalidade no mundo; sua prevalência é ainda maior em países de baixa e média renda. A autogestão é uma estratégia que comprovadamente controla doenças crônicas. Objetivo: Determinar a viabilidade e eficácia preliminar da intervenção educativa AMAS + Vida focada na autogestão da saúde dirigida a adultos com diabetes tipo 2 em uma instituição de saúde de primeiro nível em Neiva, Colômbia. Materiais e Métodos: Estudo de viabilidade, pré-teste ­ pós-teste com grupo único, para estabelecer a eficácia preliminar da intervenção. Amostra intencional de 36 adultos com diabetes tipo 2. Os instrumentos utilizados foram uma ficha de caracterização e a escala Partners in Health para medir a autogestão. Resultados: 31 adultos com diabetes completaram o acompanhamento de 3 meses, a maioria eram mulheres, com baixo nível socioeconômico e educacional, houve boa viabilidade da intervenção. Os participantes melhoraram significativamente o conhecimento sobre a doença (p < 0,001); também hábitos alimentares (p = 0,001), comportamentos de autogestão da saúde (p < 0,001) e diminuição do índice de massa corporal (p = 0,01). Não houve alterações significativas na atividade física (p = 0,125). Discussão: Intervenções baseadas na autogestão estruturadas sob a teoria da adaptação às doenças crônicas alcançam mudanças na promoção da saúde das pessoas com diabetes. Conclusões: A intervenção teve eficácia preliminar no grupo estudado com boa viabilidade. Recomenda-se continuar desenvolvendo estudos experimentais.

First-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors.

BACKGROUND: NEO201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens from patients with colorectal cancer. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells. Here, we present outcomes from a phase I trial of NEO-201 in patients with advanced solid tumors that have not responded to standard treatments. METHODS: This was a single site, open label 3 + 3 dose escalation clinical trial. NEO-201 was administered intravenously every two weeks in a 28-day cycle at dose level (DL) 1 (1 mg/kg), DL 1.5 (1.5 mg/kg) and DL 2 (2 mg/kg) until dose limiting toxicity (DLT), disease progression, or patient withdrawal. Disease evaluations were conducted after every 2 cycles. The primary objective was to assess the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of NEO-201. The secondary objective was to assess the antitumor activity by RECIST v1.1. The exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and their impact on clinical response. RESULTS: Seventeen patients (11 colorectal, 4 pancreatic and 2 breast cancers) were enrolled; 2 patients withdrew after the first dose and were not evaluable for DLT. Twelve of the 15 patients evaluable for safety discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia [1 patient] and prolonged neutropenia [1 patient] at DL 2, and grade 3 prolonged (> 72 h) febrile neutropenia [1 patient] at DL 1.5). A total of 69 doses of NEO-201 were administered (range 1-15, median 4). Common (> 10%) grade 3/4 toxicities occurred as follows: neutropenia (26/69 doses, 17/17 patients), white blood cell decrease (16/69 doses, 12/17 patients), lymphocyte decrease (8/69 doses, 6/17 patients). Thirteen patients were evaluable for disease response; the best response was stable disease (SD) in 4 patients with colorectal cancer. Analysis of soluble factors in serum revealed that a high level of soluble MICA at baseline was correlated with a downregulation of NK cell activation markers and progressive disease. Unexpectedly, flow cytometry showed that NEO-201 also binds to circulating regulatory T cells and reduction of the quantities of these cells was observed especially in patients with SD. CONCLUSIONS: NEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg, with neutropenia being the most common adverse event. Furthermore, a reduction in the percentage of regulatory T cells following NEO-201 treatment supports our ongoing phase II clinical trial evaluating the efficiency of the combination of NEO-201 with the immune checkpoint inhibitor pembrolizumab in adults with treatment-resistant solid tumors. TRIAL REGISTRATION: NCT03476681 . Registered 03/26/2018.

SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling.

The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity. Accordingly, we performed a high-throughput screening matrix to identify synergistic drug combinations with birinapant. SMAC mimetics in combination with an HDAC inhibitor showed remarkable synergy and was, therefore, selected for further evaluation. We show here that this synergy observed both in vitro and in vivo results from multiple convergent pathways to include increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling. These findings provide a rationale for the integration of SMAC mimetics and HDAC inhibitors in clinical trials for recurrent ovarian cancer where treatment options are still limited.

Technological innovation for workload allocation in nursing care management: an integrative review.

Background: Technology reduces the nursing workload, improve the quality care processes, patient's safety, and avoid staff burnout. Innovative technologies are disrupting healthcare systems by improving the efficiency of processes and management. There is a discussion on the benefits, challenges, and barriers of these technologies and considering human factors of nursing management. The aim was to analyze the influence of technologies on the distribution of workload for nursing care management. Methods: An integrative literature review was performed. Four databases were searched: Scopus, Scielo, PUBMED, and CINALH following PRISMA guidelines. Articles published from January 2016 to December 2020, published in English, Spanish and Portuguese were included. Studies were excluded when they were not original research, did not met the quality criteria or they did not answer the research questions. Quality appraisal was performed using the Crowe Critical Appraisal Tool version 1.4 (CCAT). Two reviewers independently examined the title and abstract for eligibility according to the inclusion and exclusion criteria. Results: 2818 potentially relevant articles were found, but once the inclusion and exclusion criteria in the abstracts were analyzed, 177 remained for evaluation. After following the PRISMA Guidelines, 35 studies were included in the review. Three categories were identified: Nursing workload; Information technologies and technological means for management; Technology acceptance. Conclusions: Technology has the potential to improve care management by estimating nurse workload in ICUs and non-critical units, but scientific evidence is more detailed in the former type of services. The literature provides insights about the factors that factors and the barriers that promote the technology acceptance and usability. We did not find studies comparing technologies and no scientific evidence proving improvements in care.

Adaptation by Men to the Nurse Role. "Being Craftsmen in the Construction of their Professional Trajectory" / La adaptación de los hombres al rol de enfermero. "Ser un artesano en la construcción de su trayectoria profesional" / A adaptação do homem ao papel de enfermeiro. "Ser artesão na construção da sua carreira profissional"

Objective. This work sought to describe the adaptation process by men to the nurse role. Methods.Secondary analysis of data from a collective case study that had as participants 12 male nurses working in the city of Medellín, with ages between 28 and 47 years and average time of professional experience of 11 years. Information collection was carried out through in-depth interviews. The analysis was conducted through Roy's Adaptation Model (RAM), reading of the interviews, identification of RAM's components, grouping of fragments, assignment of tags, construction of a matrix and classification. Results. The analysis performed accounts for the coping processes and adaptation by male nurses and the ineffective responses (control of emotions and emotional silencing) when practicing a role considered feminine. Conclusion.In this study, it was possible to establish that, to achieve adaptation within nursing, men use strategies related with changes in bodily appearance, management of physical strength, and management of emotions.

Objetivo. Describir el proceso de adaptación de los hombres al rol enfermero. Métodos. Análisis secundario de los datos de un estudio de casos colectivo que tuvo como participantes a 12 enfermeros que trabajan en la ciudad de Medellín, con edades entre los 28 y los 47 años y un tiempo de experiencia profesional promedio de 11 años. La recolección de la información se realizó mediante entrevistas en profundidad. El análisis se realizó a partir del Modelo de Adaptación de Roy (RAM), lectura de las entrevistas, identificación de los componentes del RAM, agrupación de fragmentos, asignación de etiquetas, construcción de una matriz y clasificación. Resultados. El análisis realizado da cuenta de los procesos de afrontamiento y adaptación de los enfermeros y las respuestas inefectivas (control de emociones y silenciamiento emocional) al ejercer un rol considerado femenino. Conclusión. En este estudio fue posible establecer que, para alcanzar una adaptación dentro de la enfermería, los hombres utilizan estrategias relacionadas con cambios en la apariencia corporal, el manejo de la fuerza física y el manejo de las emociones.

Objetivo. Descrever o processo de adaptação do homem à função de enfermagem. Métodos.Análise secundária de dados de um estudo de caso coletivo que teve como participantes 12 enfermeiros que atuam na cidade de Medellín, com idade entre 28 e 47 anos e tempo de experiência profissional média 11 anos. As informações foram coletadas por meio de entrevistas em profundidade. A análise foi realizada por meio do Modelo de Adaptação de Roy (RAM), leitura das entrevistas, identificação dos componentes do RAM, agrupamento de fragmentos, atribuição de rótulos, construção de matriz e classificação. Resultados. A análise realizada dá conta dos processos de enfrentamento e adaptação das enfermeiras e das respostas ineficazes (controle das emoções e silenciamento emocional) ao exercer um papel considerado feminino. Conclusão.Neste estudo foi possível constatar que, para conseguir uma adaptação dentro da enfermagem, os homens utilizam estratégias relacionadas a mudanças na aparência corporal, manejo da força física e manejo emocional

From Being Caregiver to Being Cared for: The Experience of Adapting to Spinal Cord Injury, a Case Study.

This narrative case study portrays a young woman's life experience and adjustment process after suffering a traumatic spinal cord injury (SCI) 5 years ago. It is analyzed retrospectively from the perspective of the middle-range theory (MRT) of adapting to chronic health conditions by Buckner and Hayden (2014), and Ricoeur's narrative philosophy is expanded. Understanding Alice's narrative from this perspective allows us to understand the process of adaptation to a condition of disability due to a spinal cord injury, from the perspective of a nurse who was forced to change her role as a caregiver to a role of being cared for, due to the changes in her body and her corporality due to the consequences of the injury. In this narrative, the focal and contextual stimuli, the coping processes with special emphasis on the intrinsic and extrinsic adaptive processes, and the results of the process are identified.

Adaptation by Men to the Nurse Role. "Being Craftsmen in the Construction of their Professional Trajectory".

OBJECTIVES: This work sought to describe the adaptation process by men to the nurse role. METHODS: Secondary analysis of data from a collective case study that had as participants 12 male nurses working in the city of Medellín, with ages between 28 and 47 years and average time of professional experience of 11 years. Information collection was carried out through in-depth interviews. The analysis was conducted through Roy s Adaptation Model (RAM), reading of the interviews, identification of RAMs components, grouping of fragments, assignment of tags, construction of a matrix and classification. RESULTS: The analysis performed accounts for the coping processes and adaptation by male nurses and the ineffective responses (control of emotions and emotional silencing) when practicing a role considered feminine. CONCLUSIONS: In this study, it was possible to establish that, to achieve adaptation within nursing, men use strategies related with changes in bodily appearance, management of physical strength, and management of emotions.

Analytics and Lean Health Care to Address Nurse Care Management Challenges for Inpatients in Emerging Economies.

PURPOSE: Prescriptive and predictive analytics and artificial intelligence (AI) provide tools to analyze data with objectivity. In this paper, we provide an overview of how these techniques can improve nursing care, and we detail a quantitative model to afford managerial insights about care management in a Hospital in Colombia. Our main purpose is to provide tools to improve key performance indicators for the care management of inpatients which includes the nurse workload. METHODS: The optimal nurse-to-patient assignment problem is addressed using analytics, lean health care, and AI. Also, we propose a new mathematical model to optimize the nurse-to-patient assignment decisions considering several variables about the patient state such as the Barthel index, their risks, the complexity of the care, and the mental state. FINDINGS: Our results show that there are several processes inherent to compassionate nursing care that can be improved using technology. By using data analytics, we can also provide insights about the high variability of the care requirements and, by using models, find nurse-to-patient assignments that are nearly perfectly balanced. CONCLUSIONS: We illustrated this improvement with a pilot test that makes the equitable distribution of nursing workload the functionality of this strategy. The findings can be useful in highly complex hospitals in Latin America. CLINICAL RELEVANCE: The proposed model presents an opportunity to make near perfectly balanced nurse-to-patient assignments according to the number of patients and their health conditions using technology.

Cysteine 202 of cyclophilin D is a site of multiple post-translational modifications and plays a role in cardioprotection.

AIMS: Cyclophilin-D is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischaemia/reperfusion injury. However, the binding of CypD to the PTP is poorly understood. Cysteine 202 (C202) of CypD is highly conserved among species and can undergo redox-sensitive post-translational modifications. We investigated whether C202 regulates the opening of PTP. METHODS AND RESULTS: We developed a knock-in mouse model using CRISPR where CypD-C202 was mutated to a serine (C202S). Infarct size is reduced in CypD-C202S Langendorff perfused hearts compared to wild type (WT). Cardiac mitochondria from CypD-C202S mice also have higher calcium retention capacity compared to WT. Therefore, we hypothesized that oxidation of C202 might target CypD to the PTP. Indeed, isolated cardiac mitochondria subjected to oxidative stress exhibit less binding of CypD-C202S to the proposed PTP component F1F0-ATP-synthase. We previously found C202 to be S-nitrosylated in ischaemic preconditioning. Cysteine residues can also undergo S-acylation, and C202 matched an S-acylation motif. S-acylation of CypD-C202 was assessed using a resin-assisted capture (Acyl-RAC). WT hearts are abundantly S-acylated on CypD C202 under baseline conditions indicating that S-acylation on C202 per se does not lead to PTP opening. CypD C202S knock-in hearts are protected from ischaemia/reperfusion injury suggesting further that lack of CypD S-acylation at C202 is not detrimental (when C is mutated to S) and does not induce PTP opening. However, we find that ischaemia leads to de-acylation of C202 and that calcium overload in isolated mitochondria promotes de-acylation of CypD. Furthermore, a high bolus of calcium in WT cardiac mitochondria displaces CypD from its physiological binding partners and possibly renders it available for interaction with the PTP. CONCLUSIONS: Taken together the data suggest that with ischaemia CypD is de-acylated at C202 allowing the free cysteine residue to undergo oxidation during the first minutes of reperfusion which in turn targets it to the PTP.

Apolipoprotein E Signals via TLR4 to Induce CXCL5 Secretion by Asthmatic Airway Epithelial Cells.

The primary function of APOE (apolipoprotein E) is to mediate the transport of cholesterol- and lipid-containing lipoprotein particles into cells by receptor-mediated endocytosis. APOE also has pro- and antiinflammatory effects, which are both context and concentration dependent. For example, Apoe-/- mice exhibit enhanced airway remodeling and hyperreactivity in experimental asthma, whereas increased APOE levels in lung epithelial lining fluid induce IL-1ß secretion from human asthmatic alveolar macrophages. However, APOE-mediated airway epithelial cell inflammatory responses and signaling pathways have not been defined. Here, RNA sequencing of human asthmatic bronchial brushing cells stimulated with APOE identified increased expression of mRNA transcripts encoding multiple proinflammatory genes, including CXCL5 (C-X-C motif chemokine ligand 5), an epithelial-derived chemokine that promotes neutrophil activation and chemotaxis. We subsequently characterized the APOE signaling pathway that induces CXCL5 secretion by human asthmatic small airway epithelial cells (SAECs). Neutralizing antibodies directed against TLR4 (Toll-like receptor 4), but not TLR2, attenuated APOE-mediated CXCL5 secretion by human asthmatic SAECs. Inhibition of TAK1 (transforming growth factor-ß-activated kinase 1), IκKß (inhibitor of nuclear factor κ B kinase subunit ß), TPL2 (tumor progression locus 2), and JNK (c-Jun N-terminal kinase), but not p38 MAPK (mitogen-activated protein kinase) or MEK1/2 (MAPK kinase 1/2), attenuated APOE-mediated CXCL5 secretion. The roles of TAK1, IκKß, TPL2, and JNK in APOE-mediated CXCL5 secretion were verified by RNA interference. Furthermore, RNA interference showed that after APOE stimulation, both NF-κB p65 and TPL2 were downstream of TAK1 and IκKß, whereas JNK was downstream of TPL2. In summary, elevated levels of APOE in the airway may activate a TLR4/TAK1/IκKß/NF-κB/TPL2/JNK signaling pathway that induces CXCL5 secretion by human asthmatic SAECs. These findings identify new roles for TLR4 and TPL2 in APOE-mediated proinflammatory responses in asthma.

EMRE is essential for mitochondrial calcium uniporter activity in a mouse model.

The mitochondrial calcium uniporter is widely accepted as the primary route of rapid calcium entry into mitochondria, where increases in matrix calcium contribute to bioenergetics but also mitochondrial permeability and cell death. Hence, regulation of uniporter activity is critical to mitochondrial homeostasis. The uniporter subunit EMRE is known to be an essential regulator of the channel-forming protein MCU in cell culture, but EMRE's impact on organismal physiology is less understood. Here we characterize a mouse model of EMRE deletion and show that EMRE is indeed required for mitochondrial calcium uniporter function in vivo. EMRE-/- mice are born less frequently; however, the mice that are born are viable, healthy, and do not manifest overt metabolic impairment, at rest or with exercise. Finally, to investigate the role of EMRE in disease processes, we examine the effects of EMRE deletion in a muscular dystrophy model associated with mitochondrial calcium overload.

Experience of Perinatal Death From the Father's Perspective.

BACKGROUND: Although perinatal deaths are still a common pregnancy outcome in developing countries, little is known about the effect perinatal death has on fathers. OBJECTIVE: The aim of the study was to understand and describe the meaning of perinatal death in a sample of fathers from northeastern Colombia. METHODS: Using purposive and snowball sampling approaches, we identified 15 participants from northeastern Colombia who agreed to participate. We used a descriptive phenomenological design. Data were collected through in-depth, semistructured interviews. RESULTS: Men suffer in solitude and hide their emotions as they feel the need to be the main supporters of their partners. Three major themes emerged: experience of loss, coming to terms with an irreparable loss, and overcoming the loss. DISCUSSION: While women are receiving care, health staff may neglect or forget men. Men suffer alone while seeking ways of attunement with their partners' emotions to support them during the grieving process. Fathers can overcome and adjust to the loss when they transcend it and find new meaning. Men felt neglected and marginalized at hospitals while their partners were receiving treatment. Health professionals should recognize and acknowledge the pain of fathers who face perinatal death and include them as much as possible in the standard of care. The results identify opportunities for healthcare providers in clinical and outpatient settings to acknowledge the importance of men within the context of pregnancy and to learn about their pain and suffering when they face a perinatal death.

The ribosomal prolyl-hydroxylase OGFOD1 decreases during cardiac differentiation and modulates translation and splicing.

The mechanisms regulating translation and splicing are not well understood. We provide insight into a new regulator of translation, OGFOD1 (2-oxoglutarate and iron dependent oxygenase domain-containing protein 1), which is a prolyl-hydroxylase that catalyzes the posttranslational hydroxylation of Pro-62 in the small ribosomal protein S23. We show that deletion of OGFOD1 in an in vitro model of human cardiomyocytes decreases translation of specific proteins (e.g., RNA-binding proteins) and alters splicing. RNA sequencing showed poor correlation between changes in mRNA and protein synthesis, suggesting that posttranscriptional regulation was the primary cause for the observed differences. We found that loss of OGFOD1 and the resultant alterations in protein translation modulates the cardiac proteome, shifting it towards higher protein amounts of sarcomeric proteins such as cardiac troponins, titin and cardiac myosin binding protein C. Furthermore, we found a decrease of OGFOD1 during cardiomyocyte differentiation. These results suggest that loss of OGFOD1 modulates protein translation and splicing, thereby leading to alterations in the cardiac proteome and highlight the role of altered translation and splicing in regulating the proteome..

Cyclophilin D-mediated regulation of the permeability transition pore is altered in mice lacking the mitochondrial calcium uniporter.

Aims: Knockout (KO) of the mitochondrial Ca2+ uniporter (MCU) in mice abrogates mitochondrial Ca2+ uptake and permeability transition pore (PTP) opening. However, hearts from global MCU-KO mice are not protected from ischaemic injury. We aimed to investigate whether adaptive alterations occur in cell death signalling pathways in the hearts of global MCU-KO mice. Methods and results: First, we examined whether cell death may occur via an upregulation in necroptosis in MCU-KO mice. However, our results show that neither RIP1 inhibition nor RIP3 knockout afford protection against ischaemia-reperfusion injury in MCU-KO as in wildtype (WT) hearts, indicating that the lack of protection cannot be explained by upregulation of necroptosis. Instead, we have identified alterations in cyclophilin D (CypD) signalling in MCU-KO hearts. In the presence of a calcium ionophore, MCU-KO mitochondria take up calcium and do undergo PTP opening. Furthermore, PTP opening in MCU-KO mitochondria has a lower calcium retention capacity (CRC), suggesting that the calcium sensitivity of PTP is higher. Phosphoproteomics identified an increase in phosphorylation of CypD-S42 in MCU-KO. We investigated the interaction of CypD with the putative PTP component ATP synthase and identified an approximately 50% increase in this interaction in MCU-KO cardiac mitochondria. Mutation of the novel CypD phosphorylation site S42 to a phosphomimic reduced CRC, increased CypD-ATP synthase interaction by approximately 50%, and increased cell death in comparison to a phospho-resistant mutant. Conclusion: Taken together these data suggest that MCU-KO mitochondria exhibit an increase in phosphorylation of CypD-S42 which decreases PTP calcium sensitivity thus allowing activation of PTP in the absence of an MCU-mediated increase in matrix calcium.

A Metabolic Basis for Endothelial-to-Mesenchymal Transition.

Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor ß (TGF-ß) family of ligands. Although required for normal heart valve development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2E-KO) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2E-KO mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.