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1.
Blood ; 137(20): 2770-2784, 2021 05 20.
Article in English | MEDLINE | ID: mdl-33512478

ABSTRACT

Dendritic cells (DCs) encompass several cell subsets that collaborate to initiate and regulate immune responses. Proper DC localization determines their function and requires the tightly controlled action of chemokine receptors. All DC subsets express CXCR4, but the genuine contribution of this receptor to their biology has been overlooked. We addressed this question using natural CXCR4 mutants resistant to CXCL12-induced desensitization and harboring a gain of function that cause the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS), a rare immunodeficiency associated with high susceptibility to the pathogenesis of human papillomavirus (HPV). We report a reduction in the number of circulating plasmacytoid DCs (pDCs) in WHIM patients, whereas that of conventional DCs is preserved. This pattern was reproduced in an original mouse model of WS, enabling us to show that the circulating pDC defect can be corrected upon CXCR4 blockade and that pDC differentiation and function are preserved, despite CXCR4 dysfunction. We further identified proper CXCR4 signaling as a critical checkpoint for Langerhans cell and DC migration from the skin to lymph nodes, with corollary alterations of their activation state and tissue inflammation in a model of HPV-induced dysplasia. Beyond providing new hypotheses to explain the susceptibility of WHIM patients to HPV pathogenesis, this study shows that proper CXCR4 signaling establishes a migration threshold that controls DC egress from CXCL12-containing environments and highlights the critical and subset-specific contribution of CXCR4 signal termination to DC biology.


Subject(s)
Dendritic Cells/physiology , Inflammation/pathology , Primary Immunodeficiency Diseases/physiopathology , Receptors, CXCR4/physiology , Warts/physiopathology , Alphapapillomavirus/genetics , Animals , Benzylamines/pharmacology , Cell Count , Cell Differentiation , Chemokine CXCL12/physiology , Chemotaxis , Cyclams/pharmacology , Dendritic Cells/classification , Epidermis/pathology , Female , Gene Knock-In Techniques , Genes, Viral , Humans , Inflammation/metabolism , Langerhans Cells/physiology , Lymphoid Tissue/pathology , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Transgenic , Organ Specificity , Parabiosis , Primary Immunodeficiency Diseases/blood , Primary Immunodeficiency Diseases/genetics , Primary Immunodeficiency Diseases/pathology , Recombinant Proteins/metabolism , Warts/blood , Warts/genetics , Warts/pathology
3.
Gastroenterol Nurs ; 44(6): 418-425, 2021.
Article in English | MEDLINE | ID: mdl-34269705

ABSTRACT

A randomized, open-label, controlled clinical trial was designed to assess the effectiveness of a motivational intervention based on the 5 R's model (relevance, risks, rewards, roadblocks, and repetition) delivered by specialized inflammatory bowel disease nurses every 3 months over a 1-year period as compared with patients who were followed regularly. Patients diagnosed with Crohn disease, aged 18 years or older, who reported being active smokers with Internet access at home and an e-mail address were eligible. A total of 144 patients (72 per group) were included (50% women, median age 40 years). They smoked a median of 10 cigarettes per day (range = 1-40) and had been smoking for a median of 22 years (range = 1-51). Motivation to quit (Richmond test) was low in 73 patients, moderate in 39 patients, and high in 32 patients. Statistically significant differences between the study groups in the predisposition to change, motivation to quit, and tobacco withdrawal were not found. However, 14 patients (20.9%) in the intervention group and 9 patients (13.2%) among controls stopped smoking at the end of the study. These findings support a higher trend toward smoking cessation associated with the motivational intervention 5 R's. This behavioral strategy can aid patients with Crohn disease to quit smoking.


Subject(s)
Crohn Disease , Smoking Cessation , Adult , Crohn Disease/therapy , Female , Humans , Male , Motivation , Smoking , Telephone
4.
Mol Pharmacol ; 96(6): 809-818, 2019 12.
Article in English | MEDLINE | ID: mdl-31040166

ABSTRACT

Atypical chemokine receptor 3 (ACKR3), previously known as C-X-C chemokine receptor type 7 (CXCR7), has emerged as a key player in several biologic processes, particularly during development. Its CXCL11 and CXCL12 scavenging activity and atypical signaling properties, together with a new array of other nonchemokine ligands, have established ACKR3 as a main regulator of physiologic processes at steady state and during inflammation. Here, we present a comprehensive review of ACKR3 expression in mammalian tissues in search of a possible connection with the receptor function. Besides the reported roles of ACKR3 during development, we discuss the potential contribution of ACKR3 to the function of the immune system, focusing on the myeloid lineage.


Subject(s)
Immunity, Cellular/physiology , Neutrophils/immunology , Neutrophils/metabolism , Receptors, CXCR/immunology , Receptors, CXCR/metabolism , Animals , Gene Expression , Humans , Immune System/immunology , Immune System/metabolism , Receptors, CXCR/genetics
5.
J Nurs Manag ; 27(6): 1294-1303, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31145500

ABSTRACT

AIM: To detect possible changes in perception of the nurse work environment, job satisfaction and burnout between the years 2009 and 2014 among nurses working in the Spanish National Health System. BACKGROUND: The global economic crisis has had a great impact on nurses in the Spanish National Health Service: tougher working conditions, lower pay and a reduction in social benefits. It is not known whether these changes affect the nurses' work environment, job satisfaction and burnout. METHOD: Comparative, cross-sectional study performed in seven hospitals in the Spanish National Health System between 2009 and 2014, through 1,454 surveys of nurses working in internal medicine, surgery and intensive care. RESULTS: Nurses participating in the second period (2012-2014) were more satisfied with their current job (p = 0.001), perceived their work environment to be more favourable (p < 0.001) and had lower levels of burnout (p < 0.01). Professional factors as 'autonomy at work,' 'opportunities for advancement,' 'professional status' and 'nursing foundations for quality care,' as well as 'collegial nurse-physician relations' and 'nurse participation in hospital affairs' were the most important variables associated with these topics. CONCLUSIONS: Professional factors may influence these changes more than labour conditions and remuneration aspects. IMPLICATIONS FOR NURSING MANAGEMENT: In times of economic recession, encouraging interpersonal relationships, autonomy and participation in decision-making may improve the work environment, satisfaction and burnout of nurses.


Subject(s)
Economic Recession/trends , Workplace/standards , Adult , Cross-Sectional Studies , Employment/methods , Employment/standards , Employment/statistics & numerical data , Female , Humans , Job Satisfaction , Male , Middle Aged , National Health Programs/statistics & numerical data , Spain , Surveys and Questionnaires
6.
Birth ; 45(4): 385-392, 2018 12.
Article in English | MEDLINE | ID: mdl-29537658

ABSTRACT

BACKGROUND: Fetal occiput posterior position in labor is associated with more painful and prolonged labor, and an increase in both maternal and fetal morbidity. The aim of this study is to assess whether the modified Sims position on the side of the fetal spine increases the rotation to occiput anterior position in women with epidural analgesia and a fetus in persistent occiput posterior (POP) position. METHODS: This is an open, randomized controlled, clinical trial. One hundred and twenty women in labor with fetuses in POP position were included. The diagnosis was performed through digital vaginal examination and confirmed with an ultrasound scan. Women were randomized into the free position group or the modified Sims on the side of the fetal spine. The primary outcome was rotation to occiput anterior, and secondary outcomes were type of delivery, postpartum perineal condition, perinatal results, and maternal satisfaction. RESULTS: In pregnant women undergoing labor in the Sims position, fetuses in POP rotated to occiput anterior in 50.8% of cases, whilst in the free position group, the rotation occurred in 21.7% (P = .001). The rate of vaginal deliveries was higher in the Sims group compared with the free position group (84.7% vs 68.3%, P = .035). DISCUSSION: The modified Sims position is a maternal posture intervention efficient in POP rotation, which decreases cesarean delivery rate. It is a simple and noninvasive intervention, reproducible, and well tolerated by pregnant women.


Subject(s)
Delivery, Obstetric/statistics & numerical data , Labor Presentation , Obstetric Labor Complications/diagnostic imaging , Patient Positioning , Posture , Adult , Analgesia, Epidural , Delivery, Obstetric/methods , Female , Head/diagnostic imaging , Humans , Pregnancy , Rotation , Spain , Ultrasonography, Prenatal , Version, Fetal/methods , Young Adult
7.
BMC Nurs ; 15: 8, 2016.
Article in English | MEDLINE | ID: mdl-26855613

ABSTRACT

BACKGROUND: Mechanical ventilation (MV) is one of the most utilised techniques in the intensive care unit (ICU), but it can cause sequelae that can negatively influence the patient's health-related quality of life (HRQL). Nursing-sensitive outcomes (NSOs) can also influence the HRQL. Assessing the HRQL of mechanically ventilated patients admitted to an ICU and its relation to nurse-sensitive outcomes will give healthcare professionals with valuable information to improve patient care. METHODS: Prospective longitudinal cohort study in which all patients admitted to the ICU at Hospital Universitari Vall d'Hebron who undergo MV for more than 48 h will be included. The study will last 12 consecutive months. HRQL will be assessed by the completion of the SF-36 and the Saint Georges Respiratory Questionnaire. Pre-admission HRQL assessment will be performed by the main caregiver, and after ICU discharge, the assessment will be performed by the patient him/herself. The same questionnaires will also be completed one year after ICU discharge. Other variables (sociodemographic and those related to reason for ICU admission, ICU length of stay, MV, ICU stressors and NSO) will be included in a multiple regression model to assess their relation to the patient's HRQL. DISCUSSION: This study will show the relationship between the HRQL perceived by patients and their main caregiver, what the HRQL is one year after discharge from ICU, and what the impact of MV, NSO and ICU stressors and other clinical outcomes on the patient's HRQL is. Determining mechanically ventilated patients' HRQL and its relation to NSO and ICU stressors as well as other clinical variables will enable early nursing interventions to try to minimise possible sequelae and improve the patient's welfare. TRIAL REGISTRATION: ClinicalTrials.gov ID:NCT02636660Registration Date: 17th December 2015.

8.
J Adv Nurs ; 70(1): 211-9, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23834526

ABSTRACT

AIMS: To determine how prevalent circadian rhythm impairments are in nurses working in medical, surgical and intensive care units in five Spanish hospitals and how the quality of night-time sleeping and sleepiness affect the nurses' morning and evening chronotypes. BACKGROUND: Shift work is a recognized work pattern for nurses in all countries. Given the important role that nurses play in hospital care, it is vital to establish what repercussions this has on the nurses' working schedules and how any disturbance in circadian rhythm affects patient safety. DESIGN: A multicentre, observational, descriptive and cross-sectional study in seven hospitals in the Spanish National Health System. METHOD: A stratified sample of 1,300 nurses is being collected in three types of units: medical, surgical and intensive care. The 3-year study started in January 2012 and will continue until December 2014, with no exclusion criteria. The Kronowise(®) will be used to monitor the nurses' circadian rhythms, by recording their activity, position and wrist temperature. We will also use three questionnaires to evaluate sleep quality, daytime drowsiness and chronotype: (a) Pittsburg Sleep Quality Index; (b) Epworth Daytime Sleepiness Scale; and (c) Morning and Evening Questionnaire. Data will be collected from each hospital and statistical analysis will be carried out using the SPSS 19.0. DISCUSSION: The study findings will show the current state of the nurses' circadian rhythms and how shift work can affect them and their job performance. Funding for this 3-year study was granted in December 2011 by the Spanish Health Research Fund (PI 11/00646, Health Ministry). This project is also funded by the Instituto de Salud Carlos III (RETICEF, RD12/0043/0011, RD12/0043/0006).


Subject(s)
Circadian Rhythm/physiology , Nursing Staff, Hospital/statistics & numerical data , Sleep Wake Disorders/etiology , Work Schedule Tolerance/physiology , Cross-Sectional Studies , Female , Humans , Male , Nurse Midwives/statistics & numerical data , Nurses/statistics & numerical data , Sleep Wake Disorders/epidemiology , Spain/epidemiology
9.
Appl Nurs Res ; 26(4): e5-9, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24135089

ABSTRACT

OBJECTIVE: The objective of this study is to evaluate the content validity of the Iberian Spanish version of the questionnaire The Practice Environment Scale of the Nursing Work Index (PES-NWI) by using the Content Validity Indexing (CVI). METHODS: A descriptive cross-sectional observational study was conducted. The Spanish version of the questionnaire was translated from the American English instrument through forward and back translation processes. Experts evaluated the translated items through content validity indexing. Once the assessments were completed, CVI indicators were calculated: number of agreements, item Content Validity Index and overall content validity and modified kappa coefficient of the instrument. RESULTS: The overall content validity of the instrument was 0.82. The average modified kappa coefficient of the items was 0.80, with a rating of 'excellent'. Only 4 of the items were rated as weak or poor. CONCLUSIONS: The study demonstrates that the content validity of the Spanish version of the PES-NWI is acceptable. Some results indicate that some items have cross-cultural applicability challenges that need to be addressed in future research studies. Use of the instrument in other Spanish language speaking countries should be taken with caution since some words may not reflect the language of the healthcare systems there.


Subject(s)
Nursing Process , Translating , Cross-Sectional Studies , Spain , Surveys and Questionnaires
10.
Biomedicines ; 11(4)2023 Apr 18.
Article in English | MEDLINE | ID: mdl-37189823

ABSTRACT

Atherosclerosis is a chronic inflammatory and degenerative process that mainly occurs in large- and medium-sized arteries and is morphologically characterized by asymmetric focal thickenings of the innermost layer of the artery, the intima. This process is the basis of cardiovascular diseases (CVDs), the most common cause of death worldwide. Some studies suggest a bidirectional link between atherosclerosis and the consequent CVD with COVID-19. The aims of this narrative review are (1) to provide an overview of the most recent studies that point out a bidirectional relation between COVID-19 and atherosclerosis and (2) to summarize the impact of cardiovascular drugs on COVID-19 outcomes. A growing body of evidence shows that COVID-19 prognosis in individuals with CVD is worse compared with those without. Moreover, various studies have reported the emergence of newly diagnosed patients with CVD after COVID-19. The most common treatments for CVD may influence COVID-19 outcomes. Thus, their implication in the infection process is briefly discussed in this review. A better understanding of the link among atherosclerosis, CVD, and COVID-19 could proactively identify risk factors and, as a result, develop strategies to improve the prognosis for these patients.

11.
Front Cell Infect Microbiol ; 13: 1138232, 2023.
Article in English | MEDLINE | ID: mdl-37260709

ABSTRACT

Human papillomaviruses (HPVs) are highly prevalent commensal viruses that require epithelial stratification to complete their replicative cycle. While HPV infections are most often asymptomatic, certain HPV types can cause lesions, that are usually benign. In rare cases, these infections may progress to non-replicative viral cycles associated with high HPV oncogene expression promoting cell transformation, and eventually cancer when not cleared by host responses. While the consequences of HPV-induced transformation on keratinocytes have been extensively explored, the impact of viral replication on epithelial homeostasis remains largely unexplored. Gap junction intercellular communication (GJIC) is critical for stratified epithelium integrity and function. This process is ensured by a family of proteins named connexins (Cxs), including 8 isoforms that are expressed in stratified squamous epithelia. GJIC was reported to be impaired in HPV-transformed cells, which was attributed to the decreased expression of the Cx43 isoform. However, it remains unknown whether and how HPV replication might impact on the expression of Cx isoforms and GJIC in stratified squamous epithelia. To address this question, we have used 3D-epithelial cell cultures (3D-EpCs), the only model supporting the productive HPV life cycle. We report a transcriptional downregulation of most epithelial Cx isoforms except Cx45 in HPV-replicating epithelia. At the protein level, HPV replication results in a reduction of Cx43 expression while that of Cx45 increases and displays a topological shift toward the cell membrane. To quantify GJIC, we pioneered quantitative gap-fluorescence loss in photobleaching (FLIP) assay in 3D-EpCs, which allowed us to show that the reprogramming of Cx landscape in response to HPV replication translates into accelerated GJIC in living epithelia. Supporting the pathophysiological relevance of our observations, the HPV-associated Cx43 and Cx45 expression pattern was confirmed in human cervical biopsies harboring HPV. In conclusion, the reprogramming of Cx expression and distribution in HPV-replicating epithelia fosters accelerated GJIC, which may participate in epithelial homeostasis and host immunosurveillance.


Subject(s)
Carcinoma, Squamous Cell , Papillomavirus Infections , Humans , Connexins/genetics , Connexins/metabolism , Connexin 43/genetics , Connexin 43/metabolism , Human Papillomavirus Viruses , Gap Junctions/metabolism , Epithelium , Cell Communication/physiology , Cell Transformation, Neoplastic
12.
Nat Commun ; 13(1): 1076, 2022 02 28.
Article in English | MEDLINE | ID: mdl-35228537

ABSTRACT

Despite the high prevalence of both cervico-vaginal human papillomavirus (HPV) infection and bacterial vaginosis (BV) worldwide, their causal relationship remains unclear. While BV has been presumed to be a risk factor for HPV acquisition and related carcinogenesis for a long time, here, supported by both a large retrospective follow-up study (n = 6,085) and extensive in vivo data using the K14-HPV16 transgenic mouse model, we report a novel blueprint in which the opposite association also exists. Mechanistically, by interacting with several core members (NEMO, CK1 and ß-TrCP) of both NF-κB and Wnt/ß-catenin signaling pathways, we show that HPV E7 oncoprotein greatly inhibits host defense peptide expression. Physiologically secreted by the squamous mucosa lining the lower female genital tract, we demonstrate that some of these latter are fundamental factors governing host-microbial interactions. More specifically, several innate molecules down-regulated in case of HPV infection are hydrolyzed, internalized and used by the predominant Lactobacillus species as amino acid source sustaining their growth/survival. Collectively, this study reveals a new viral immune evasion strategy which, by its persistent/negative impact on lactic acid bacteria, ultimately causes the dysbiosis of vaginal microbiota.


Subject(s)
Microbiota , Papillomavirus Infections , Vaginosis, Bacterial , Amino Acids , Animals , Female , Follow-Up Studies , Lactobacillus/physiology , Mice , Microbiota/physiology , Mucous Membrane , Peptides , Retrospective Studies , Vagina/microbiology , Vaginosis, Bacterial/microbiology
13.
J Gerontol A Biol Sci Med Sci ; 77(4): 781-789, 2022 04 01.
Article in English | MEDLINE | ID: mdl-34407184

ABSTRACT

BACKGROUND: The purpose of this study was to evaluate the relationship of lower-limb muscle power with mortality and hospitalization. METHODS: A total of 1 928 participants from the Toledo Study for Healthy Aging were included. Muscle power was assessed with the 5-repetition sit-to-stand test and participants were classified into different groups of relative power (ie, normalized to body mass) according to sex-specific tertiles and their inability to perform the test. Mean follow-up periods for hospitalization and all-cause mortality were 3.3 and 6.3 years, respectively. RESULTS: Compared to the high relative muscle power group, men with low (HR [95% CI] = 2.1 [1.2-3.6]) and women with very low and low (HR [95% CI] = 4.7 [3.0-7.4] and 1.8 [1.2-2.7]) relative power had an increased age-adjusted risk of hospitalization. After adjusting for several covariates (age, physical activity, body mass index education, depression, comorbidities, disability, and handgrip strength), these effects were attenuated (men and women with very low relative power: HR [95% CI] = 1.6 [0.9-2.9] and 2.8 [1.6-4.9]). The very low relative muscle power group had also an increased all-cause mortality risk (age-adjusted) in both men and women (HR [95% CI] = 2.3 [1.4-3.9] and 2.9 [1.6-5.3]). After adjusting for all the covariates, a significantly increased mortality risk was observed only in men (HR [95% CI] = 2.1 [1.1-3.8]; women HR [95% CI] = 1.6 [0.8-3.2]), with very low levels of relative power. CONCLUSIONS: Relative muscle power was independently and negatively associated with mortality and hospitalization in older adults. An augmented all-cause mortality risk was noted in the lowest group of relative muscle power.


Subject(s)
Hand Strength , Muscle Strength , Aged , Exercise , Female , Hand Strength/physiology , Hospitalization , Humans , Male , Muscle, Skeletal , Muscles
14.
J Clin Nurs ; 20(13-14): 1936-47, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21539627

ABSTRACT

AIMS AND OBJECTIVE: To examine attitudes towards research and perceived barriers and facilitators of research utilisation in clinical practice in a broad cross-section of Spanish nurses. BACKGROUND: Nurses' attitudes towards research are critical in determining whether study findings are used to improve practice. DESIGN: Cross-sectional comparative survey in Hospitals, Primary Care Centres and University-affiliated schools of nursing. METHODS: Surveys were completed by 917 nurses: 69 who received funding from the Spanish national agency (1998-2004) and a nationally representative sample of 848 nurses who did not have the same research experience (the Comparison group). Two instruments (BARRIERS and Attitudes towards nursing research) were translated and culturally adapted for use in Spain. A descriptive analysis of demographic and practice characteristics was performed. Total scale scores, as well as subscale scores, were computed and compared across the two groups using one-way analysis of variance (anova) and multivariate analysis of variance (manova) with post hoc tests. Pearson product-moment correlation coefficients were computed between the total tool scores and subscales measuring barriers and attitudes in both groups. RESULTS: The investigators differed from other nurses on several demographic and work characteristics (more males, older age and more likely to work a fixed day shift schedule). On the whole, investigators showed more favourable attitudes but perceived several elements as posing greater barriers to research utilisation than the Comparison groups. Across all respondents, issues related to the quality of research were rated as the greatest barriers to research utilisation, followed by organisational barriers, barriers involving the communication of findings and finally, those related to nurses' values, awareness and skills. CONCLUSIONS: Very similar profiles of perceptions and attitudes regarding research were found in these samples of Spanish nurses relative to those from other countries in earlier reports. Nurses who had experience conducting research demonstrated more favourable research-related attitudes and perceived barriers differently than those without such experience. RELEVANCE TO CLINICAL PRACTICE: Understanding different organisational and experience perspectives is important to identify challenges and opportunities to ensure research utilisation in clinical practice.


Subject(s)
Attitude of Health Personnel , Nurses/psychology , Nursing Research , Adult , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Research Personnel , Spain
15.
Cells ; 10(11)2021 11 13.
Article in English | MEDLINE | ID: mdl-34831376

ABSTRACT

Dendritic cells (DCs) are key players in the control of tolerance and immunity. Glucocorticoids (GCs) are known to regulate DC function by promoting their tolerogenic differentiation through the induction of inhibitory ligands, cytokines, and enzymes. The GC-induced effects in DCs were shown to critically depend on increased expression of the Glucocorticoid-Induced Leucine Zipper protein (GILZ). GILZ expression levels were further shown to control antigen-presenting cell function, as well as T-cell priming capacity of DCs. However, the pattern of GILZ expression in DC subsets across tissues remains poorly described, as well as the modulation of its expression levels in different pathological settings. To fill in this knowledge gap, we conducted an exhaustive analysis of GILZ relative expression levels in DC subsets from various tissues using multiparametric flow cytometry. This study was performed at steady state, in the context of acute as well as chronic skin inflammation, and in a model of cancer. Our results show the heterogeneity of GILZ expression among DC subsets as well as the complexity of its modulation, that varies in a cell subset- and context-specific manner. Considering the contribution of GILZ in the control of DC functions and its potential as an immune checkpoint in cancer settings, these results are of high relevance for optimal GILZ targeting in therapeutic strategies.


Subject(s)
Dendritic Cells/pathology , Inflammation/pathology , Organ Specificity , Transcription Factors/metabolism , Acute Disease , Animals , Biomarkers/metabolism , Cell Line, Tumor , Cell Movement , Chronic Disease , Langerhans Cells/pathology , Lymph Nodes/metabolism , Mice, Inbred C57BL , Mice, Transgenic , Neoplasms/pathology , Skin/pathology
16.
Front Neurosci ; 14: 838, 2020.
Article in English | MEDLINE | ID: mdl-32973430

ABSTRACT

Inherited retinal diseases encompass a highly heterogenous group of disorders caused by a wide range of genetic variants and with diverse clinical symptoms that converge in the common trait of retinal degeneration. Indeed, mutations in over 270 genes have been associated with some form of retinal degenerative phenotype. Given the immune privileged status of the eye, cell replacement and gene augmentation therapies have been envisioned. While some of these approaches, such as delivery of genes through recombinant adeno-associated viral vectors, have been successfully tested in clinical trials, not all patients will benefit from current advancements due to their underlying genotype or phenotypic traits. Gene editing arises as an alternative therapeutic strategy seeking to correct mutations at the endogenous locus and rescue normal gene expression. Hence, gene editing technologies can in principle be tailored for treating retinal degeneration. Here we provide an overview of the different gene editing strategies that are being developed to overcome the challenges imposed by the post-mitotic nature of retinal cell types. We further discuss their advantages and drawbacks as well as the hurdles for their implementation in treating retinal diseases, which include the broad range of mutations and, in some instances, the size of the affected genes. Although therapeutic gene editing is at an early stage of development, it has the potential of enriching the portfolio of personalized molecular medicines directed at treating genetic diseases.

17.
J Leukoc Biol ; 107(6): 1123-1135, 2020 06.
Article in English | MEDLINE | ID: mdl-32374043

ABSTRACT

Chemokines play critical roles in numerous physiologic and pathologic processes through their action on seven-transmembrane (TM) receptors. The N-terminal domain of chemokines, which is a key determinant of signaling via its binding within a pocket formed by receptors' TM helices, can be the target of proteolytic processing. An illustrative case of this regulatory mechanism is the natural processing of CXCL12 that generates chemokine variants lacking the first two N-terminal residues. Whereas such truncated variants behave as antagonists of CXCR4, the canonical G protein-coupled receptor of CXCL12, they are agonists of the atypical chemokine receptor 3 (ACKR3/CXCR7), suggesting the implication of different structural determinants in the complexes formed between CXCL12 and its two receptors. Recent analyses have suggested that the CXCL12 N-terminus first engages the TM helices of ACKR3 followed by the receptor N-terminus wrapping around the chemokine core. Here we investigated the first stage of ACKR3-CXCL12 interactions by comparing the activity of substituted or N-terminally truncated variants of CXCL12 toward CXCR4 and ACKR3. We showed that modification of the first two N-terminal residues of the chemokine (K1R or P2G) does not alter the ability of CXCL12 to activate ACKR3. Our results also identified the K1R variant as a G protein-biased agonist of CXCR4. Comparative molecular dynamics simulations of the complexes formed by ACKR3 either with CXCL12 or with the P2G variant identified interactions between the N-terminal 2-4 residues of CXCL12 and a pocket formed by receptor's TM helices 2, 6, and 7 as critical determinants for ACKR3 activation.


Subject(s)
Chemokine CXCL12/chemistry , Cyclic AMP/chemistry , Receptors, CXCR4/chemistry , Receptors, CXCR/chemistry , Amino Acid Sequence , Benzylamines , Binding Sites , Chemokine CXCL11/chemistry , Chemokine CXCL11/genetics , Chemokine CXCL11/metabolism , Chemokine CXCL12/genetics , Chemokine CXCL12/metabolism , Cyclams , Cyclic AMP/metabolism , Gene Expression , HEK293 Cells , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Molecular Dynamics Simulation , Mutation , Oligopeptides/chemistry , Oligopeptides/pharmacology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Receptors, CXCR/genetics , Receptors, CXCR/metabolism , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/genetics , Receptors, CXCR4/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , beta-Arrestins/genetics , beta-Arrestins/metabolism
18.
J Am Med Dir Assoc ; 21(9): 1260-1266.e2, 2020 09.
Article in English | MEDLINE | ID: mdl-32005416

ABSTRACT

OBJECTIVES: To develop short versions of the Frailty Trait Scale (FTS) for use in clinical settings. DESIGN: Prospective population-based cohort study. SETTING AND PARTICIPANTS: Data from 1634 participants from the Toledo Study for Healthy Aging. METHODS: The 12-item Frailty Trait Scale (FTS) reduction was performed based on an area under the curve (AUC) analysis adjusted by age, sex, and comorbidity. Items that maximized prognostic information for adverse events were selected. Each item score was done at the same time as the reduction, identifying the score that maximized the predictive ability for adverse events. For each short version of the FTS, cutoffs that optimized the prognostic information (sensitivity and specificity) were chosen, and their predictive value was later compared with a surrogate gold standard for frailty (the Fried Phenotype). RESULTS: Two short forms, the 5-item (FTS5) (range 0-50) and 3-item (FTS3) (range 0-30), were identified, both with AUCs for health adverse events similar to the 12-item FTS. The identified cutoffs were >25 for the FTS5 scale and >15 for the FTS3. The frailty prevalence with these cutoffs was 24% and 20% for the FTS5 and FTS3, respectively, whereas frailty according to Fried Phenotype (FP) reached 8% and prefrailty reached 41%. In general, the FTS5 showed better prognostic performance than the FP, especially with prefrail individuals, in whom the FTS5 form identified 65% of participants with an almost basal risk and 35% with a very high risk for mortality (OR: 4) and frailty (OR: 6.6-8.7), a high risk for hospitalization (OR: 1.9-2.1), and a moderate risk for disability (OR: 1.7) who could be considered frail. The FTS3 form had worse performance than the FTS5, showing 31% of false negatives between frail participants identified by FP with a high risk of adverse events. CONCLUSIONS AND IMPLICATIONS: The FTS5 is a short scale that is easy to administer and has a similar performance to the FTS, and it can be used in clinical settings for frailty diagnosis and evolution.


Subject(s)
Frailty , Aged , Cohort Studies , Frail Elderly , Frailty/diagnosis , Geriatric Assessment , Humans , Phenotype , Prospective Studies
20.
Curr Aging Sci ; 10(4): 282-290, 2017.
Article in English | MEDLINE | ID: mdl-28412925

ABSTRACT

Bacground: This article tackles social support as a meta-variable that is reinforced by a set of social variables, which correlate and act as predictors of social welfare and life quality of the older person. OBJECTIVE: The objective of the study is to know how social support, networks and social contacts can influence the health of the elderly person, especially if these are interrelated factors. METHOD: The population studied are individuals from both sexes living in Toledo (Spanish people) and who were 65 years of age or over. Several scales were applied to assess the frequency of and the degree of satisfaction with perceived social support received from different sources in relation to social support. The co relational analysis showed significant positive associations between scores and measures of and social support, social relations, contact and social networks. RESULTS: We conclude that the support in general is very good, over 90% of people from the sample have someone who would help if needed. Social and health factors are interrelated with social support. Social contact can also be considered as a life quality estimate. He progressive loss of contact over the years is a social factor that affects the quality of life. CONCLUSION: The meta-analysis we find that social support and the emotional factor, along with social interactions, have powerful effects on preventing morbidity and mortality, which are important social indicators. We conclude that social support based on positive social interactions provides an optimal state of health in the older person.


Subject(s)
Aging/psychology , Psychosocial Support Systems , Quality of Life , Social Welfare , Adaptation, Psychological , Age Factors , Aged , Disability Evaluation , Female , Geriatric Assessment , Humans , Interpersonal Relations , Loneliness , Male , Mental Health , Sex Factors
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