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Non-Suicidal Self-Injury (NSSI) is associated with a heightened overall risk of future psychopathological problems. However, elucidating specific characteristics that determine an increased risk for certain individuals remains an area requiring further exploration. This study aimed to identify latent subgroups in a sample of college students with NSSI. Additionally, it sought to explore the differential associations of these subgroups with their psychopathological status (e.g., borderline symptoms and suicidal tendencies) both at baseline and after two years. The sample comprised 259 participants (89% females, Mage = 20.39, SD = 1.90) who reported engaging in NSSI in the last year. Three latent groups were found. The group exhibiting severe NSSI-features, high emotion dysregulation, and low perceived social support was the profile with high-risk of psychopathology both at baseline and follow-up. The findings enhance our understanding of the complex association between NSSI and future mental health issues, aiding in the early identification of at-risk individuals.
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Conducta Autodestructiva , Estudiantes , Humanos , Femenino , Conducta Autodestructiva/psicología , Estudiantes/psicología , Estudiantes/estadística & datos numéricos , Masculino , Adulto Joven , Estudios de Seguimiento , Universidades , Ideación Suicida , Apoyo Social , Factores de Riesgo , Adolescente , Regulación Emocional , Adulto , Trastorno de Personalidad Limítrofe/psicologíaRESUMEN
Robotics adoption has increased in colorectal surgery. While there are well-established advantages and standardised techniques for cancer patients, the use of robotic surgery in inflammatory bowel disease (IBD) has not been studied yet. To evaluate the feasibility and safety of robotic surgery for IBD patients. Prospectively data in IBD patients having robotic resection at Guy's and St Thomas' hospital. All resections performed by a single colorectal surgeon specialised in IBD, utilising DaVinci platform. July 2021 to January 2023, 59 robotic IBD cases performed, 14 ulcerative colitis (UC) and 45 Crohn's disease (CD). Average age; CD patients 35, UC 33 years. Average Body mass index (BMI); 23 for CD and 26.9 for UC patients. In total, we performed 31 ileo-caecal resections (ICR) with primary anastomosis (18 Kono-S anastomosis, 6 mechanical anastomosis and 7 ileo-colostomy), of those 4 had multivisceral resections (large bowel, bladder, ovary). Furthermore, 14 subtotal colectomy (1 emergency), 8 proctectomy, 3 panproctocolectomy and 3 ileoanal J pouch. 18 of the 45 patients (45.0%) with Crohn's disease had ongoing fistulating disease to other parts of the GI tract (small or large bowel). ICR were performed using different three ports position, depending on the anatomy established prior to surgery with magnetic resonance images (MRI). One patient had conversion to open due to anaesthetic problems and one patient required re-operation to refashion stoma. 98.0% cases completed robotically. Median Length of hospital stay (LOS) was 7 days for CD and 7 for UC cases, including LOS in patients on pre-operative parenteral nutrition. Robotic colorectal techniques can be safely used for patients with IBD, even with fistulating disease. Future research and collaborations are necessary to standardize technique within institutions.
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Colitis Ulcerosa , Neoplasias Colorrectales , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Proctocolectomía Restauradora , Procedimientos Quirúrgicos Robotizados , Femenino , Humanos , Enfermedad de Crohn/cirugía , Procedimientos Quirúrgicos Robotizados/métodos , Estudios Retrospectivos , Enfermedades Inflamatorias del Intestino/cirugía , Colitis Ulcerosa/cirugía , Neoplasias Colorrectales/cirugíaRESUMEN
La Autolesión No Suicida (ANS) se define como un dolor auto-infligido que se utiliza como un mecanismo para aliviar la angustia psicoló-gica. Aunque ANS es común en el trastorno límite de la personalidad (TLP), también es un problema creciente en estudiantes universitarios. Si bien la desregulación emocional y la urgencia negativa están asociadas con ANS, poco se sabe sobre las dimensiones específicas que predicen la moti-vación (funciones) y la frecuencia de las autolesiones. Se exploró la relación entre la desregulación emocional, la urgencia negativa, y ANS en 86 adultos jóvenes, divididos en tres grupos: estudiantes universitarios con ANS, pa-cientes TLP con ANS y un grupo de control sano sin ANS. Realizamos análisis de regresión múltiple para predecir las funciones y frecuencia de ANS. La no aceptación de las emociones, una dimensión especifica de la desregulación emocional, predijo de manera única las funciones intraperso-nales de ANS, pero no las funciones interpersonales. Por último, la falta de estrategias de regulación emocional predijo la frecuencia de ANS solo en individuos con una alta urgencia negativa, es decir, individuos que tienden a actuar impulsivamente cuando experimentan emociones negativas, pero no en aquellos con una baja urgencia negativa. Los hallazgos resaltan las moti-vaciones subyacentes a la autolesión y revelan facetas de la desregulación emocional relevantes para el tratamiento de ANS.(AU)
Non-suicidal self-injury (NSSI) is defined as self-inflicted pain, and it is used as a mechanism to alleviate psychological distress. Although NSSI is prevalent in Borderline Personality Disorder (BPD), it is also an increasing concern among college student populations. While emotion dysregulation and negative urgency are associated with NSSI, little is known about which dimensions specifically predict the motivations (NSSI-functions) and frequency of self-harm. The current study explored the rela-tionship between emotion dysregulation, negative urgency, and NSSI in 86 young adults, divided into three groups: college students with NSSI, BPD patients with NSSI, and a healthy control group without NSSI. We con-ducted multiple regression analyses to predicted NSSI-functions and NSSI-frequency. Non-acceptance of emotions, a specific dimension of emotion dysregulation, uniquely predicted intrapersonal NSSI-functions (e.g., regu-lating distressing emotions), but not interpersonal NSSI-functions (e.g., communicating distress). Lastly, poor emotion regulation strategies pre-dicted NSSI-frequency only in individuals with high negative urgency, that is, individuals who tend to act impulsively when experiencing negative emotions, but not in those with low negative urgency. Findings shed light on the underlying motivations for engaging in self-injury, and they reveal facets of emotion dysregulation relevant for NSSI treatment.(AU)
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Humanos , Masculino , Femenino , Adulto Joven , Conducta Autodestructiva/psicología , Trastorno de Personalidad Limítrofe , Conducta del Adolescente , Conducta Autodestructiva , Autocontrol , Trastornos Disruptivos, del Control de Impulso y de la Conducta , Salud Mental , Psicología Social , Psicología , Estudios de Casos y Controles , PsiquiatríaRESUMEN
Allergies are a common and increasing health problem affecting millions of people worldwide. This increase is attributed to genetic predisposition, air pollution, climate change, lack of physical activity, and alterations in eating habits. The Mediterranean diet (MD), which includes a lot of fruits and vegetables, whole grains, legumes, nuts, olive oil, and fish, has been linked to a variety of health benefits, including a lower risk of chronic and allergic disease. This paper explores the effects of the dietary components of the MD on food allergies. Electronic databases PubMed, Scopus, Science Direct, and EBSCO were used to conduct this systematic review. Out of 696 studies initially identified, five human and four animal studies were included. Risk of bias was determined using the Office of Health Assessment and Translation tool. In human studies, when the intervention was given during pregnancy and lactation, a beneficial effect was observed. When the intervention was given during pregnancy and until birth or to the infant for six months, no effect was observed. The animal studies indicated a beneficial effect between the food components of the MD and food allergies. Although the results are promising, the limited number of studies highlights the need for more research.
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Dieta Mediterránea , Hipersensibilidad a los Alimentos , Embarazo , Animales , Femenino , Humanos , Hipersensibilidad a los Alimentos/prevención & control , Verduras , Frutas , Aceite de OlivaRESUMEN
BACKGROUND: Non-suicidal self-injury (NSSI) is a serious public health concern among adolescents, especially in clinical settings. Social support plays a critical role in the onset and maintenance of NSSI in adolescence. NSSI is closely associated with borderline personality disorder (BPD), yet no previous work has analyzed the mediating role of borderline traits in the relationship between perceived social support (PSS) and NSSI. This study aimed to address this gap. METHODS: Participants were 228 adolescent patients (12 to 18 years old), who completed a clinical interview and self-report measures of BPD-traits, current psychological distress, emotion dysregulation and PSS. They were grouped based on the presence (vs. absence) of NSSI. Univariate and multivariate logistic regression analyses were used to identify risk factors of NSSI, and a mediation analysis was conducted to examine the intermediary role of borderline traits in the relationship between PSS and NSSI. RESULTS: NSSI was highly prevalent in our sample (58%) and was associated with higher clinical severity. Low PSS predicted NSSI in univariate, but not multivariate regression. Mediation analyses showed that borderline traits fully accounted for the relationship between low PSS and NSSI, even when controlling for current psychological distress and gender. LIMITATIONS: Cross-sectional design through self-report assessment. CONCLUSIONS: Findings suggest that adolescents with low PSS are especially vulnerable for developing NSSI due to elevated BPD traits. In clinical settings, interventions aimed to reduce borderline symptoms may be a promising treatment option for adolescents with NSSI and low PSS.
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Trastorno de Personalidad Limítrofe , Conducta Autodestructiva , Adolescente , Trastorno de Personalidad Limítrofe/epidemiología , Trastorno de Personalidad Limítrofe/psicología , Niño , Estudios Transversales , Humanos , Personalidad , Conducta Autodestructiva/psicología , Apoyo SocialRESUMEN
Background: Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in MKRN3, DLK1, KISS1, and KISS1R genes were investigated in patients with CPP. Methods: Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the MKRN3 gene. All children found negative (n = 44) for the MKRN3 gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by in silico computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the MKRN3 gene, mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes was designed. Results: Three previously described pathogenic MKRN3 variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic MKRN3 variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the MKRN3. Among the 44 CPP patients submitted to WES, nine rare DLK1 variants were identified in 11 girls, two rare KISS1 variants in six girls, and two rare MAGEL2 variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP. Conclusion: The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP.
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Pubertad Precoz/genética , Encefalopatías/epidemiología , Encefalopatías/genética , Proteínas de Unión al Calcio/genética , Niño , Preescolar , Estudios de Cohortes , Chipre/epidemiología , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Kisspeptinas/genética , Masculino , Proteínas de la Membrana/genética , Mutación , Pubertad Precoz/epidemiología , Receptores de Kisspeptina-1/genética , Ubiquitina-Proteína Ligasas/genética , Secuenciación del ExomaRESUMEN
Non-suicidal self-injury (NSSI) is an increasingly prevalent phenomenon associated with many detrimental outcomes, ranging from poor academic performance to suicide attempts. Research on self-harming behaviors has identified emotion dysregulation, negative affect, and borderline pathology as strong risk factors of NSSI, whereas the potential protective effects of metacognitive skills such as decentering have not yet been explored. The current study combined ecological momentary assessment (EMA) and self-report measures to explore potential risk and protective factors of NSSI in a clinical group of Borderline Personality Disorder (BPD) patients with NSSI (N = 22), a subclinical group of college students with NSSI (N = 19), and a non-clinical healthy control group (N = 23). Participants completed self-report measures of borderline pathology, emotion dysregulation, decentering ability, and negative emotional symptoms, and they used the Sinjur App (EMA instrument) at least three times a day for 15 days to capture negative affect and NSSI in daily life. A multilevel mixed-effect regression analysis with both self-report and EMA measures was conducted to identify predictors of NSSI. The multilevel analysis showed that only momentary frustration directly predicted NSSI. Momentary guilt and anger only predicted NSSI when interacting with more stable traits of borderline pathology and negative emotional symptoms. Most importantly, greater decentering capacity protected against self-injury and attenuated the association between momentary sadness and NSSI. Findings contribute novel knowledge about NSSI, documenting the protective effects of decentering and highlighting the benefit of interventions that target metacognitive emotion regulation skills.
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Trastorno de Personalidad Limítrofe , Conducta Autodestructiva , Evaluación Ecológica Momentánea , Humanos , Autoinforme , Conducta Autodestructiva/epidemiología , Intento de Suicidio , Adulto JovenRESUMEN
The authors compared self-reported and behavioral responses to reward and punishment in individuals diagnosed with borderline personality disorder (BPD) or avoidant personality disorder (APD) relative to a healthy comparison (HC) group. As predicted, self-reported sensitivity to reward was significantly higher in the BPD group than in the APD and HC groups. Also as predicted, self-reported sensitivity to punishment was significantly elevated in both disordered groups but significantly higher in APD than in BPD. These hypothesized patterns were also evident in responses to behavioral tasks: Participants with BPD made more errors of commission and fewer errors of omission than HC participants on a passive avoidance learning task, and participants with APD showed greater reactivity to losses than other participants on a probabilistic reversal learning task. Results help characterize differences between these two disorders.
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Trastorno de Personalidad Limítrofe , Castigo , Humanos , Trastornos de la Personalidad , RecompensaRESUMEN
Following the COVID-19 lockdown, the BSc in Human Biology Program of the University of Nicosia switched from face-to-face to online delivery mode. Herein we describe how we identified and managed the challenges that arose to successfully complete the Semester.
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Biología/educación , COVID-19/epidemiología , Curriculum , Educación a Distancia , Pandemias , SARS-CoV-2 , HumanosRESUMEN
This article was migrated. The article was marked as recommended. Purpose of the article Cross border partnerships require curricula, faculty and students to negotiate challenges associated with national regulatory frameworks, contexts and cultures. This study investigated student attitude and behaviours when encountering learning about health services in host and home students in the context of problem based learning. Materials and Methods First year graduate entry students' health systems interest and exposure and their perceptions of the dynamics of learning in PBL were investigated via a questionnaire comprising open and closed questions. Results and Conclusions Results showed a difference between home and host students in the ways they learned about home health systems and their attitudes to the value of learning about home and international health systems. There was no difference in the quantity of health service related learning objectives generated. Both groups reported noticing differences between the PBL cases and clinical practice, however, perceptions of the reasons for the differences varied between home and host students. We are interested in the way in which this perception of difference was reported as either a stimulus or a barrier to learning.
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Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is caused by mutations in the CYP21A2 gene. The study refers to CAH patients of Greek-Cypriot ancestry between years 2007 and 2018. One hundred and twenty patients with various degrees of CAH were categorized and genotyped. The patients were categorized in 4 mutation groups based on their clinical and biochemical findings. The majority of patients (85.0%) belonged to the non-classic (NC)-CAH form and the disorder was more often diagnosed in females (71.7%). The most severe classic salt-wasting (SW) form was identified in 11 neonates (9.2%). Seven (5.8%) children were also identified with the simple virilizing (SV) form and a median presentation age of 5 years [interquartile range (IQR) 3.2-6.5]. In the 240 nonrelated alleles, the most frequent mutation was p.Val281Leu (60.0%) followed by c.655 A/C>G (IVS2-13A/C>G) (8.8%), p.Pro453Ser (5.8%), DelEx1-3 (4.6%), p.Val304Met (4.6%), and p.Gln318stop (4.2%). Other less frequent mutations including rare deletions were also identified. Following our recent report that the true carrier frequency of CYP21A2 in Greek-Cypriots is 1:10, this study reports that the CAH prevalence is predicted around 1.7 cases per 10 000 people. Therefore, the up-to-date 120 CAH patients identified by our group make only the 6.9% of the ones estimated (approximately 1750) to exist in the Greek Cypriot population. The compiled data from a coherent population such as the Greek-Cypriot could be valuable for the antenatal diagnosis, management and genetic counselling of the existing and prospect families with CAH.
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Hiperplasia Suprarrenal Congénita/genética , Esteroide 21-Hidroxilasa/genética , Hiperplasia Suprarrenal Congénita/enzimología , Alelos , Niño , Preescolar , Chipre , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Mutación Puntual , Estudios Retrospectivos , Esteroide 21-Hidroxilasa/metabolismoRESUMEN
Microbial physiology is a basic course taught throughout biomedical science disciplines. Students study the structure, growth, and metabolism of microorganisms and often find it difficult to learn the information, usually because they fail to see the wider applications. The current microbiology laboratory series describes how to transform a "cookbook" undergraduate laboratory to an inquiry-based one by incorporating problem-based learning. The students use a food poisoning case study that develops over a series of seven experiments and take on the role of the microbiology technician who is responsible for coming up with the answer and submitting a report to a clinician. The case provides coherence to the sessions, and the students are given the opportunity to learn about, and practice, common techniques they would encounter in a clinical microbiology laboratory. Those include the aseptic method, cultivation of bacteria, quantification of bacteria in culture, isolation of pure culture, morphological observation by light microscopy, Gram staining, the use of selective and differential media, and the effectiveness of a variety of antimicrobials and antibiotics. This laboratory series has been designed so that it can be implemented in any setting, using simple materials and inexpensive, nonspecialized equipment. The experiments are carried out in small groups, and a facilitator may tutor up to two groups of 10 students at a time. The current method has been successfully implemented for the past 2 yr, and the students demonstrated greater motivation in learning and understanding.
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Técnicas Microbiológicas/métodos , Microbiología/educación , Aprendizaje Basado en Problemas/métodos , Estudiantes , HumanosRESUMEN
BACKGROUND: The onset of puberty is influenced by the interplay of stimulating and restraining factors, many of which have a genetic origin. Premature activation of the GnRH secretion in central precocious puberty (CPP) may arise either from gain-of-function mutations of the KISS1 and KISS1R genes or from loss-of-function manner mutations of the MKRN3 gene leading to MKRN3 deficiency. OBJECTIVE: To explore the genetic causes responsible for CPP and the potential role of the RING finger protein 3 (MKRN3) gene. DESIGN AND PATIENTS: We investigated potential sequence variations in the intronless MKRN3 gene by Sanger sequencing of the entire 507 amino acid coding region of exon 1 in a family with two affected girls presented with CPP at the age of 6 and 5·7 years, respectively. RESULTS: A novel heterozygous g.Gly312Asp missense mutation in the MKRN3 gene was identified in these siblings. The imprinted MKRN3 missense mutation was also identified as expected in the unaffected father and followed as expected an imprinted mode of inheritance. In silico analysis of the altered missense variant using the computational algorithms Polyphen2, SIFT and Mutation Taster predicted a damage and pathogenic alteration causing CPP. The pathogenicity of the alteration at the protein level via an in silico structural model is also explored. CONCLUSION: A novel mutation in the MKRN3 gene in two sisters with CPP was identified, supporting the fundamental role of this gene in the suppression of the hypothalamic GnRH neurons.
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Simulación por Computador , Predisposición Genética a la Enfermedad/genética , Mutación Missense , Pubertad Precoz/genética , Ribonucleoproteínas/genética , Secuencia de Aminoácidos , Niño , Preescolar , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , Conformación Proteica , Ribonucleoproteínas/química , Hermanos , Ubiquitina-Proteína LigasasRESUMEN
Systemic lupus erythematosus (SLE) T cells exhibit several activation signaling anomalies including defective Ca(2+) response and increased NF-AT nuclear translocation. The duration of the Ca(2+) signal is critical in the activation of specific transcription factors and a sustained Ca(2+) response activates NF-AT. Yet, the distribution of Ca(2+) responses in SLE T cells is not known. Furthermore, the mechanisms responsible for Ca(2+) alterations are not fully understood. Kv1.3 channels control Ca(2+) homeostasis in T cells. We reported a defect in Kv1.3 trafficking to the immunological synapse (IS) of SLE T cells that might contribute to the Ca(2+) defect. The present study compares single T cell quantitative Ca(2+) responses upon formation of the IS in SLE, normal, and rheumatoid arthritis (RA) donors. Also, we correlated cytosolic Ca(2+) concentrations and Kv1.3 trafficking in the IS by two-photon microscopy. We found that sustained [Ca(2+)](i) elevations constitute the predominant response to antigen stimulation of SLE T cells. This defect is selective to SLE as it was not observed in RA T cells. Further, we observed that in normal T cells termination of Ca(2+) influx is accompanied by Kv1.3 permanence in the IS, while Kv1.3 premature exit from the IS correlates with sustained Ca(2+) responses in SLE T cells. Thus, we propose that Kv1.3 trafficking abnormalities contribute to the altered distribution in Ca(2+) signaling in SLE T cells. Overall these defects may explain in part the T cell hyperactivity and dysfunction documented in SLE patients.
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Linfocitos T CD4-Positivos/metabolismo , Señalización del Calcio/inmunología , Canal de Potasio Kv1.3/metabolismo , Lupus Eritematoso Sistémico/inmunología , Subgrupos de Linfocitos T/metabolismo , Adulto , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Señalización del Calcio/efectos de los fármacos , Línea Celular Transformada , Femenino , Humanos , Sinapsis Inmunológicas/inmunología , Canal de Potasio Kv1.3/inmunología , Lupus Eritematoso Sistémico/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/fisiología , Masculino , Persona de Mediana Edad , Bloqueadores de los Canales de Potasio/farmacología , Transporte de Proteínas/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patologíaRESUMEN
The immunological synapse (IS), a highly organized structure that forms at the point of contact between a T cell and an APC, is essential for the proper development of signaling events, including the Ca(2+) response. Kv1.3 channels control Ca(2+) homeostasis in human T cells and move into the IS upon Ag presentation. However, the process involved in channel accumulation in the IS and the functional implications of this localization are not yet known. Here we define the movement of Kv1.3 into the IS and study whether Kv1.3 localization into the IS influences Ca(2+) signaling in Jurkat T cells. Crosslinking of the channel protein with an extracellular Ab limits Kv1.3 mobility and accumulation at the IS. Moreover, Kv1.3 recruitment to the IS does not involve the transport of newly synthesized channels and it does not occur through recycling of membrane channels. Kv1.3 localization in the IS modulates the Ca(2+) response. Blockade of Kv1.3 movement into the IS by crosslinking significantly increases the amplitude of the Ca(2+) response triggered by anti-CD3/anti-CD28-coated beads, which induce the formation of the IS. On the contrary, the Ca(2+) response induced by TCR stimulation without the formation of the IS with soluble anti-CD3/anti-CD28 Abs is unaltered. The results presented herein indicate that, upon Ag presentation, membrane-incorporated Kv1.3 channels move along the plasma membrane to localize in the IS. This localization is important to control the amplitude of the Ca(2+) response, and disruption of this process can account for alterations of downstream Ca(2+)-dependent signaling events.
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Calcio/metabolismo , Sinapsis Inmunológicas/inmunología , Canal de Potasio Kv1.3/metabolismo , Linfocitos T/inmunología , Anticuerpos/farmacología , Antígenos/inmunología , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , Complejo CD3/inmunología , Complejo CD3/metabolismo , Calcio/inmunología , Humanos , Sinapsis Inmunológicas/metabolismo , Células Jurkat , Canal de Potasio Kv1.3/antagonistas & inhibidores , Canal de Potasio Kv1.3/inmunología , Activación de Linfocitos/inmunología , Linfocitos T/citología , Linfocitos T/metabolismoRESUMEN
Understanding the molecular mechanisms underlying dysregulated immune responses in human immunodeficiency virus type 1 (HIV-1) infection is crucial for the control of HIV/AIDS. Despite the postulate that HIV envelope glycoprotein gp120-CD4 interactions lead to impaired T-cell responses, the precise mechanisms underlying such association are not clear. To address this, we analyzed Lck and F-actin redistribution into the immunological synapse in stimulated human primary CD4(+) T cells from HIV-1-infected donors. Similar experiments were performed with CD4(+) T cells from HIV-uninfected donors, which were exposed to anti-CD4 domain 1 antibodies, as an in vitro model of gp120-CD4 interactions, or aldithriol-inactivated HIV-1 virions before stimulation. CD4(+) T cells from HIV-infected patients exhibited a two- to threefold inhibition of both Lck and F-actin recruitment into the synapse, compared to cells from uninfected donors. Interestingly, defective recruitment of Lck was ameliorated following suppressive highly active antiretroviral therapy. Engagement of the CD4 receptor on T cells from HIV-uninfected donors before anti-CD3/CD28 stimulation led to similar defects. Furthermore, the redistribution of Lck into lipid rafts was abrogated by CD4 preengagement. Our results suggest that the engagement of CD4 by HIV gp120 prior to T-cell receptor stimulation leads to dysregulation of early signaling events and could consequently play an important role in impaired CD4(+) T-cell function.
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Antígenos CD4/inmunología , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , Sinapsis Inmunológicas , Activación de Linfocitos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Actinas/metabolismo , Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , VIH-1 , HumanosRESUMEN
Aberrant T cell responses during T cell activation and immunological synapse (IS) formation have been described in systemic lupus erythematosus (SLE). Kv1.3 potassium channels are expressed in T cells where they compartmentalize at the IS and play a key role in T cell activation by modulating Ca(2+) influx. Although Kv1.3 channels have such an important role in T cell function, their potential involvement in the etiology and progression of SLE remains unknown. This study compares the K channel phenotype and the dynamics of Kv1.3 compartmentalization in the IS of normal and SLE human T cells. IS formation was induced by 1-30 min exposure to either anti-CD3/CD28 Ab-coated beads or EBV-infected B cells. We found that although the level of Kv1.3 channel expression and their activity in SLE T cells is similar to normal resting T cells, the kinetics of Kv1.3 compartmentalization in the IS are markedly different. In healthy resting T cells, Kv1.3 channels are progressively recruited and maintained in the IS for at least 30 min from synapse formation. In contrast, SLE, but not rheumatoid arthritis, T cells show faster kinetics with maximum Kv1.3 recruitment at 1 min and movement out of the IS by 15 min after activation. These kinetics resemble preactivated healthy T cells, but the K channel phenotype of SLE T cells is identical to resting T cells, where Kv1.3 constitutes the dominant K conductance. The defective temporal and spatial Kv1.3 distribution that we observed may contribute to the abnormal functions of SLE T cells.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Comunicación Celular/inmunología , Canal de Potasio Kv1.3/metabolismo , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Subgrupos de Linfocitos T/inmunología , Adulto , Anciano , Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/patología , Señalización del Calcio/inmunología , Femenino , Reordenamiento Génico de Linfocito T , Homeostasis/inmunología , Humanos , Inmunofenotipificación , Cinética , Canal de Potasio Kv1.3/biosíntesis , Canal de Potasio Kv1.3/fisiología , Lupus Eritematoso Sistémico/patología , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Unión Proteica/inmunología , Transporte de Proteínas/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Fase de Descanso del Ciclo Celular/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patologíaRESUMEN
T cell receptor engagement results in the reorganization of intracellular and membrane proteins at the T cell-antigen presenting cell interface forming the immunological synapse (IS), an event required for Ca(2+) influx. KCa3.1 channels modulate Ca(2+) signaling in activated T cells by regulating the membrane potential. Nothing is known regarding KCa3.1 membrane distribution during T cell activation. Herein, we determined whether KCa3.1 translocates to the IS in human T cells using YFP-tagged KCa3.1 channels. These channels showed electrophysiological and pharmacological properties identical to wild-type channels. IS formation was induced by either anti-CD3/CD28 antibody-coated beads for fixed microscopy experiments or Epstein-Barr virus-infected B cells for fixed and live cell microscopy. In fixed microscopy experiments, T cells were also immunolabeled for F-actin or CD3epsilon, which served as IS formation markers. The distribution of KCa3.1 was determined with confocal and fluorescence microscopy. We found that, upon T cell activation, KCa3.1 channels localize with F-actin and CD3epsilon to the IS but remain evenly distributed on the cell membrane when no stimulus is provided. Detailed imaging experiments indicated that KCa3.1 channels are recruited in the IS shortly after antigen presentation and are maintained there for at least 15-30 min. Interestingly, pretreatment of activated T cells with the specific KCa3.1 blocker TRAM-34 blocked Ca(2+) influx, but channel redistribution to the IS was not prevented. These results indicate that KCa3.1 channels are a part of the signaling complex that forms at the IS upon antigen presentation.