Mechanism of RPE Cell Death in α-Crystallin Deficient Mice: A Novel and Critical Role for MRP1-Mediated GSH Efflux

Absence of α-crystallins (αA and αB) in retinal pigment epithelial (RPE) cells renders them susceptible to oxidant-induced cell death. We tested the hypothesis that the protective effect of α-crystallin is mediated by changes in cellular glutathione (GSH) and elucidated the mechanism of GSH efflux. In α-crystallin overexpressing cells resistant to cell death, cellular GSH was >2 fold higher than vector control cells and this increase was seen particularly in mitochondria. The high GSH levels associated with α-crystallin overexpression were due to increased GSH biosynthesis. On the other hand, cellular GSH was decreased by 50% in murine retina lacking αA or αB crystallin. Multiple multidrug resistance protein (MRP) family isoforms were expressed in RPE, among which MRP1 was the most abundant. MRP1 was localized to the plasma membrane and inhibition of MRP1 markedly decreased GSH efflux. MRP1-suppressed cells were resistant to cell death and contained elevated intracellular GSH and GSSG. Increased GSH in MRP1-supressed cells resulted from a higher conversion of GSSG to GSH by glutathione reductase. In contrast, GSH efflux was significantly higher in MRP1 overexpressing RPE cells which also contained lower levels of cellular GSH and GSSG. Oxidative stress further increased GSH efflux with a decrease in cellular GSH and rendered cells apoptosis-prone. In conclusion, our data reveal for the first time that 1) MRP1 mediates GSH and GSSG efflux in RPE cells; 2) MRP1 inhibition renders RPE cells resistant to oxidative stress-induced cell death while MRP1 overexpression makes them susceptible and 3) the antiapoptotic function of α-crystallin in oxidatively stressed cells is mediated in part by GSH and MRP1. Our findings suggest that MRP1 and α crystallin are potential therapeutic targets in pathological retinal degenerative disorders linked to oxidative stress

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Complex PTSD, affect dysregulation, and borderline personality disorder. Borderline Personal. Disord. Emot

Abstract Complex PTSD (cPTSD) was formulated to include, in addition to the core PTSD symptoms, dysregulation in three psychobiological areas: (1) emotion processing, (2) self-organization (including bodily integrity), and (3) relational security. The overlap of diagnostic criteria for cPTSD and borderline personality disorder (BPD) raises questions about the scientific integrity and clinical utility of the cPTSD construct/diagnosis, as well as opportunities to achieve an increasingly nuanced understanding of the role of psychological trauma in BPD. We review clinical and scientific findings regarding comorbidity, clinical phenomenology and neurobiology of BPD, PTSD, and cPTSD, and the role of traumatic victimization (in general and specific to primary caregivers), dissociation, and affect dysregulation. Findings suggest that BPD may involve heterogeneity related to psychological trauma that includes, but extends beyond, comorbidity with PTSD and potentially involves childhood victimization-related dissociation and affect dysregulation consistent with cPTSD. Although BPD and cPTSD overlap substantially, it is unwarranted to conceptualize cPTSD either as a replacement for BPD, or simply as a sub-type of BPD. We conclude with implications for clinical practice and scientific research based on a better differentiated view of cPTSD, BPD and PTSD. Keywords: Borderline personality disorder, Complex PTSD, Dissociation, Affect dysregulation Review Individuals who experience complex (i.e., developmentally adverse interpersonal) trauma (e.g., maltreatment, prolonged family or community violence, torture or exploitation) -especially but not exclusively in formative periods (e.g., early childhood, adolescence)-are at risk not only for posttraumatic stress disorder (PTSD) but also other psychiatric disorders [1], including personality disorders Two decades ago, complex PTSD (cPTSD) was defined as a syndrome involving pathological dissociation, emotion dysregulation, somatization, and altered core schemas about the self, relationships, and sustaining beliefs (i.e., morality, spirituality) in the aftermath of exposure to traumatic interpersonal victitmization. cPTSD was proposed as an alternative for conceptualizing and treating the symptoms of adults who had suffered prolonged and severe interpersonal trauma, many of whom were diagnosed with BPD cPTSD has been both proposed and disputed as a valid and usefu

The Need for Inclusion of Psychological Trauma in the Professional Curriculum: A Call to Action

An appreciable disparity exists between the need for services by professionals with expertise in psychological trauma and the availability of these services. Despite the establishment of a solid base of scientific literature on trauma and the growing attunement of society and the media to the adverse psychological impact of traumatic events, this area has yet to be decisively incorporated into the core curriculum of graduate training in psychology and other professions. This paper provides an overview of the prevalence, scope, and impact of trauma in the general population and the current lack of adequate resources to address the psychological difficulties engendered by traumatic experiences. Existing models of trauma training are discussed, and strategies for expanding the availability of trauma training are recommended