Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity.

Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.

How mood is affected by environment and upsetting events: The moderating role of psychological flexibility.

OBJECTIVE: Patients suffering from psychological disorders report decreased quality of life and low mood. The relationship of these symptoms to daily upsetting events or environments, and in the context of active coping mechanisms is poorly understood. The present study thus investigates the association between mood, psychological flexibility, upsetting events, and environment in the daily life of outpatients. METHOD: We investigated 80 outpatients at the beginning of treatment, using event sampling methodology (ESM). Patients' mood, occurrence of upsetting events, current environment, and psychological flexibility were sampled six times per day during a one-week intensive longitudinal examination. Data were analyzed using linear mixed models (LMMs). RESULTS: Participants reported worse mood the more upsetting events they experienced. Further, participants reported better mood when in private environments (e.g., with friends), and worse mood when at the hospital, compared to being at home. Higher levels of psychological flexibility, however, were associated with better mood, irrespective of the occurrence of upsetting events or current environment. CONCLUSION: Results suggest that mood is positively associated with psychological flexibility, not despite, but especially during the dynamic and context-specific challenges of daily life. Psychological flexibility may thus potentially act as a buffer against distress-provoking situations as patients go about their daily lives. TRIAL REGISTRATION: ISRCTN.org identifier: ISRCTN11209732.

Psychotherapy for Chronic In- and Outpatients with Common Mental Disorders: The "Choose Change" Effectiveness Trial.

INTRODUCTION: Treatment non-response occurs regularly, but psychotherapy is seldom examined for such patients. Existing studies targeted single diagnoses, were relatively small, and paid little attention to treatment under real-world conditions. OBJECTIVE: The Choose Change trial tested whether psychotherapy was effective in treating chronic patients with treatment non-response in a transdiagnostic sample of common mental disorders across two variants of treatment delivery (inpatient and outpatient). METHODS: The controlled nonrandomized effectiveness trial was conducted between May 2016 and May 2021. The study took place in two psychiatric clinics with N = 200 patients (n = 108 inpatients and n = 92 outpatients). Treatment variants were integrated inpatient care versus outpatient care based on acceptance and commitment therapy (ACT) for approximately 12 weeks. Therapists delivered individualized and non-manualized ACT. Main outcome measures were symptoms (Brief Symptom Checklist [BSCL]); well-being (Mental Health Continuum-Short Form [MHC-SF]), and functioning (WHO Disability Assessment Schedule [WHO-DAS]). RESULTS: Both inpatients and outpatients showed decreases in symptomatology (i.e., BSCL: d = 0.68) and increases in well-being and functioning (MHC-SF: d = 0.60 and WHO-DAS: d = 0.70), with more improvement in the inpatients during treatment. Both groups maintained gains 1 year following treatment, and the groups did not significantly differ from each other at this timepoint. Psychological flexibility moderated impact of stress on outcomes. CONCLUSIONS: Psychotherapy as practiced under routine conditions is effective for a sample of patients with common mental disorders, a long history of treatment experience and burden of disease, in both inpatient and outpatient settings. TRIAL REGISTRATION: This study was registered in the ISRCTN registry on May 20, 2016, with the registration number ISRCTN11209732.

Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly affects cardiac function. METHODS: We used genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole-organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and postconditioning therapeutic agents. RESULTS: Analysis of human complex trait genetics indicates that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using human induced pluripotent stem cell-derived cardiomyocytes in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacologic inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and 2 models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as preconditioning or postconditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no effect on cardiac ion channels regulating baseline electromechanical coupling and physiologic performance. CONCLUSIONS: Our data provide compelling evidence for a novel pharmacologic strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

Donation After Circulatory Death: A New Frontier.

PURPOSE OF REVIEW: To highlight the current global experience with DCD heart transplantation and explore the evolution of, and compare preservation strategies; examine early clinical outcomes, and discuss the growing use of DCD donors as a new frontier in heart transplantation. RECENT FINDINGS: The two strategies of DCD heart preservation include NMP using the OCS Heart and TA-NRP followed by either: NMP or CSS. Better understanding the limits of cold ischaemia following TA-NRP will aid in distant procurement. Asystolic warm ischaemia plays an important role in determining immediate post-operative graft function and potential need for mechanical support. Large volume DCD heart transplant units show no difference in survival between DCD and DBD donor heart transplants. In a previously non-utilised source of donor hearts, often viewed as an "unknown frontier" in heart transplantation, DCD hearts are a suitable alternative to brain-dead donor hearts and are likely to remain a permanent part of the heart transplantation landscape. Global uptake is currently increasing, and as understanding of preservation strategies and tolerable ischaemic times improve, utilisation of DCD hearts will continue to grow.

Prevention and Reversal of Frailty in Heart Failure　- A Systematic Review.

BACKGROUND: Frailty is prevalent in patients with heart failure (HF) and associated with increased morbidity and mortality. Hence, there has been increased interest in the reversibility of frailty following treatment with medication or surgery. This systematic review aimed to assess the reversibility of frailty in patients with HF before and after surgical interventions aimed at treating the underlying cause of HF. It also aimed to assess the efficacy of cardiac rehabilitation and prehabilitation in reversing or preventing frailty in patients with HF.Methods and Results:Searches of PubMed, MEDLINE and Academic Search Ultimate identified studies with HF patients undergoing interventions to reverse frailty. Titles, abstracts and full texts were screened for eligibility based on the PRISMA guidelines and using predefined inclusion/exclusion criteria in relation to participants, intervention, control, outcome and study design. In total, 14 studies were included: 3 assessed the effect of surgery, 7 assessed the effect of rehabilitation programs, 2 assessed the effect of a prehabilitation program and 2 assessed the effect of program interruptions on HF patients. CONCLUSIONS: Overall, it was found that frailty is at least partially reversible and potentially preventable in patients with HF. Interruption of rehabilitation programs resulted in deterioration of the frailty status. Future research should focus on the role of prehabilitation in mitigating frailty prior to surgical intervention.

The spatiotemporal movement of patients in and out of a psychiatric hospital: an observational GPS study.

BACKGROUND: Movement is a basic component of health. Little is known about the spatiotemporal movement of patients with mental disorders. The aim of this study was to determine how spatiotemporal movement of patients related to their symptoms and wellbeing. METHOD: A total of 106 patients (inpatients (n = 69) and outpatients (n = 37)) treated for a wide range of mental disorders (transdiagnostic sample) carried a GPS-enabled smartphone for one week at the beginning of treatment. Algorithms were applied to establish spatiotemporal clusters and subsequently related to known characteristics of these groups (i.e., at the hospital, at home). Symptomatology, Wellbeing, and Psychological flexibility were also assessed. RESULTS: Spatiotemporal patterns of inpatients and outpatients showed differences consistent with predictions (e.g., outpatients showed higher active areas). These patterns were largely unassociated with symptoms (except for agoraphobic symptoms). Greater movement and variety of movement were more predictive of wellbeing, however, in both inpatients and outpatients. CONCLUSION: Measuring spatiotemporal patterns is feasible, predictive of wellbeing, and may be a marker of patient functioning. Ethical issues of collecting GPS data are discussed.

Interictal Hyperperfusion in the Higher Visual Cortex in Patients With Episodic Migraine.

BACKGROUND: Migraine pathophysiology is complex and probably involves cortical and subcortical alterations. Structural and functional brain imaging studies indicate alterations in the higher order visual cortex in patients with migraine. Arterial spin labeling magnetic resonance imaging (ASL-MRI) is a non-invasive imaging method for assessing changes in cerebral blood flow (CBF) in vivo. OBJECTIVE: To examine if interictal CBF differs between patients with episodic migraine (EM) with or without aura and healthy controls (HC). METHODS: We assessed interictal CBF using 2D pseudo-continuous ASL-MRI on a 3 Tesla Philips scanner (University Hospital Zurich, Switzerland) in EM (N = 17, mean age 32.7 ± 9.9, 13 females) and HC (N = 19, mean age 31.0 ± 9.3, 11 females). RESULTS: Compared to HC, EM showed exclusively hyperperfusion in the right MT+ and Cohen's d effect size was 0.99 (HC mean CBF ± SD: 33.1 ± 5.9 mL/100 g/minutes; EM mean CBF: 40.9 ± 9.4 mL/100 g/minutes). EM with aura (N = 13, MwA) revealed hyperperfusion compared to HC in the right MT+ and superior temporal gyrus. For MT, Cohen's d effect size was 1.34 (HC mean CBF ± SD: 33.1 ± 5.9 mL/100 g/minutes; MwA mean CBF: 43.3 ± 8.6 mL/100 g/minutes). For the superior temporal gyrus, Cohen's d effect size was 1.28 (HC mean CBF ± SD: 40.1 ± 4.9 mL/100 g/minutes; MwA mean CBF: 47.4 ± 6.4 mL/100 g/minutes). In EM, anxiety was positively associated with CBF in the parietal operculum and angular gyrus. CONCLUSIONS: Our results suggest that extrastriate brain regions probably involved in cortical spreading depression are associated with CBF changes in the interictal state. We conclude that ASL-MRI is a sensitive method to identify local neuro-functional abnormalities in CBF in patients with EM in the interictal state.

"Choose change": design and methods of an acceptance and commitment therapy effectiveness trial for transdiagnostic treatment-resistant patients.

BACKGROUND: Acceptance and Commitment Therapy (ACT) has been successfully established in hundreds of efficacy trials. It is less understood, however, how ACT works in real-world settings. Furthermore, little is known about how contextual variables such as treatment setting (inpatient vs. outpatient), social network and environment of the patient impact outcome. METHODS: This paper describes the methods of the Choose Change study that compares transdiagnostic inpatients (n = 85) and outpatients (n = 85) with varying degrees of treatment experience and treatment success (i.e., no previous treatment vs. previous remission vs. treatment-resistant). Patients received ACT during an intensive treatment phase lasting approximately twelve treatment sessions, and were accompanied up to twelve months following intensive treatment. Main outcomes include symptoms, functioning, and well-being. Multiple levels of data are investigated, including treatment context, weekly assessments, a behavioral approach test, multiple follow-up phases, and ambulatory assessment using Event Sampling Methodology, to examine patients' daily context. DISCUSSION: We aim to investigate antecedents, consequences, and inherent processes that contribute to the maintenance or fluctuations of psychological disorders and the efficacy of ACT treatment. Furthermore, this study intends to increase understanding of how accurately participants can report on their own experiences, in order to expand our knowledge of how to probe for such information in the future. The results of Choose Change will provide basic clinical theory and clinical care with important and meaningful insights into the effectiveness of ACT, trans diagnostically, in in- and outpatients, and in a naturalistic setting. TRIAL REGISTRATION: This study was retrospectively registered in the ISRCTN Registry (registration number ISRCTN11209732 ) on May 20th 2016.

PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells.

Current approaches in tissue engineering are geared toward generating tissue-specific stem cells. Given the complexity and heterogeneity of tissues, this approach has its limitations. An alternate approach is to induce terminally differentiated cells to dedifferentiate into multipotent proliferative cells with the capacity to regenerate all components of a damaged tissue, a phenomenon used by salamanders to regenerate limbs. 5-Azacytidine (AZA) is a nucleoside analog that is used to treat preleukemic and leukemic blood disorders. AZA is also known to induce cell plasticity. We hypothesized that AZA-induced cell plasticity occurs via a transient multipotent cell state and that concomitant exposure to a receptive growth factor might result in the expansion of a plastic and proliferative population of cells. To this end, we treated lineage-committed cells with AZA and screened a number of different growth factors with known activity in mesenchyme-derived tissues. Here, we report that transient treatment with AZA in combination with platelet-derived growth factor-AB converts primary somatic cells into tissue-regenerative multipotent stem (iMS) cells. iMS cells possess a distinct transcriptome, are immunosuppressive, and demonstrate long-term self-renewal, serial clonogenicity, and multigerm layer differentiation potential. Importantly, unlike mesenchymal stem cells, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner and, unlike embryonic or pluripotent stem cells, do not form teratomas. Taken together, this vector-free method of generating iMS cells from primary terminally differentiated cells has significant scope for application in tissue regeneration.

Targeted deletion of Traf2 allows immunosuppression-free islet allograft survival in mice.

AIMS/HYPOTHESIS: Administration of anti-CD40 ligand (CD40L) antibodies has been reported to allow long-term islet allograft survival in non-human primates without the need for exogenous immunosuppression. However, the use of anti-CD40L antibodies was associated with thromboembolic complications. Targeting downstream intracellular components shared between CD40 and other TNF family co-stimulatory molecules could bypass these complications. TNF receptor associated factor 2 (TRAF2) integrates multiple TNF receptor family signalling pathways that are critical for T cell activation and may be a central node of alloimmune responses. METHODS: T cell-specific Traf2-deficient mice (Traf2TKO) were generated to define the role of TRAF2 in CD4+ T cell effector responses that mediate islet allograft rejection in vivo. In vitro allograft responses were tested using mixed lymphocyte reactions and analysis of IFN-γ and granzyme B effector molecule expression. T cell function was assessed using anti-CD3/CD28-mediated proliferation and T cell polarisation studies. RESULTS: Traf2TKO mice exhibited permanent survival of full MHC-mismatched pancreatic islet allografts without exogenous immunosuppression. Traf2TKO CD4+ T cells exhibited reduced proliferation, activation and acquisition of effector function following T cell receptor stimulation; however, both Traf2TKO CD4+ and CD8+ T cells exhibited impaired alloantigen-mediated proliferation and acquisition of effector function. In polarisation studies, Traf2TKO CD4+ T cells preferentially converted to a T helper (Th)2 phenotype, but exhibited impaired Th17 differentiation. Without TRAF2, thymocytes exhibited dysregulated TNF-mediated induction of c-Jun N-terminal kinase (JNK) and canonical NFκB pathways. Critically, targeting TRAF2 in T cells did not impair the acute phase of CD8-dependent viral immunity. These data highlight a specific requirement for a TRAF2-NFκB and TRAF2-JNK signalling cascade in T cell activation and effector function in rejecting islet allografts. CONCLUSION/INTERPRETATION: Targeting TRAF2 may be useful as a therapeutic approach for immunosuppression-free islet allograft survival that avoids the thromboembolic complications associated with the use of anti-CD40L antibodies.

TRAF2 regulates peripheral CD8(+) T-cell and NKT-cell homeostasis by modulating sensitivity to IL-15.

In this study, a critical and novel role for TNF receptor (TNFR) associated factor 2 (TRAF2) is elucidated for peripheral CD8(+) T-cell and NKT-cell homeostasis. Mice deficient in TRAF2 only in their T cells (TRAF2TKO) show ∼40% reduction in effector memory and ∼50% reduction in naïve CD8(+) T-cell subsets. IL-15-dependent populations were reduced further, as TRAF2TKO mice displayed a marked ∼70% reduction in central memory CD8(+) CD44(hi) CD122(+) T cells and ∼80% decrease in NKT cells. TRAF2TKO CD8(+) CD44(hi) T cells exhibited impaired dose-dependent proliferation to exogenous IL-15. In contrast, TRAF2TKO CD8(+) T cells proliferated normally to anti-CD3 and TRAF2TKO CD8(+) CD44(hi) T cells exhibited normal proliferation to exogenous IL-2. TRAF2TKO CD8(+) T cells expressed normal levels of IL-15-associated receptors and possessed functional IL-15-mediated STAT5 phosphorylation, however TRAF2 deletion caused increased AKT activation. Loss of CD8(+) CD44(hi) CD122(+) and NKT cells was mechanistically linked to an inability to respond to IL-15. The reduced CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell populations in TRAF2TKO mice were rescued in the presence of high dose IL-15 by IL-15/IL-15Rα complex administration. These studies demonstrate a critical role for TRAF2 in the maintenance of peripheral CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell homeostasis by modulating sensitivity to T-cell intrinsic growth factors such as IL-15.

BAFF regulates activation of self-reactive T cells through B-cell dependent mechanisms and mediates protection in NOD mice.

Targeting the BAFF/APRIL system has shown to be effective in preventing T-cell dependent autoimmune disease in the NOD mouse, a spontaneous model of type 1 diabetes. In this study we generated BAFF-deficient NOD mice to examine how BAFF availability would influence T-cell responses in vivo and the development of spontaneous diabetes. BAFF-deficient NOD mice which lack mature B cells, were protected from diabetes and showed delayed rejection of an allogeneic islet graft. Diabetes protection correlated with a failure to expand pathogenic IGRP-reactive CD8(+) T cells, which were maintained in the periphery at correspondingly low levels. Adoptive transfer of IGRP-reactive CD8(+) T cells with B cells into BAFF-deficient NOD mice enhanced IGRP-reactive CD8(+) T-cell expansion. Furthermore, when provoked with cyclophosphamide, or transferred to a secondary lymphopenic host, the latent pool of self-reactive T cells resident in BAFF-deficient NOD mice could elicit beta cell destruction. We conclude that lack of BAFF prevents the procurement of B-cell-dependent help necessary for the emergence of destructive diabetes. Indeed, treatment of NOD mice with the BAFF-blocking compound, BR3-Fc, resulted in a delayed onset and reduced incidence of diabetes.

Heart Transplantation From DCD Donors in Australia: Lessons Learned From the First 74 Cases.

Heart transplantation from donation after circulatory death (DCD) donors has the potential to substantially increase overall heart transplant activity. The aim of this report is to review the first 8 y of our clinical heart transplant program at St Vincent's Hospital Sydney, to describe how our program has evolved and to report the impact that changes to our retrieval protocols have had on posttransplant outcomes. Since 2014, we have performed 74 DCD heart transplants from DCD donors utilizing a direct procurement protocol followed by normothermic machine perfusion. Changes to our retrieval protocol have resulted in a higher retrieval rate from DCD donors and fewer rejections of DCD hearts during normothermic machine perfusion. Compared with our previously reported early experience in the first 23 transplants, we have observed a significant reduction in the incidence of severe primary graft dysfunction from 35% (8/23) to 8% (4/51) in the subsequent 51 transplant recipients ( P < 0.01). The only withdrawal time interval significantly associated with severe primary graft dysfunction was the asystolic warm ischemic time: 15 (12-17) versus 13 (11-14) min ( P < 0.05). One- and 5-y survival of DCD heart transplant recipients was 94% and 88%, comparable to that of a contemporary cohort of donation after brain death recipients: 87 and 81% ( P -value was not significant). In conclusion, heart transplantation from DCD donors has become a major contributor to our overall transplant activity accounting for almost 30% of all transplants performed by our program in the last 2 y, with similar DCD and donation after brain death outcomes.

Meaningful Relationships in Community and Clinical Samples: Their Importance for Mental Health.

Meaningful relationships are centrally important for human functioning. It remains unclear, however, which aspects of meaningful relationships impact wellbeing the most and whether these differ between psychiatric patients and members of the community. Information about relationship attributes and functions were collected in community members (N = 297) and psychiatric patients (N = 177). Relationship attributes and functions were examined for differences between groups (community vs. patients), their impact on wellbeing and symptoms, and the size of network (one vs. many relationships). Community members reported fewer relationships, higher frequency of contact and less desire for change when compared to the psychiatric patients. Nevertheless, both groups reported relatively high levels of fulfilled functions. Quality of the relationship and investment into the relationship was associated with both wellbeing and symptoms for both the community and the patient group. Almost all functions were associated with wellbeing and symptoms for the community group. However, for the patient group, only few functions (sexual partner, go-to person for compassion, go-to person when happy) were associated with wellbeing and no functions were associated with symptoms. Contrary to our hypotheses, the results show that psychiatric patients do not have a deficit in fulfilling relationships. Most people report a well-functioning network of meaningful, high-quality relationships. Patients benefit from meaningful, function-fulfilling relationships just as much as community members. Results are discussed with respect to how targeting relationships can be used clinically.

Having versus not having social interactions in patients diagnosed with depression or social phobia and controls.

Humans need meaningful social interactions, but little is known about the consequences of not having them. We examined meaningful social interactions and the lack thereof in patients diagnosed with major depressive disorder (MDD) or social phobia (SP) and compared them to a control group (CG). Using event-sampling methodology, we sampled participants' everyday social behavior 6 times per day for 1 week in participants' natural environment. We investigated the quality and the proportion of meaningful social interactions (when they had meaningful social interactions) and degree of wishing for and avoidance of meaningful social interactions (when they did not have meaningful social interactions). Groups differed on the quality and avoidance of meaningful social interactions: Participants with MDD and SP reported perceiving their meaningful social interactions as lower quality (in terms of subjective meaningfulness) than the CG, with SP patients reporting even lower quality than the MDD patients. Further, both MDD and SP patients reported avoiding meaningful social interactions significantly more often than the CG. Although the proportion of meaningful social interactions was similar in all groups, the subjective quality of meaningful social interactions was perceived to be lower in MDD and SP patients. Future research might further identify what variables influenced the reinforcement of the MDD and SP patients so that they engaged in the same number of meaningful social interactions even though the quality of their meaningful social interactions was lower. Increasing awareness of what happens when patients do or do not have meaningful social interactions will help elucidate a potentially exacerbating or maintaining factor of the disorders.

The Effect of Increasing Donor Age on Myocardial Ischemic Tolerance in a Rodent Model of Donation After Circulatory Death.

Hearts from older donors or procured via donation after circulatory death (DCD) can alleviate transplant waitlist; however, these hearts are particularly vulnerable to injury caused by warm ischemic times (WITs) inherent to DCD. This study investigates how the combination of increasing donor age and pharmacologic supplementation affects the ischemic tolerance and functional recovery of DCD hearts and how age impacts cardiac mitochondrial respiratory capacity and oxidative phosphorylation. METHODS: Wistar rats (12-, 18-, and 24-mo-old) were subjected to DCD with 20-min fixed WIT. Hearts were procured, instrumented onto a Langendorff perfusion circuit, flushed with Celsior preservation solution with or without supplementation (glyceryl trinitrate [GTN]/erythropoietin [EPO]/zoniporide [Z]) and perfused (Krebs-Henseleit buffer, 37°C Langendorff 30-min, working 30-min). Cardiac functional recovery of aortic flow (AF), coronary flow (CF), cardiac output (CO), and lactate dehydrogenase release were measured. Native heart tissue (3-, 12-, and 24-mo) were assessed for mitochondrial respiratory capacity. RESULTS: Unsupplemented 18- and 24-month DCD hearts showed a 6-fold decrease in AF recovery relative to unsupplemented 12-month DCD hearts. GTN/EPO/Z supplementation significantly increased AF and CO recovery of 18-month DCD hearts to levels comparable to supplemented 12-month hearts; however, GTN/EPO/Z did not improve 24-month DCD heart recovery. Compared to 12-month heart tissue, 24-month hearts exhibited significantly impaired mitochondrial oxygen flux at complex I, II, and uncoupled maximal respiration stage. CONCLUSIONS: Reduced ischemic tolerance after DCD was associated with increasing age. Pharmacologic supplementation improves functional recovery of rat DCD hearts but only up to age 18 months, possibly attributed to a decline in mitochondrial respiratory capacity with increasing age.

The everyday lives of in- and outpatients when beginning therapy: The importance of values-consistent behavior.

BACKGROUND/OBJECTIVE: The manifestation of functional impairment in patients' daily lives and interference with things they value is poorly understood. If values are compromised in patients, as theory suggests, social contexts (and the lack thereof) are especially important - though this is currently unexplored. We therefore examined whether daily values-consistent behavior was associated with the importance of a value and whether it involved social or non-social activity. METHOD: Using Event Sampling Methodology, we examined daily values-consistent behavior in 57 transdiagnostic inpatients and 43 transdiagnostic outpatients at the beginning of treatment. Patients' values-consistent behavior, its importance, and (social vs non-social) context was sampled six times per day during a one-week intensive longitudinal examination. RESULTS: Across both groups, the probability of subsequent values-consistent behavior increased if (1) it was judged as more important by the patient or (2) if it was embedded in a social context. The probability of reporting values-consistent behavior was higher for outpatients than inpatients. CONCLUSIONS: Clinicians are encouraged to examine the values of their patients more closely and to especially monitor important and/or social values. Incorporating these into clinical work might increase patients' values-consistent behavior, which can play a role in reducing suffering.

ANTECEDENTES/OBJETIVO: La interferencia funcional en la experiencia cotidiana y los valores personales de pacientes está insuficientemente estudiada. Si sus valores son perturbados, los contextos sociales ­y su carencia­ son especialmente importantes, pero esto permanece inexplorado. Examinamos si los comportamientos coherentes con los valores están asociados a la importancia acordada e implicación en actividades sociales/no sociales. MÉTODO: Se empleó metodología de muestreo de eventos para examinar la coherencia del comportamiento diario con los valores de 57 pacientes en clínica hospitalaria y 43 en clínica ambulatoria al comienzo de un tratamiento transdiagnóstico. A través de una investigación longitudinal intensiva durante siete días, el comportamiento coherente con los valores, su importancia y el contexto de la actividad en curso (social/no social) fueron muestreados seis veces por día. RESULTADOS: En ambos grupos, la probabilidad de comportamiento coherente con los valores aumentó cuando (1) este era considerado como más importante y (2) cuando este se produjo en un contexto social. La probabilidad de tal comportamiento fue mayor para los pacientes en tratamiento ambulatorio que para aquellos en tratamiento clínico. CONCLUSIONES: Se recomida explorar los valores de los pacientes, particularmente aquellos juzgados como más importantes y/o sociales. Su incorporación en la práctica clínica podría promover la coherencia entre valores y comportamientos subsecuentes.

Treating treatment non-responders: A meta-analysis of randomized controlled psychotherapy trials.

BACKGROUND: Non-responsiveness to treatment occurs in approximately one third of patients. Randomized clinical trials of psychotherapy options for these patients are scarce and systematic knowledge about whether psychotherapy is a viable option is lacking. OBJECTIVES: This meta-analysis aimed to 1) determine the amount of evidence available for treatment non-response using psychotherapy relative to pharmacological procedures; 2) systematically review randomized controlled psychotherapy trials (RCTs) used to treat non-responders; and 3) examine whether some psychotherapies are more efficacious than others. DATA SOURCES: Online databases were systematically examined and references of relevant systematic reviews were hand-searched. STUDY ELIGIBILITY CRITERIA: RCTs that administered a psychotherapy new to non-responders were considered. All Mood and Anxiety Disorders were considered. No limitations were made with respect to type of treatment. REVIEW METHOD: A meta-analytic review of the psychotherapy RCTs for treatment non-responders. RESULTS: Results showed that psychotherapy was successful in treating treatment non-responders with a medium to large effect size. Between-group comparisons did not reveal significant differences in treatment effects for any of the assessed disorder or treatment types. Effects were maintained at follow-up. CONCLUSIONS: Psychotherapy is a viable treatment option for treatment non-responders. More attention to this group of patients is needed and more research with better quality studies is warranted. Recommendations are discussed.

Cyclosporine A as a Cardioprotective Agent During Donor Heart Retrieval, Storage, or Transportation: Benefits and Limitations.

BACKGROUND: Storage of donor hearts in cardioplegic solutions supplemented with conditioning agents activating endogenous mitochondrial protective signaling enhanced their postreperfusion recovery. The present study investigates the role of timing and duration of cardiac exposure to cyclosporine A (CsA), another putative mitochondrial protectant, on cardiac functional recovery and potential mechanisms of CsA action in an isolated working rat heart model of donor heart retrieval and storage. METHODS: After measurement of baseline function, hearts were arrested and stored for 6 hours at 4°C in either Celsior alone or Celsior + CsA (0.2 µM), then reperfused for 45 minutes in Krebs solution, when functional recovery was assessed. Two additional groups of Celsior-alone stored hearts were exposed to 0.2 µM CsA for the initial 15 minutes (nonworking period) or the full 45-minute period of reperfusion. Coronary effluent was collected pre- and poststorage for assessment of lactate dehydrogenase release. Tissue samples were collected at the end of each study for immunoblotting and histological studies. RESULTS: CsA supplementation during cold storage or the first 15-minute reperfusion significantly improved functional recovery and significantly increased phospho-AMPKαThr172 and phospho-ULK-1Ser757. Hearts exposed to CsA for 45 minutes at reperfusion recovered poorly with no phospho-AMP-activated protein kinase α activation, decreased phospho-eNOSSer633, and decreased mitochondrial cytochrome c content with increased lactate dehydrogenase release. CONCLUSIONS: Inclusion of CsA during cold storage is cardioprotective. Effects of CsA addition to the perfusate during reperfusion were time dependent, with benefits at 15 minutes but not 45 minutes of reperfusion. The toxic effect with the presence of CsA for the full 45-minute reperfusion is associated with impaired mitochondrial integrity and decreased eNOS phosphorylation.