Exploiting Co(III)-Cyclopentadienyl Complexes To Develop Anticancer Agents.

In recent years, organometallic complexes have attracted much attention as anticancer therapeutics aiming at overcoming the limitations of platinum drugs that are currently marketed. Still, the development of half-sandwich organometallic cobalt complexes remains scarcely explored. Four new cobalt(III)-cyclopentadienyl complexes containing N,N-heteroaromatic bidentate, and phosphane ligands were synthesized and fully characterized by elemental analysis, spectroscopic techniques, and DFT methods. The cytotoxicity of all complexes was determined in vitro by the MTS assay in colorectal (HCT116), ovarian (A2780), and breast (MDA-MB-231 and MCF-7) human cancer cell lines and in a healthy human cell line (fibroblasts). The complexes showed high cytotoxicity in cancer cell lines, mostly due to ROS production, apoptosis, autophagy induction, and disruption of the mitochondrial membrane. Also, these complexes were shown to be nontoxic in vivo in an ex ovo chick embryo yolk sac membrane (YSM) assay.

Oxide-silicate petrology and geochemistry of subducted hydrous ultramafic rocks beyond antigorite dehydration (Central Alps, Switzerland).

Oxide minerals contained in ultramafic rocks are useful tools to assess the redox conditions of the rock and fluids liberated upon progressive serpentinite dehydration during subduction, as these minerals contain a relevant redox-sensitive element, iron. Previous studies have revealed that magnetite predominates across the antigorite-out reaction. However, the fate of magnetite and other oxides at higher pressure and temperature conditions has remained underexplored. We present a comprehensive petrological and geochemical study of oxide-sulfide-silicate mineral assemblages in metaperidotites beyond antigorite- and chlorite-out reactions (T = 650-850 °C and P = 1-3 GPa). Several ultramafic lenses, covering different bulk rock compositions and extents of oxidation upon oceanic serpentinization, were investigated from the Central Alps, Switzerland. Results point to two endmember scenarios: (i) Most frequently, metaperidotites have olivine with a Mg# of 89-91 (defined as molar Mg/(Mg + Fetot) × 100) and contain low oxide modes (0.06-1.41 vol.%), hematite is absent, and redox conditions are weakly oxidized and buffered by orthopyroxene-olivine-magnetite. (ii) Rare occurrence, high olivine Mg# > 94.5 metaperidotites display coexisting hematite and magnetite, high oxide modes (up to 4 vol.%), and redox conditions are hematite-magnetite (HM) buffered (Δlog10fO2,QFM of + 3 to + 4). Spinel displays evolving compositions from magnetite over chromite to Al-Cr-spinel, roughly correlating with increasing temperature. Most of the samples buffered by the olivine-orthopyroxene-magnetite assemblage contain coexisting pentlandite ± pyrrhotite, thus identifying stable sulfides beyond antigorite dehydration for these weakly oxidized samples (Δlog10fO2,QFM < 2.5). No sulfides were recognized in the highly oxidized sample. The transition of magnetite to chromite at around 700 °C goes along with a shift in fO2 to lower values. At the prevailing oxygen fugacity in the weakly oxidized metaperidotites sulfur in a coexisting fluid is always present in its reduced form. However, oxidized sulfur can be stable in the dehydration fluids released from highly oxidized serpentinites. Supplementary Information: The online version contains supplementary material available at 10.1007/s00410-023-02032-w.

In vitro activity of imipenem/relebactam against Pseudomonas aeruginosa isolates recovered from ICU patients in Spain and Portugal (SUPERIOR and STEP studies).

OBJECTIVES: To study the in vitro activity of imipenem/relebactam and comparators and the imipenem/relebactam resistance mechanisms in a Pseudomonas aeruginosa collection from Portugal (STEP, 2017-18) and Spain (SUPERIOR, 2016-17) surveillance studies. METHODS: P. aeruginosa isolates (n = 474) were prospectively recovered from complicated urinary tract (cUTI), complicated intra-abdominal (cIAI) and lower respiratory tract (LRTI) infections in 11 Portuguese and 8 Spanish ICUs. MICs were determined (ISO broth microdilution). All imipenem/relebactam-resistant P. aeruginosa isolates (n = 30) and a subset of imipenem/relebactam-susceptible strains (n = 32) were characterized by WGS. RESULTS: Imipenem/relebactam (93.7% susceptible), ceftazidime/avibactam (93.5% susceptible) and ceftolozane/tazobactam (93.2% susceptible) displayed comparable activity. The imipenem/relebactam resistance rate was 6.3% (Portugal 5.8%; Spain 8.9%). Relebactam restored imipenem susceptibility to 76.9% (103/134) of imipenem-resistant isolates, including MDR (82.1%; 32/39), XDR (68.8%; 53/77) and difficult-to-treat (DTR) isolates (67.2%; 45/67). Among sequenced strains, differences in population structure were detected depending on the country: clonal complex (CC)175 and CC309 in Spain and CC235, CC244, CC348 and CC253 in Portugal. Different carbapenemase gene distributions were also found: VIM-20 (n = 3), VIM-1 (n = 2), VIM-2 (n = 1) and VIM-36 (n = 1) in Spain and GES-13 (n = 13), VIM-2 (n = 3) and KPC-3 (n = 2) in Portugal. GES-13-CC235 (n = 13) and VIM type-CC175 (n = 5) associations were predominant in Portugal and Spain, respectively. Imipenem/relebactam showed activity against KPC-3 strains (2/2), but was inactive against all GES-13 producers and most of the VIM producers (8/10). Mutations in genes affecting porin inactivation, efflux pump overexpression and LPS modification might also be involved in imipenem/relebactam resistance. CONCLUSIONS: Microbiological results reinforce imipenem/relebactam as a potential option to treat cUTI, cIAI and LRTI caused by MDR/XDR P. aeruginosa isolates, except for GES-13 and VIM producers.

Sleep-disordered breathing patterns in hospitalized patients with acute heart failure across the entire spectrum of ejection fraction.

BACKGROUND: Sleep-disordered breathing (SDB) is prevalent in heart failure (HF). Yet, scarce data exist on sleep-patterns in acute HF and differences in specific subgroups. Our goal was to assess SDB prevalence in hospitalized patients with decompensated HF across the entire spectrum of left ventricle ejection fraction (LVEF). METHODS: Single-center retrospective study enrolling patients admitted for acute HF between 2013 and 2018. All patients were screened for SDB with an ApneaLink™ Plus device before discharge while euvolemic and receiving oral therapy. Those with a sleep study time < 3 h were excluded. HF with reduced, moderately reduced, and preserved LVEF (HFrEF, HFmrEF, and HFpEF) was defined by a LVEF < 40%, 40-49%, and ≥ 50%, respectively. SDB was defined by an apnea-hypopnea index (AHI) ≥ 5/h. RESULTS: Overall, 221 patients were included (mean age 75 ± 11 years). Seventy-two (33%) had HFrEF, 26 (11%) HFmrEF, and 123 (56%) HFpEF. In total, 176 (80%) met the criteria for mild SDB, while 59% and 38% had an AHI ≥ 15/h or ≥ 30/h, respectively. SDB prevalence was high and similar between HFrEF, HFmrEF, and HFpEF. Yet, SDB was often more severe in HFrEF when compared to HFpEF. HFmrEF had intermediate characteristics, with an AHI closer to HFrEF. CONCLUSION: In a cohort of patients admitted for acute HF, SDB was highly prevalent in all subgroups, including HFmrEF. The pervasiveness and severity of SDB was particularly noted in HFrEF. These findings suggest that routine SDB screening may be warranted following acute HF.

Single-shot spatial coherence characterization of x-ray ultrafast sources.

Spatial coherence is an impactful source parameter in many applications ranging from atomic and molecular physics to metrology or imaging. In lensless imaging, for example, it can strongly affect the image formation, especially when the source exhibits shot-to-shot variations. Single-shot characterization of the spatial coherence length of a source is thus crucial. However, current techniques require either parallel intensity measurements or the use of several masks. Based on the method proposed by González et al. [J. Opt. Soc. Am. A28, 1107 (2011)JOAOD60740-323210.1364/JOSAA.28.001107], we designed a specific arrangement of a two-dimensional non-redundant array of apertures, which allows, through its far field interference pattern, for a single-shot measurement of the spatial coherence, while being robust against beam-pointing instabilities. The strategic configuration of the pinholes allows us to disentangle the degree of spatial coherence from the intensity distribution, thus removing the need for parallel measurement of the beam intensity. An experimental validation is performed using a high-harmonic source. A statistical study in different regimes shows the robustness of the method.

CLIF-C AD Score Predicts Development of Acute Decompensations and Survival in Hospitalized Cirrhotic Patients.

BACKGROUND AND AIMS: Patients with decompensated cirrhosis are at increased risk of mortality, even in absence of ACLF. The CLIF-C AD score (CLIF-C ADs) was proposed as a prognostic score but lacks sufficient validation. Our aim was to describe clinical characteristics and hospital evolution according to score groups and evaluate prognostic capability of CLIF-C ADs alone or in combination with other scores. METHODS: Two hundred and sixty-six patients (55 ± 14 years, ascites in 63%, MELD 14 ± 5) were included, and classified as high, intermediate and low CLIF-C ADs in 13, 60 and 27% of cases. Development of new complications of cirrhosis during hospitalization and survival at 3 months were evaluated. RESULTS: Patients with high CLIF-C ADs had more severe systemic inflammation parameters and higher frequency of organ dysfunction. CLIF-C ADs ≥ 60, when compared to intermediate and low groups, was associated with higher incidence of complications of cirrhosis (90% vs 70% and 49%, p < 0.001) and lower survival (93%, 80% and 50%, p < 0.0001). In multivariate analysis, CLIF-C ADs, ascites and MELD were predictors of survival [(AUROC 0.76 (95% CI 0.69-0.83)]. Absence of ascites or MELD < 14 identified patients with intermediate CLIF-C ADs and good survival (89 and 84%, respectively). CONCLUSION: CLIF-C ADs predicts survival in cirrhotic patients with AD. High CLIF-C ADs is associated with higher frequency of organ dysfunction, increased risk of new complications of cirrhosis and high short-term mortality. On the contrary, individuals with low CLIF-C ADs, as well as those with intermediate score without ascites or with low MELD have excellent prognoses.

Microglia cytoarchitecture in the brain of adenosine A2A receptor knockout mice: Brain region and sex specificities.

Microglia cells exert a critical role in brain development, mainly supported by their immune functions, which predicts an impact on the genesis of psychiatric disorders. In fact, microglia stress during gestation is, for instance, associated with chronic anxiety and cognitive deficits accompanied by long-lasting, region- and sex-specific changes in microglia morphology. We recently reported that the pattern of microglia morphologic plasticity, which is sex-determined, impacts on anxious-like behaviour and cognition. We also reported that the pharmacologic blockade of adenosine A2A receptors (A2A R) is able to reshape microglia morphology, in a sex-specific manner and with behavioural sequelae. In order to better understand the role of A2A R in the sex differentiation of microglia, we now compared their morphology in wild-type and A2A R knockout male and female C57BL/6 mice in two cardinal brain regions implicated in anxiety-like behaviour and cognition, the prefrontal cortex (PFC) and the dorsal hippocampus (dHIP). We report interregional differences between PFC and dHIP in a sex-specific manner: while males presented more complex microglia in the dHIP, microglia from females had a more complex morphology in the PFC. Surprisingly, the genetic deletion of A2A R did not alter these sex differences, but promoted the exclusive remodelling (increase in complexity) in PFC microglia from females. These findings further support the existence of a heterogeneous microglial network, distinct between sexes and brain regions, and help characterizing the role of A2A R in the sex- and brain region-specific morphologic differentiation of microglia.

Effect of biologic disease-modifying anti-rheumatic drugs targeting remission in axial spondyloarthritis: systematic review and meta-analysis.

OBJECTIVES: To assess the efficacy of biologic DMARDs (bDMARDs) in achieving Assessment of Spondyloarthritis International Society partial remission (ASAS-PR) and/or Ankylosing Spondylitis Disease Activity Score inactive disease (ASDAS-ID), as remission-like surrogates, in axial SpA (axSpA). METHODS: Data from randomized controlled trials (RCTs), including long-term extensions, were included. A systematic literature review was performed using the MEDLINE database (first search May 2018, updated February 2020) and PICO criteria according to Patients-adults with radiographic or non-radiographic axSpA; Intervention-any bDMARD; Comparator-placebo and/or any different drug; Outcomes-ASAS-PR and/or ASDAS-ID as primary or secondary endpoints. Meta-analysis was performed after assessment of the homogeneity of study designs, populations and outcomes. RESULTS: After screening 155 references, a total of 22 RCTs and 28 long-term extensions were retrieved. ASAS-PR was the dominant remission-like definition used. Concerning TNF inhibitors, 14/17 RCTs provided evidence of efficacy in reaching remission at different time points: 12, 16, 24 and 28 weeks (ASAS-PR in 16-62% of patients and ASDAS-ID in 24-40% of patients). With a limited number of studies available, IL-17A inhibitors exhibited remission rates of 15-21% for ASAS-PR and 11-16% for ASDAS-ID at week 16. A meta-analysis regarding ASAS-PR was performed considering RCTs with a similar duration (12, 16 or 24 weeks). The relative risk for achieving remission was 3.864 (95% CI 2.937, 5.085). CONCLUSION: bDMARDs have a clear impact in axSpA remission evaluated by ASAS-PR. Nevertheless, these data show an unmet need for improved reporting of remission-like outcomes.

Region-specific control of microglia by adenosine A2A receptors: uncoupling anxiety and associated cognitive deficits in female rats.

Epidemiologic studies have provided compelling evidence that prenatal stress, through excessive maternal glucocorticoids exposure, is associated with psychiatric disorders later in life. We have recently reported that anxiety associated with prenatal exposure to dexamethasone (DEX, a synthetic glucocorticoid) correlates with a gender-specific remodeling of microglia in the medial prefrontal cortex (mPFC), a core brain region in anxiety-related disorders. Gender differences in microglia morphology, the higher prevalence of anxiety in women and the negative impact of anxiety in cognition, led us to specifically evaluate cognitive behavior and associated circuits (namely mPFC-dorsal hippocampus, dHIP), as well as microglia morphology in female rats prenatally exposed to dexamethasone (in utero DEX, iuDEX). We report that iuDEX impaired recognition memory and deteriorated neuronal synchronization between mPFC and dHIP. These functional deficits are paralleled by microglia hyper-ramification in the dHIP and decreased ramification in the mPFC, showing a heterogeneous remodeling of microglia morphology, both postnatally and at adulthood in different brain regions, that differently affect mood and cognition. The chronic blockade of adenosine A2A receptors (A2A R), which are core regulators of microglia morphology and physiology, ameliorated the cognitive deficits, but not the anxiety-like behavior. Notably, A2A R blockade rectified both microglia morphology in the dHIP and the lack of mPFC-dHIP synchronization, further heralding their role in cognitive function.

Effectiveness of direct-acting agents for hepatitis C and liver stiffness changing after sustained virological response.

BACKGROUND AND AIM: Few studies have evaluated sustained virological response (SVR) rates by direct-acting agents (DAAs) and liver stiffness measurement (LSM) changing post-SVR in limited-resource settings. We aimed to describe the effectiveness of DAAs for hepatitis C virus treatment and to assess the changing of LSM post-SVR. METHODS: This retrospective study analyzed data of consecutive hepatitis C virus-infected patients treated by DAAs from 2015 to 2017 in two tertiary centers in Brazil. SVR rates were reported by intention-to-treat and per-protocol analyses. LSM by transient elastography performed before treatment and post-SVR was compared, and logistic regression models were performed. RESULTS: Six hundred seventy-one patients (63% female, 62 years [55-68], 89% genotype 1, 8% HIV co-infected, and 64% with cirrhosis) were included. Most patients were treated by sofosbuvir/daclatasvir ± ribavirin (74%) and sofosbuvir/simeprevir ± ribavirin (21%). SVR rates (95% confidence interval [CI]) were 94.6% (92.7-96.1) and 97.8% (96.4-98.7) for intention-to-treat and per-protocol analyses, respectively. The leading adverse event was anemia (9.6% [95% CI 7.6-12.1]). Pretreatment and post-SVR12 LSM were available in 400 patients. LSM had significantly decreased after SVR (13.6 kPa [interquartile range, 10.0-21.6] vs 10.2 kPa [7.0-17.6], P < 0.001). A total of 167 patients (42%) decreased at least 30% of LSM post-SVR. The absence of type 2 diabetes (odds ratio = 1.52 [95% CI 1.05-2.21], P = 0.028) and presence of platelet count ≥ 150 × 109 /mm3 (odds ratio = 1.75 [1.23-2.50], P = 0.002) were independently associated with a significant LSM regression (≥ 30%) post-SVR. CONCLUSION: DAAs were highly effective and safe, and LSM significantly decreased after SVR in a real-life cohort in Brazil. The absence of type 2 diabetes and presence of high platelet count were independently associated with LSM decrease post-SVR.

The Dyslexia-susceptibility Protein KIAA0319 Inhibits Axon Growth Through Smad2 Signaling.

KIAA0319 is a transmembrane protein associated with dyslexia with a presumed role in neuronal migration. Here we show that KIAA0319 expression is not restricted to the brain but also occurs in sensory and spinal cord neurons, increasing from early postnatal stages to adulthood and being downregulated by injury. This suggested that KIAA0319 participates in functions unrelated to neuronal migration. Supporting this hypothesis, overexpression of KIAA0319 repressed axon growth in hippocampal and dorsal root ganglia neurons; the intracellular domain of KIAA0319 was sufficient to elicit this effect. A similar inhibitory effect was observed in vivo as axon regeneration was impaired after transduction of sensory neurons with KIAA0319. Conversely, the deletion of Kiaa0319 in neurons increased neurite outgrowth in vitro and improved axon regeneration in vivo. At the mechanistic level, KIAA0319 engaged the JAK2-SH2B1 pathway to activate Smad2, which played a central role in KIAA0319-mediated repression of axon growth. In summary, we establish KIAA0319 as a novel player in axon growth and regeneration with the ability to repress the intrinsic growth potential of axons. This study describes a novel regulatory mechanism operating during peripheral nervous system and central nervous system axon growth, and offers novel targets for the development of effective therapies to promote axon regeneration.

The impact of illness-related shame on psychological health and social relationships: Testing a mediational model in students with chronic illness.

This study explores the impact of illness-related shame on the quality of social relationships and psychological health in chronic patients. We aimed to examine the roles of fear of receiving compassion from others and experiential avoidance as potential mediators of this relationship. Although some studies have demonstrated the negative impact of chronic illness-related shame on psychological functioning, the mechanisms that may underlie this link remain understudied. The sample was comprised by 115 college students, which had been diagnosed with at least 1 chronic illness. Participants completed self-report measures on an online platform. This study's design was cross-sectional. A path analysis was conducted using structural equation modelling. Results showed that the impact of illness-related shame on both psychological health (R2  = .45) and the quality of social relationships (R2  = .33) was fully accounted by fear of compassion from others and experiential avoidance. This model revealed an excellent fit. Fear of receiving compassion from others was the main mediator of the illness-related shame link with the quality of social relationships (ß = -.22). The main mediator of the association between shame-related chronic illness and psychological health was experiential avoidance (ß = -.21).This study shed light on possible psychological mechanisms linking feelings of shame associated with having a chronic condition and impaired social relationships and mental health. On one hand, resisting feelings of compassion and care from others and, on the other hand, avoiding difficult internal experiences and situations that might trigger them seem to underlie the impact of shame on psychological and social functioning in chronic patients.

Empathy and feelings of guilt experienced by nurses: A cross-sectional study of their role in burnout and compassion fatigue symptoms.

AIMS: The main goal of this study was to explore the relationships between empathy, empathy-based pathogenic guilt and professional quality of life (burnout and compassion fatigue). We aim to test a model in which we hypothesize that when empathic feelings are related to pathogenic guilt, burnout and compassion fatigue symptoms may be increased. BACKGROUND: Empathy is at the core of nursing practice, and has been associated with positive outcomes not only for the healthcare provider but also for the patient. However, empathy is also at the core of guilt feelings that, when excessive and misdirected, can lead to pathogenic guilt beliefs. We focused on two types of empathy-based guilt characterized by excessive responsibility over others' well-being and how these can be related to professional quality of life. METHODS AND PARTICIPANTS: This study is a cross-sectional self-report survey. Data were collected during 2014 and 2015. Two hundred ninety-eight nurses from public hospitals in Portugal's north and center region were surveyed. Professional quality of life (burnout and compassion fatigue), empathy, and empathy-based guilt were measured using validated self-report measures. RESULTS: Correlation analyses showed that empathy-based guilt was positively associated with empathy, and with burnout and compassion fatigue. Results from multiple mediation models further indicated when empathy is associated with empathy-based guilt, this leads to greater levels of burnout and compassion fatigue. CONCLUSIONS: Given the nature of their work, nurses who experience pathogenic guilt feelings may have compromised well-being, and this should be addressed in training programs aiming at preventing or treating burnout and compassion fatigue.

BEfree: A new psychological program for binge eating that integrates psychoeducation, mindfulness, and compassion.

Binge eating disorder (BED) is associated with several psychological and medical problems, such as obesity. Approximately 30% of individuals seeking weight loss treatments present binge eating symptomatology. Moreover, current treatments for BED lack efficacy at follow-up assessments. Developing mindfulness and self-compassion seem to be beneficial in treating BED, although there is still room for improvement, which may include integrating these different but complimentary approaches. BEfree is the first program integrating psychoeducation-, mindfulness-, and compassion-based components for treating women with binge eating and obesity. OBJECTIVE: To test the acceptability and efficacy up to 6-month postintervention of a psychological program based on psychoeducation, mindfulness, and self-compassion for obese or overweight women with BED. DESIGN: A controlled longitudinal design was followed in order to compare results between BEfree (n = 19) and waiting list group (WL; n = 17) from preintervention to postintervention. Results from BEfree were compared from preintervention to 3- and 6-month follow-up. RESULTS: BEfree was effective in eliminating BED; in diminishing eating psychopathology, depression, shame and self-criticism, body-image psychological inflexibility, and body-image cognitive fusion; and in improving obesity-related quality of life and self-compassion when compared to a WL control group. Results were maintained at 3- and 6-month follow-up. Finally, participants rated BEfree helpful for dealing with impulses and negative internal experiences. CONCLUSIONS: These results seem to suggest the efficacy of BEfree and the benefit of integrating different components such as psychoeducation, mindfulness, and self-compassion when treating BED in obese or overweight women. KEY PRACTITIONER MESSAGE: The current study provides evidence of the acceptability of a psychoeducation, mindfulness, and compassion program for binge eating in obesity (BEfree); Developing mindfulness and self-compassionate skills is an effective way of diminishing binge eating, eating psychopathology and depression, and increasing quality of life in women with obesity; Integrating psychoeducation, mindfulness, and compassion seem to be effective in diminishing binge eating, with results maintained up to 6-month postintervention.

Evaluating the Multifactor Structure of the Long and Short Versions of the Self-Compassion Scale in a Clinical Sample.

OBJECTIVE: There has been a growing interest in the concept of self-compassion in Eastern psychology. The aim of the present study was to explore the dimensionality of the widely used Self-Compassion Scale (SCS; long and short versions) in both clinical and nonclinical samples METHOD: Several confirmatory factor analyses (CFAs) were computed in a mixed clinical (n = 316) and a nonclinical sample (n = 1128) from the Portuguese population. Also, differences were tested between the groups in the SCS 6 factors. RESULTS: The CFA supported both a 6-factor model and a hierarchical model in both samples. The SCS also showed good psychometric properties, with good internal consistency, test-retest reliability, and convergent validity. Our study further suggests that individuals with several psychopathological disorders showed significantly lower self-compassionate abilities. CONCLUSIONS: The SCS (long and short versions) is thus a reliable instrument to assess self-compassion and is useful for research and, in particular, clinical practice.

Exploring self-criticism: confirmatory factor analysis of the FSCRS in clinical and nonclinical samples.

The Forms of Self-criticizing/Attacking and Self-reassuring Scale (FSCRS) is a self-report questionnaire that assesses the forms of self-criticism and self-reassurance. The aim of this study was to explore the latent structure of the FSCRS in nonclinical and clinical samples. Data from 381 participants from the general population and from 304 participants from clinical settings were subjected to confirmatory factor analyses to explore several structural models reflecting alternative representations of the FSCRS dimensionality. Overall, the model with the best fit to the data, in both samples, was the three-factor model (inadequate self, hated self and reassured self subscales) replicating the FSCRS original structure. The scale showed good psychometric characteristics, and the three factors discriminated between the clinical and nonclinical samples. To our knowledge, this is the first study to confirm the factor structure of the FSCRS in a purely clinical sample, and to test alternative models. This study adds to the existent literature that has been supporting the conceptualization of self-criticism as a multidimensional construct. Given the good psychometric properties of the Portuguese version of the FSCRS, its use is encouraged and recommended for the assessment of self-criticism in both clinical and research settings.

T cell apoptosis and induction of Foxp3+ regulatory T cells underlie the therapeutic efficacy of CD4 blockade in experimental autoimmune encephalomyelitis.

The pathogenesis of multiple sclerosis requires the participation of effector neuroantigen-specific T cells. Thus, T cell targeting has been proposed as a promising therapeutic strategy. However, the mechanism underlying effective disease prevention following T cell targeting remains incompletely known. We found, using several TCR-transgenic strains, that CD4 blockade is effective in preventing experimental autoimmune encephalopathy and in treating mice after the disease onset. The mechanism does not rely on direct T cell depletion, but the anti-CD4 mAb prevents the proliferation of naive neuroantigen-specific T cells, as well as acquisition of effector Th1 and Th17 phenotypes. Simultaneously, the mAb favors peripheral conversion of Foxp3(+) regulatory T cells. Pre-existing effector cells, or neuroantigen-specific cells that undergo cell division despite the presence of anti-CD4, are committed to apoptosis. Therefore, protection from experimental autoimmune encephalopathy relies on a combination of dominant mechanisms grounded on regulatory T cell induction and recessive mechanisms based on apoptosis of neuropathogenic cells. We anticipate that the same mechanisms may be implicated in other T cell-mediated autoimmune diseases that can be treated or prevented with Abs targeting T cell molecules, such as CD4 or CD3.

Predictors of painkiller dependence among people with pain in the general population.

OBJECTIVES: Self-medication with painkillers is widespread and increasing, and evidence about influences on painkiller dependence is needed to inform efforts to prevent and treat problem painkiller use. DESIGN: Online questionnaire survey. PARTICIPANTS: People in the general population who had pain and used painkillers in the last month (N = 112). MEASUREMENTS: Pain frequency and intensity, use of over-the-counter and prescription painkillers, risk of substance abuse (Screener and Opioid Assessment for Patients with Pain [SOAPP] scale), depression, anxiety, stress, alexithymia, pain catastrophizing, pain anxiety, pain self-efficacy, pain acceptance, mindfulness, self-compassion, and painkiller dependence (Leeds Dependence Questionnaire). RESULTS: In multiple regression, the independent predictors of painkiller dependence were prescription painkiller use (ß 0.21), SOAPP score (ß 0.31), and pain acceptance (ß -0.29). Prescription painkiller use mediated the influence of pain intensity. Alexithymia, anxiety, and pain acceptance all moderated the influence of pain. CONCLUSIONS: The people most at risk of developing painkiller dependence are those who use prescription painkillers more frequently, who have a prior history of substance-related problems more generally, and who are less accepting of pain. Based on these findings, a preliminary model is presented with three types of influence on the development of painkiller dependence: 1) pain leading to painkiller use, 2) risk factors for substance-related problems irrespective of pain, and 3) psychological factors related to pain. The model could guide further research among the general population and high-risk groups, and acceptance-based interventions could be adapted and evaluated as methods to prevent and treat painkiller dependence.

Recall of threat and submissiveness in childhood and psychopathology: the mediator effect of self-criticism.

UNLABELLED: Research has robustly shown that early negative parenting experiences are associated with psychopathology and self-criticism in adulthood. This study investigates recall of personal feelings of perceived threat and subordination in childhood and its relation to psychopathology. In addition, we explore the mediator role of self-criticism in this association. A sample of 193 subjects from the general population completed self-report questionnaires measuring the study variables. The mediator analyses suggested that the impact of submissiveness experiences in childhood on depression and anxiety is mediated by self-criticism. Our findings highlight the route through which the recall of personal feelings of perceived involuntary subordination to parents contributes to depression and anxiety in adulthood. KEY PRACTITIONER MESSAGE: Although the relation between early experiences of abuse and later psychological problems is now well established, there has been less study on subtler forms of threat and subordinate behaviour in childhood. Given ours and previous findings, therapists should be aware of, and prone to explore, these early experiences. Most studies exploring early negative experiences mainly refer to attachment theory-related constructs (e.g., attachment style). We also highlight the importance of noting rank structure and rank style in the family. Self-criticism seems to be a key process in the relation between early aversive experiences of subordination and psychopathology. Given the idea that self-reassuring operates through a different affect system, helping people develop inner warmth and compassion for the self may be important to counteract feelings of self-hatred and self-attack.