CD155/PVR determines acute myeloid leukemia targeting by Delta One T cells.

ABSTRACT: Relapsed or refractory acute myeloid leukemia (AML) remains a major therapeutic challenge. We have recently developed a Vδ1+ γδ T cell-based product for adoptive immunotherapy, named Delta One T (DOT) cells, and demonstrated their cytolytic capacity to eliminate AML cell lines and primary blasts in vitro and in vivo. However, the molecular mechanisms responsible for the broad DOT-cell recognition of AML cells remain poorly understood. Here, we dissected the role of natural killer (NK) cell receptor ligands in AML cell recognition by DOT cells. Screening of multiple AML cell lines highlighted a strong upregulation of the DNAM-1 ligands, CD155/pulmonary vascular resistance (PVR), CD112/nectin-2, as well as the NKp30 ligand, B7-H6, in contrast with NKG2D ligands. CRISPR-mediated ablation revealed key nonredundant and synergistic contributions of PVR and B7-H6 but not nectin-2 to DOT-cell targeting of AML cells. We further demonstrate that PVR and B7-H6 are critical for the formation of robust immunological synapses between AML and DOT cells. Importantly, PVR but not B7-H6 expression in primary AML samples predicted their elimination by DOT cells. These data provide new mechanistic insight into tumor targeting by DOT cells and suggest that assessing PVR expression levels may be highly relevant to DOT cell-based clinical trials.

Zieve's Syndrome: An Underdiagnosed Cause of Non-immune Hemolytic Anemia.

Zieve's syndrome is an underdiagnosed condition characterized by the triad of jaundice, hemolytic anemia, and hyperlipidemia in the setting of chronic alcohol use. It may be accompanied by acute alcoholic hepatitis. The distinction between the coexistence of acute alcoholic hepatitis with Zieve's syndrome and Zieve's syndrome in isolation is crucial, given the different treatments and prognoses in these situations. A 35-year-old woman presented with complaints of abdominal discomfort, nausea, and vomiting in the previous week. She was a heavy drinker with resultant cirrhosis, splenomegaly, and esophageal varices. An ancillary test showed hemolytic anemia, moderately elevated transaminases, hyperbilirubinemia, and coagulopathy. A negative direct Coombs test established the anemia as non-immune, supporting the diagnosis of Zieve's syndrome despite the absence of hyperlipidemia. Maddrey's discriminant function score was 92 points, so she was treated with supportive measures, as well as corticosteroids in the setting of acute alcoholic hepatitis. The patient showed a favorable clinical and analytical evolution and was discharged home one month following admission with her hemoglobin levels stabilized. Previous literature focused on the distinction between Zieve's syndrome and acute alcoholic hepatitis but they may coexist.

Combining inflammatory miRNA molecules as diagnostic biomarkers for depression: a clinical study.

Background: Inflammation has been implicated in core features of depression pathophysiology and treatment resistance. Therefore, new challenges in the discovery of inflammatory mediators implicated in depression have emerged. MicroRNAs (miRNAs) have been found aberrantly expressed in several pathologies, increasing their potential as biomarkers and therapeutical targets. In this study, the aim was to assess the changes and biomarker potential of inflammation-related miRNAs in depression patients. Methods: Depression diagnosis was performed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 40 healthy controls and 32 depression patients were included in the study. The levels of inflammatory cytokines were measured in plasma, and expression levels of cytokines and inflammation-related miRNAs were evaluated in peripheral blood mononuclear cells (PBMCs). Results: Depression patients were found to have a pro-inflammatory profile in plasma, with significantly higher levels of TNF-α and CCL2 compared with controls. In PBMCs of depression patients, TNF-α and IL-6 expression levels were significantly up and downregulated, respectively. Moreover, miR-342 levels were found upregulated, while miR-146a and miR-155 were significantly downregulated. miR-342 expression levels were positively correlated with TNF-α. Importantly, when analyzed as a diagnostic panel, receiver operating characteristics (ROC) analysis of miR-342, miR-146a, miR-155 in combination, showed to be highly specific and sensitive in distinguishing between depression patients and healthy controls. Conclusion: In summary, these findings suggest that inflammation-related miRNAs are aberrantly expressed in depression patients. Moreover, we show evidences on the potential of the combination of dysregulated miRNAs as a powerful diagnostic tool for depression.

Seascape Genomics and Phylogeography of the Sailfish (Istiophorus platypterus).

Permeable phylogeographic barriers characterize the vast open ocean, boosting gene flow and counteracting population differentiation and speciation of widely distributed and migratory species. However, many widely distributed species consists of distinct populations throughout their distribution, evidencing that our understanding of how the marine environment triggers population and species divergence are insufficient. The sailfish is a circumtropical and highly migratory billfish that inhabits warm and productive areas. Despite its ecological and socioeconomic importance as a predator and fishery resource, the species is threatened by overfishing, requiring innovative approaches to improve their management and conservation status. Thus, we presented a novel high-quality reference genome for the species and applied a seascape genomics approach to understand how marine environmental features may promote local adaptation and how it affects gene flow between populations. We delimit two populations between the Atlantic and Indo-Western Pacific oceans and detect outlier loci correlated with sea surface temperature, salinity, oxygen, and chlorophyll concentrations. However, the most significant explanatory factor that explains the differences between populations was isolation by distance. Despite recent population drops, the sailfish populations are not inbred. For billfishes in general, genome-wide heterozygosity was found to be relatively low compared to other marine fishes, evidencing the need to counteract overfishing effects. In addition, in a climate change scenario, management agencies must implement state-of-the-art sequencing methods, consider our findings in their management plans, and monitor genome-wide heterozygosity over time to improve sustainable fisheries and the long-term viability of its populations.

Randomized clinical study of injectable dextrin-based hydrogel as a carrier of a synthetic bone substitute.

OBJECTIVES: This study aimed to improve the performance and mode of administration of a glass-reinforced hydroxyapatite synthetic bone substitute, Bonelike by Biosckin® (BL®), by association with a dextrin-based hydrogel, DEXGEL, to achieve an injectable and moldable device named DEXGEL Bone. METHODS: Twelve participants requiring pre-molar tooth extraction and implant placement were enrolled in this study. BL® granules (250-500 µm) were administered to 6 randomized participants whereas the other 6 received DEXGEL Bone. After 6 months, a bone biopsy of the grafted area was collected for histological and histomorphometric evaluation, prior to implant placement. The performance of DEXGEL Bone and BL® treatments on alveolar preservation were further analyzed by computed tomography and Hounsfield density analysis. Primary implant stability was analyzed by implant stability coefficient technique. RESULTS: The healing of defects was free of any local or systemic complications. Both treatments showed good osseointegration with no signs of adverse reaction. DEXGEL Bone exhibited increased granule resorption (p = 0.029) accompanied by a tendency for more new bone ingrowth (although not statistically significant) compared to the BL® group. The addition of DEXGEL to BL® granules did not compromise bone volume or density, being even beneficial for implant primary stability (p = 0.017). CONCLUSIONS: The hydrogel-reinforced biomaterial exhibited an easier handling, a better defect filling, and benefits in implant stability. CLINICAL RELEVANCE: This study validates DEXGEL Bone safety and performance as an injectable carrier of granular bone substitutes for alveolar ridge preservation. TRIAL REGISTRATION: European Databank on Medical Devices (EUDAMED) No. CIV-PT-18-01-02,705; Registo Nacional de Estudos Clínicos, RNEC, No. 30122.

Biomarkers for rhythmic and discrete dynamic primitives in locomotion.

Rehabilitation can promote brain plasticity and improve motor control after central nervous system injuries. Our working model is that motor control is encoded using dynamic primitives: submovements, oscillations, and mechanical impedances. We hypothesize that therapies focusing on these primitives can achieve greater motor recovery. At the observational level, these primitives lead to discrete and rhythmic movements. Here, we propose two novel biomarkers to evaluate rhythmic and discrete movements in gait based on the feet forward position: the smoothness of their relative position, using the mean-squared jerk ratio (MSJR), to assess rhythmicity; and the angle between principal components of consecutive trajectories (dPCA), to detect discrete movements amidst rhythmic motion. We applied these methods to kinematic data collected with healthy individuals during experiments employing the MIT-Skywalker: level-ground walking at five speeds, with and without imposed ankle stiffness; walking at constant speed on ascending, descending, and laterally tilted slopes; and performing sidesteps. We found a decrease in MSJR as speed increases, related to increased rhythmicity, even with imposed stiffness. Rhythmicity seems unaffected by the terrain perturbations imposed. Finally, dPCA successfully detects sidesteps, discrete events amidst rhythmic movement. These biomarkers appear to accurately assess rhythmic and discrete movements during walking and can potentially improve clinical evaluation and rehabilitation of neurological patients.

Long-term outcomes of primary cardiovascular prevention: A retrospective study at a referral center in Portugal.

INTRODUCTION AND OBJECTIVES: Lifestyle changes are frequently insufficient to reduce cardiovascular (CV) risk in patients with dyslipidemia. This study aims to characterize the long-term evolution of lipid profile and CV risk of patients under primary prevention. METHODS: A retrospective study was performed of outpatients at a Portuguese cardiovascular risk clinic with ≥2 CV risk factors, followed for ≥2 years between 1995 and 2015. Statin therapy had been initiated early, in accordance with the clinic's practice. After written informed consent was obtained, sociodemographic and clinical characteristics were collected from medical charts, at baseline and last visit. Changes in lipid profile and CV risk scores were estimated. Associations between HDL-C or LDL-C changes and gender, age, observation time and treatments were assessed through bivariate analysis and multiple linear regression models. RESULTS: Out of 516 participants with mean follow-up of 11.4±4.3 years, 56.6% were female and 91.5% received statins. Lipid profile showed statistically significant improvement, including median changes in LDL-C and HDL-C of -77.0 mg/dl and +19 mg/dl, respectively. CV risk also showed statistically significant improvements according to all scores. Statin therapy resulted in a mean HDL-C increase of 7.4 mg/dl (independently of gender and other treatments) and a mean LDL-C reduction of 51.8 mg/dl (irrespective of age and other treatments). CONCLUSION: Results from this long-term real-life study indicate that primary prevention, specifically early and continuous therapy with intermediate-intensity statins as an add-on to lifestyle interventions, was important in obtaining consistent and adequate metabolic correction in patients with additional risk factors.

Diving into the vertical dimension of elasmobranch movement ecology.

Knowledge of the three-dimensional movement patterns of elasmobranchs is vital to understand their ecological roles and exposure to anthropogenic pressures. To date, comparative studies among species at global scales have mostly focused on horizontal movements. Our study addresses the knowledge gap of vertical movements by compiling the first global synthesis of vertical habitat use by elasmobranchs from data obtained by deployment of 989 biotelemetry tags on 38 elasmobranch species. Elasmobranchs displayed high intra- and interspecific variability in vertical movement patterns. Substantial vertical overlap was observed for many epipelagic elasmobranchs, indicating an increased likelihood to display spatial overlap, biologically interact, and share similar risk to anthropogenic threats that vary on a vertical gradient. We highlight the critical next steps toward incorporating vertical movement into global management and monitoring strategies for elasmobranchs, emphasizing the need to address geographic and taxonomic biases in deployments and to concurrently consider both horizontal and vertical movements.

Catechol-O-methyltransferase activity in individuals with substance use disorders: a case control study.

BACKGROUND: Impulsivity and substance use disorders (SUD) have been both associated with changes in dopaminergic processes. In this study, we intended to evaluate the dopaminergic function in imprisoned SUD offenders through the determination of s-COMT activity. METHODS: The study included 46 male individuals from a Portuguese penal institution. The participants were assessed through a battery of standardised instruments: Psychopathy Checklist-Revised (PCL-R), Barratt Impulsivity Scale Version 11 (BIS-11), and the European version of the Addiction Severity Index (EuropASI). In addition, s-COMT erythrocyte activity was evaluated. RESULTS: Overall, 73.9% (n = 34) of the individuals had Antisocial personality disorder (ASPD) and 58.7% (n = 27) presented SUD. We evidenced, for the first time, that, in individuals with SUD, s-COMT activity was correlated with the severity of drug dependence (EuropASI) (p = 0.009), and with BIS-11 factors self-control (p < 0.0001) and non-planning (p = 0.002). CONCLUSIONS: This study opens new perspectives regarding the pharmacological intervention on substance dependence through the interference on dopamine pathways.

Cancer germline antigens and tumor-agnostic CD8+ T cell evasion.

Cancer germline antigens (CGAs) are expressed in immune-privileged germline tissues, while epigenetically silenced in somatic tissues. CGAs become re-expressed in tumors and can promote oncogenesis. Tumors prominently exploit mechanisms similar to those in germline tissues to shield from immunosurveillance. We hypothesize that CGAs contribute towards tumor escape from immune effector CD8+ T cells. For illustrative purposes, we assessed the co-presence or -absence of CGAs with these cells in multiple tumor types. Considering a broad array of CD8+ T cell evasive mechanisms, we exemplify the co-occurrence of gene transcripts of eight CGAs with those of adhesion molecules, endothelial cells, and/or the Wnt pathway. We present a novel concept of CGAs and their association with CD8+ T cell evasion, which may be relevant for future immunotherapeutic interventions.

Multivariable passive ankle impedance in stroke patients: A preliminary study.

Multivariable ankle mechanical impedance was estimated in four stroke survivors, in coupled dorsi- plantarflexion and inversion-eversion. We applied external torque perturbation with an ankle robot and used multi-input, multi-output stochastic system identification methods to estimate impedance, in both paretic and nonparetic limbs. Subjects were instructed to remain at rest throughout the four trials performed on each leg. Impedance projected onto the directions of maximum and minimum stiffness was fit to a 2nd order linear model, including inertia, viscosity and stiffness. For most trials, stiffness and damping in dorsi-plantarflexion are increased on the paretic side. However, for two subjects, overall impedance is not increased in the absence of sustained involuntary tonic contraction, registering values comparable to the non-paretic side. Thus, we speculate that the intrinsic properties of the paretic ankle remained unaffected at the evaluated pose. Spasticity (hyperflexive stretch reflex) would have systematically increased stiffness and damping, even in the absence of involuntary contraction. Hence, we speculate that these two subjects did not exhibit spasticity, while the remaining two subjects did, since impedance was increased, with no involuntary tonic muscle contraction. Regarding inversion-eversion, impedance in this direction remained unaffected by stroke. We evaluated two volunteers before and after the application of botulinum toxin. Surprisingly, ankle stiffness was not reduced, but anisotropy was normalized.

Capacitar para cuidar perante a pandemia SARS-CoV-2: Intervenção de Enfermagem Comunitária ao cuidador formal / Empowering people to care in the face of the SARS-CoV-2 pandemic: Community Nursing Intervention for the formal caregiver

Capacitar para cuidar perante a pandemia SARS-CoV-2: Intervenção de Enfermagem Comunitária ao cuidador formal A situação pandémica atual, provocada pelo Coronavírus 2019, trouxe consigo desafios excecionais à Saúde Pública a nível mundial, despoletando a necessidade de desenvolvimento de competências nos cidadãos, capacitando-os para a adoção de medidas preventivas e protetoras, numa ótica de prevenção e promoção da saúde. O cuidador formal, prestador de cuidados, maioritariamente dirigidos à população idosa, surge assim como foco com necessidade de investimento nesta área. Este relatório descreve o percurso desenvolvido no estágio, que decorreu numa Unidade de Cuidados na Comunidade, seguindo a metodologia do Planeamento em Saúde, suportado conceptualmente pelo Modelo de Sistemas de Betty Neuman (2011). Do diagnóstico efetuado, foram hierarquizadas as prioridades de intervenção, a partir das quais foi desenvolvido o projeto de intervenção comunitária "Capacitar para cuidar perante a pandemia SARS-CoV-2". As atividades desenvolvidas permitiram contribuir diretamente para a formação dos profissionais, contribuindo para o fortalecimento da linha de defesa dos Sistemas contra a SARS-CoV-2.

Enabling to care for the SARS-CoV-2 pandemic: Community Nursing Intervention to the formal caregiving The current pandemic situation, caused by Coronavirus 2019, has brought with it exceptional challenges to Public Health worldwide, triggering the need to develop skills in citizens, enabling them to adopt preventive and protective measures, in a perspective of prevention and promotion of health. The formal caregiver, care provider, mostly directed to the elderly population, thus appears as a focus with need for investment in this area. This report describes the path developed in the internship, which took place in a Community Care Unit, following the Health Planning methodology, conceptually supported by the Systems Model of Betty Neuman (2011). From the diagnosis made, the intervention priorities were ranked, from which the community intervention project "Enabling to care in the face of the SARS-CoV-2 pandemic" was developed. The activities carried out made it possible to directly contribute to the training of professionals, contributing to the strengthening of the System´s line of defense against SARS-CoV-2.

Comparative eye and liver differentially expressed genes reveal monochromatic vision and cancer resistance in the shortfin mako shark (Isurus oxyrinchus).

The shortfin mako, Isurus oxyrinchus is an oceanic pelagic shark found worldwide in tropical and subtropical waters. However, the understanding of its biology at molecular level is still incipient. We sequenced the messenger RNA isolated from eye and liver tissues. De novo transcriptome yielded a total of 705,940 transcripts. A total of 3774 genes were differentially expressed (DEGs), with 1612 in the eye and 2162 in the liver. Most DEGs in the eye were related to structural and signaling functions, including nonocular and ocular opsin genes, whereas nine out of ten most overexpressed genes in the liver were related to tumor suppression, wound healing, and human diseases. Furthermore, DEGs findings provide insights on the monochromatic shark vision and a repertory of cancer-related genes, which may be insightful to elucidate shark resistance to cancer. Therefore, our results provide valuable sequence resources for future functional and population studies.

Putative shared mechanisms in autism spectrum disorders and attention deficit hyperactivity disorder, a systematic review of the role of oxidative stress.

Oxidative stress is now believed to play a crucial role for neurodevelopment disorders such as autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). To review the most recent literature regarding the role of oxidative stress for the pathophysiology of ASD and ADHD, we conducted a systematic search of the relevant literature and further discuss the clinical and research implications of this knowledge. A systematic search in PubMed database retrieved 132 articles, of which 33 were included in the review. This review found relevant evidence concerning the role of oxidative status in ASD and ADHD, albeit with some contradictory findings. In order to overcome the incongruities found, more studies are needed in the study of neurodevelopmental disorders, with more thorough study designs and particular attention to the accuracy of the diagnostic tools used for the cases included.

Impulsive and premeditated aggression in male offenders with antisocial personality disorder.

INTRODUCTION: Aggression is a clinical symptom of various psychiatric disorders that can be conceptualised as a physical act towards another person with the intent to cause harm. In antisocial personality disorder (ASPD), aggression is a frequent manifestation that differently compromise therapeutic and prognostic goals according to its impulsive or premeditated categorisation. ASPD is characterised by high levels of impulsivity, psychopathic traits, and a high prevalence of co-morbid substance use disorders (SUDs). Aggression in ASPD patients may determine long and recurrent imprisonment thus representing a challenge clinicians and legal experts face. OBJECTIVES: Our aims were to characterise impulsive and premeditated aggression in male ASPD offenders as well as to determine the potential role of SUDs, impulsivity, and psychopathic traits as predictors. MATERIALS AND METHODS: In this cross-sectional study we evaluated a sample of ASPD offenders with a battery of clinical and psychometric, standardised instruments: the Psychopathy Checklist-Revised (PCL-R), the European Version of the Addiction Severity Index (EuropASI), the Barratt Impulsivity Scale Version 11 (BIS-11), and the Impulsive/Premeditated Aggression Scale (IPAS). RESULTS: We used a total sample of 134 offenders, all of whom were male. ASPD patients (n = 96) had a 71.9% prevalence of impulsive aggression and a 28.1% prevalence of premeditated aggression. ASPD patients with impulsive aggression had significantly lower scores of total PCL-R (p<0.01) factor 1 and interpersonal facet 1 (p<0.05), compared with ASPD patients with premeditated aggression. ASPD patients with impulsive aggression and ASPD patients with premeditated aggression had comparable BIS-11 mean scores, and exhibited an equal prevalence of SUDs. The interpersonal facet 1of the PCL-R predicted the aggression type (p<0.05) in ASPD patients, and the exponential beta value for facet 1 was 1.42 (CI = 1.03; 1.95). CONCLUSIONS: The aggression type that is associated with ASPD is mainly impulsive in nature. ASPD patients who have higher scores of psychopathic traits have a lower probability of exhibiting impulsive aggression and a higher probability of exhibiting premeditated aggression. Although ASPD patients have high levels of impulsivity and a high frequency of SUDs, these two variables were not predictors of the aggression type.

The neurophysiological correlates of the triarchic model of psychopathy: An approach to the basic mechanisms of threat conditioning and inhibitory control.

The psychopathic traits boldness, meanness, and disinhibition are theorized to be underlined by trait fearlessness and externalizing vulnerability as etiologic neurobiological processes. However, little is known about the neurophysiological correlates of these traits. In this work, we explored how the three traits are associated with event-related potential (ERP) components targeted at the etiological processes in a partial delayed threat conditioning task and in a go/no-go task. Fifty community-dwelling volunteers (25 women), without history of neurological or psychiatric conditions, were recruited and assessed for psychopathic traits using the triarchic psychopathy measure. Participants performed a threat conditioning task, and a go/no-go task while undergoing an electroencephalography recording. Results from the threat conditioning task showed that boldness was significantly associated with reduced late positive potential. Concerning the go/no-go task, disinhibition was significantly associated with reduced error-related negativity ERP component. Overall, distinct psychopathic traits were found to be associated with distinct neurophysiological correlates of threat conditioning and response inhibition. This is consistent with models of psychopathy entailing trait fearlessness and externalizing proneness, and related brain mechanisms, as distinct processes underlying the expression of psychopathic traits.

COVID-19 Suicide Survivors-A Hidden Grieving Population.

Present time has been dominated by the COVID-19 pandemic. People are grieving several non-death related situations: the loss of a job, of a status, of a role, of their life. Restrictive measures and uncertainty about the future makes individuals vulnerable to feelings of hopelessness and helplessness. Mental health support has been hindered and teams are reinventing themselves to reach people in need. Nevertheless, decompensation of previous psychiatric disorders, increasing levels of depression and anxiety, economical handicaps and fear of the infection, are prompting several cases of COVID-19 related suicides worldwide. Every suicide affects between 5 and 80 individuals, which are known as suicide survivors. Suicide grief is particularly challenging, with rates of complicated grief as high as 40%. Suicide survivors are at increased risk of developing depression, anxiety disorders and of suicidal behaviors. Moreover, feelings of guilt and shame, as well as social stigma, are major obstacles for them to reach form help. This article aims to review the existing literature on COVID-19 related suicides, complicated grief in suicide survivors and highlight modifiable risk factors for both conditions, as well as propose some public health measures to reduce the impact of the pandemic context on self-inflicted harm and its consequences on families, friends and the community. Obstacles to access to mental health support need to be overcome through the use of technology. Technicians should actively approach populations more vulnerable to develop suicidal ideation. Social media have the obligation to provide accurate an non-sensationalistic information. Families and friends should maintain social proximity, despite the need for physical distancing. When a suicide death occurs, police forces and health staff should be prepared to share the news with the family using an empathic and humane approach and providing psychological support. Funerals, memorials and other services should be held as much as possible. Closer contacts should be signalized and closely followed in order to detect the need for specific interventions. Help seeking behaviors should be promoted. Additionally, people should be educated on suicide and its impacts, in order to reduce stigma.

Neuropsychiatric Symptoms of Multiple Sclerosis: State of the Art.

Multiple Sclerosis (MS) is a chronic disabling neuroinflammatory disease. Psychiatric manifestations have a high prevalence in MS patients and may worsen the illness progression and the patients' quality of life (QoL). Depression is a highly prevalent condition in MS patients, associated with poorer adherence to treatment, decreased functional status and QoL, and increased suicide risk. Diagnosis and treatment of this disorder is challenging because of symptom overlap. Other prevalent psychiatric comorbidities are anxiety disorders, bipolar disorder, psychotic disorders, substance misuse and personality disorders. As the illness progresses, personality changes can happen, as well as affect abnormalities. Cognitive changes occur frequently in MS patients, and affect features like processing speed, attention, learning, memory, visual spatial capabilities, and some language deficits. Disease-modifying treatments may reduce cognitive impairment because of their container action on the brain's lesion burden. Other QoL determinants such as fatigue, pain, sexual dysfunction, exercise, resilience and social support should be taken into account, in order to promote the individuals' well-being. Further studies are needed in order to elucidate the effectiveness of pharmacotherapy and more neuroimaging studies are required to clarify the relationship between structural changes and psychiatric comorbidities.