Posttranslational Modification of Human Cytochrome CYP4F11 by 4-Hydroxynonenal Impairs ω-Hydroxylation in Malaria Pigment Hemozoin-Fed Monocytes: The Role in Malaria Immunosuppression.

Malaria is a frequent parasitic infection becomes life threatening due to the disequilibrated immune responses of the host. Avid phagocytosis of malarial pigment hemozoin (HZ) and HZ-containing Plasmodium parasites incapacitates monocyte functions by bioactive lipoperoxidation products 4-hydroxynonenal (4-HNE) and hydroxyeicosatetraenoic acids (HETEs). CYP4F conjugation with 4-HNE is hypothesised to inhibit ω-hydroxylation of 15-HETE, leading to sustained monocyte dysfunction caused by 15-HETE accumulation. A combined immunochemical and mass-spectrometric approach identified 4-HNE-conjugated CYP4F11 in primary human HZ-laden and 4-HNE-treated monocytes. Six distinct 4-HNE-modified amino acid residues were revealed, of which C260 and H261 are localized in the substrate recognition site of CYP4F11. Functional consequences of enzyme modification were investigated on purified human CYP4F11. Palmitic acid, arachidonic acid, 12-HETE, and 15-HETE bound to unconjugated CYP4F11 with apparent dissociation constants of 52, 98, 38, and 73 µM, respectively, while in vitro conjugation with 4-HNE completely blocked substrate binding and enzymatic activity of CYP4F11. Gas chromatographic product profiles confirmed that unmodified CYP4F11 catalysed the ω-hydroxylation while 4-HNE-conjugated CYP4F11 did not. The 15-HETE dose dependently recapitulated the inhibition of the oxidative burst and dendritic cell differentiation by HZ. The inhibition of CYP4F11 by 4-HNE with consequent accumulation of 15-HETE is supposed to be a crucial step in immune suppression in monocytes and immune imbalance in malaria.

An Optimized Dihydrodibenzothiazepine Lead Compound (SBI-0797750) as a Potent and Selective Inhibitor of Plasmodium falciparum and P. vivax Glucose 6-Phosphate Dehydrogenase 6-Phosphogluconolactonase.

In Plasmodium, the first two and rate-limiting enzymes of the pentose phosphate pathway, glucose 6-phosphate dehydrogenase (G6PD) and the 6-phosphogluconolactonase, are bifunctionally fused to a unique enzyme named GluPho, differing structurally and mechanistically from the respective human orthologs. Consistent with the enzyme's essentiality for malaria parasite proliferation and propagation, human G6PD deficiency has immense impact on protection against severe malaria, making PfGluPho an attractive antimalarial drug target. Herein we report on the optimized lead compound N-(((2R,4S)-1-cyclobutyl-4-hydroxypyrrolidin-2-yl)methyl)-6-fluoro-4-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide (SBI-0797750), a potent and fully selective PfGluPho inhibitor with robust nanomolar activity against recombinant PfGluPho, PvG6PD, and P. falciparum blood-stage parasites. Mode-of-action studies have confirmed that SBI-0797750 disturbs the cytosolic glutathione-dependent redox potential, as well as the cytosolic and mitochondrial H2O2 homeostasis of P. falciparum blood stages, at low nanomolar concentrations. Moreover, SBI-0797750 does not harm red blood cell (RBC) integrity and phagocytosis and thus does not promote anemia. SBI-0797750 is therefore a very promising antimalarial lead compound.

Relaxometric studies of erythrocyte suspensions infected by Plasmodium falciparum: a tool for staging infection and testing anti-malarial drugs.

PURPOSE: Malaria is a global health problem with the most malignant form caused by Plasmodium falciparum (P. falciparum). Parasite maturation in red blood cells (RBCs) is accompanied by changes including the formation of paramagnetic hemozoin (HZ) nanocrystals, and increased metabolism and variation in membrane lipid composition. Herein, MR relaxometry (MRR) was applied to investigate water exchange across RBCs' membrane and HZ formation in parasitized RBCs. METHODS: Transverse water protons relaxation rate constants (R2 = 1/T2 ) were measured for assessing HZ formation in P. falciparum-parasitized human RBCs. Moreover, water exchange lifetimes across the RBC membrane (τi ) were assessed by measuring longitudinal relaxation rate constants (R1 = 1/T1 ) at 21.5 MHz in the presence of a gadolinium complex dissolved in the suspension medium. RESULTS: τi increased after invasion of parasites (ring stage, mean τi / τi0 = 1.234 ± 0.022) and decreased during maturation to late trophozoite (mean τi / τi0 = 0.960 ± 0.075) and schizont stages (mean τi / τi0 = 1.019 ± 0.065). The HZ accumulation in advanced stages was revealed by T2 -shortening. The curves reporting R2 (1/T2 ) vs. magnetic field showed different slopes for non-parasitized RBCs (npRBCs) and parasitized RBCs (pRBCs), namely 0.003 ± 0.001 for npRBCs, 0.009 ± 0.002, 0.028 ± 0.004 and 0.055 ± 0.002 for pRBCs at ring-, early trophozoite-, and late trophozoite stage, respectively. Antimalarial molecules dihydroartemisinin and chloroquine elicited measurable changes in parasitized RBCs, namely dihydroartemisinin modified τi , whereas the interference of chloroquine with HZ formation was detectable by a significant T2 increase. CONCLUSIONS: MRR can be considered a useful tool for reporting on P. falciparum blood stages and for screening potential antimalarial molecules.

Involvement of p38 MAPK in haemozoin-dependent MMP-9 enhancement in human monocytes.

The lipid moiety of natural haemozoin (nHZ, malarial pigment) was previously shown to enhance expression and release of human monocyte matrix metalloproteinase-9 (MMP-9), and a major role for 15-(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid (15-HETE), a nHZ lipoperoxidation product, was proposed. Here, the underlying mechanisms were investigated, focusing on the involvement of mitogen-activated protein kinases (MAPKs). Results showed that nHZ promoted either early or late p38 MAPK phosphorylation; however, nHZ did not modify basal phosphorylation/expression ratios of extracellular signal-regulated kinase-1/2 and c-jun N-terminal kinase-1/2. 15-HETE mimicked nHZ effects on p38 MAPK, whereas lipid-free synthetic (s)HZ and delipidized (d)HZ did not. Consistently, both nHZ and 15-HETE also promoted phosphorylation of MAPK-activated protein kinase-2, a known p38 MAPK substrate; such an effect was abolished by SB203580, a synthetic p38 MAPK inhibitor. SB203580 also abrogated nHZ-dependent and 15-HETE-dependent enhancement of MMP-9 mRNA and protein (latent and activated forms) levels in cell lysates and supernatants. Collectively, these data suggest that in human monocytes, nHZ and 15-HETE upregulate MMP-9 expression and secretion through activation of p38 MAPK pathway. The present work provides new evidence on mechanisms underlying MMP-9 deregulation in malaria, which might be helpful to design new specific drugs for adjuvant therapy in complicated malaria.

Emotional Dysregulation and Sleep Problems: A Transdiagnostic Approach in Youth.

BACKGROUND: Sleep is a complex phenomenon that affects several aspects of life, including cognitive functioning, emotional regulation, and overall well-being. Sleep disturbances, especially during adolescence, can negatively impact emotional regulation, making it a critical factor in targeting psychopathology. METHODS: This study explores the interplay between emotional dysregulation (ED) and sleep patterns in a sample of 90 adolescent patients by means of self- and parent-rated clinical measures. RESULTS: Our findings reveal a bidirectional relationship between ED and sleep problems. Adolescents with higher affective instability experience poorer sleep quality, while those with worse sleep quality exhibit higher internalizing problems. Additionally, emotional reactivity is associated with disrupted circadian rhythms. CONCLUSIONS: These results emphasize the significance of addressing sleep problems in the context of psychopathology treatment, potentially leading to improved outcomes. Further research is needed to determine the most effective treatment strategies, including nonpharmacological and pharmacological interventions. Understanding the intricate relationship between sleep problems and emotion regulation offers insights for more targeted and effective treatment approaches for youths struggling with ED.

Clozapine Treatment for Aggressive Behaviors in Youths with Neurodevelopmental Disorders.

Objectives: The aim of this study was to assess effectiveness and tolerability of Clozapine in the treatment of aggression in youth with Neurodevelopmental Disorders. Methods: Patients were consecutively admitted at our third-level university hospital with nationwide catchment from June 2018 to October 2022, and followed up to July 2023. Eligibility criteria were as follows: (1) Autism Spectrum Disorder (ASD) and/or Intellectual Disability/Borderline Cognitive Functioning, (2) behavioral dyscontrol with physical aggression; (3) age range between 8 and 18 years; (4) clinical indication for Clozapine treatment after at least two failed trials with other Second-Generation Antipsychotics (SGAs); (5) availability of an at least 6-month-long follow-up. To evaluate the response to Clozapine, we used the Clinical Global Impressions (CGI) rating scales (Clinical Global Impressions-Severity [CGI-S] and Clinical Global Impressions-Improvement [CGI-I]), the Children's Global Assessment Scale (CGAS), and the Aberrant Behavior Checklist (ABC). Results: Twenty-six children and adolescents (21 boys, age 13.47 ± 2.05 years, follow-up duration 9.77 ± 3.50 months) were included in the analysis. Clinical severity (CGI-S) and functional impairment (Clinical Global Assessment Scale) significantly improved, as well as the ABC Total Score and the scores in several subscales. Sixteen patients (61.54%) were responders (CGI-I ≤2), and 13 (50.00%) displayed remission of aberrant behaviors (ΔABC-Total >35), while response/remission condition was not affected by add-on medications and psychotherapy. Most frequent side effects were increased appetite (50.00%), sialorrhea (38.46%), and increased repetitive behaviors (26.92%). Two patients presented epileptic seizures, while no patients presented leucopoenia. Conclusions: Our results suggest that Clozapine may be helpful in ameliorating treatment-resistant aggression in youth with neurodevelopmental conditions. Possible pharmacological strategies for the management of most frequent side effects are also suggested.

Micromolar Dihydroartemisinin Concentrations Elicit Lipoperoxidation in Plasmodium falciparum-Infected Erythrocytes.

Malaria is still the most important parasitic infectious disease. Numerous substances are known to have antimalarial activity; among them, artemisinin is the most widely used one, and artemisinin-based combination therapy (ACT) is recommended for the treatment of Plasmodium falciparum (P.f.) malaria. Antitumor, immunomodulatory, and other therapeutic applications of artemisinin are under extensive study. Several different mechanisms of action were proposed for dihydroartemisinin (DHA), the active metabolite of artemisinin, such as eliciting oxidative stress in target cells. The goal of this study is to monitor the generation of reactive oxygen species (ROS) and lipid peroxidation product 4-hydroxynonenal (4-HNE) by DHA in P.f.-infected human erythrocytes. Checking ROS and 4-HNE-protein adducts kinetics along the maturation of the parasite, we detected the highest level of 4-HNE in ring forms of P.f. due to DHA treatment. Low micromolar concentrations of DHA quickly induced levels of 4-HNE-adducts which are supposed to be damaging. Mass spectrometry identified the P.f. protein cysteine proteinase falcipain-1 as being heavily modified by 4-HNE, and plausibly, 4-HNE conjugation with vital P.f. proteins might contribute to DHA-elicited parasite death. In conclusion, significant 4-HNE accumulation was detectable after DHA treatment, though, at concentrations well above pharmacologically effective ranges in malaria treatment, but at concentrations described for antitumor activity. Thus, lipid peroxidation with consequent 4-HNE conjugation of functionally relevant proteins might be considered as a uniform mechanism for how DHA potentiates antimalarials' action in ACT and controls the progression of tumors.

Persistent Non-Suicidal Self-Injury and Suicidality in Referred Adolescents: A Longitudinal Study Exploring the Role of Cyclothymic Temperament.

Non-suicidal self-injury (NSSI) is deliberate harm to the body surface without suicidal intent, though it may be a predictor of suicide attempts. Our aim was to test the hypothesis that persisting and recovering NSSI may have a different longitudinal risk for suicidal ideation and behavior and that the intensity of Cyclothymic Hypersensitive Temperament (CHT) may increase this risk. Fifty-five patients (mean age 14.64 ± 1.77 years) referred for mood disorders according to the DSM-5 were consecutively recruited and followed-up for a mean of 19.79 ± 11.67 months and grouped according to the presence/absence of NSSI at baseline and follow-up into three groups: without NSSI (non-NSSI; n = 22), with NSSI recovered at follow-up (past-NSSI; n = 19), and with persistent NSSI at follow-up (pers-NSSI; n = 14). At follow-up, both NSSI groups were more severely impaired and failed to improve internalizing problems and dysregulation symptoms. Both NSSI groups reported higher scores in suicidal ideation compared to non-NSSI, but only pers-NSSI presented higher scores in suicidal behavior. CHT was higher in pers-NSSI, followed by past-NSSI and then by non-NSSI. Our data support a continuity between NSSI and suicidality, and they suggest the prognostic validity of persistent NSSI, associated with highest CHT scores.

Callous-Unemotional Traits and Intelligence in Children with Externalizing Behavioral Problems.

Research on the association between callous-unemotional (CU) traits and intelligence yielded contradictory results. Moreover, several previous studies focused on global intelligence scores or verbal vs. nonverbal/performance abilities usually evaluated with short/abbreviated instruments. The current study builds on these previous works and explores the link between CU traits and intelligence using the full version of the Wechsler Intelligence Scale for Children-4th Edition (WISC-IV), which provides four different verbal and nonverbal abilities scores. This guarantees a more detailed evaluation of children's intelligence and its relation to CU traits. The sample included children (N = 149; age 6-14 years old) with severe behavioral problems. Clinicians administered the WISC-IV, and parents completed questionnaires evaluating the child's externalizing problems and CU traits. Findings showed that CU traits were associated with lower verbal comprehension scores after also controlling for gender, age, externalizing problems, and the other WISC-IV indexes. In addition, CU traits and externalizing problems did not interact in predicting the WISC-IV indexes, and there were no significant differences in the WISC-IV indexes between children with CU traits and high vs. low externalizing problems. The current study suggests the relevance of assessing and addressing verbal abilities in children with behavioral problems and CU traits.

Sensory Profiles in School-Aged Children with Autism Spectrum Disorder: A Descriptive Study Using the Sensory Processing Measure-2 (SPM-2).

Background: Sensory reactivity is considered one of the diagnostic criteria for Autism Spectrum Disorders (ASD) and has been associated with poorer functional outcomes, behavioral difficulties, and autism severity across the lifespan. The characterization of the sensory processing in ASD has thus become crucial to identify the sensory and motor features influencing the development of personal autonomy. Objectives: The present study has two aims: (1) to compare the sensory processing between school-aged children with ASD and typically developing peers (TD); (2) to evaluate whether, within the ASD sample, the cognitive level and reported sensory symptoms explain the scores exhibited at the Sensory Processing Measure (SPM-2). Methods: The SPM-2 test was administered to the parents of 105 children with ASD and 70 TD. The ASD group was further subdivided into two groups, namely high and low functioning based on their cognitive level (High Functioning (HF), IQ > 80; Low Functioning (LF), IQ < 80). Results: ASD children exhibited higher scores throughout the SPM-2 total score and its multiple subscales. Within ASD, while HF and LF children did not differ in terms of the SPM-2 total score, a significant difference was found for the hearing, social participation, and balance and motion subscales. Conclusions: Aside from classical knowledge that the ASD population suffers from sensory processing disorders, we revealed that different sensory patterns are associated with high or low cognitive functioning. Beyond its neurobiological interest, such knowledge may be of fundamental importance for individualizing psychoeducational interventions in preschool- and school-aged children and later developmental stages.

Early Sensory Profile in Autism Spectrum Disorders Predicts Emotional and Behavioral Issues.

Background: Abnormal sensory reactivity is considered one of the diagnostic criteria for autism spectrum disorders (ASD) and has been associated with autism severity, poorer functional outcomes, and behavioral difficulties across the lifespan. Its early characterization could provide valuable insights into the processes favoring the instantiation of maladaptive behaviors. Objectives: The present study has two aims: (1) to describe the sensory profile of preschool children with ASD compared with an age-matched population of children with a diagnosis of language disorder (DLD) and typically developing (TD) control peers; (2) to explore within each group whether the sensory alterations play a predictive role in the instantiation of emotional and behavioral issues. Methods: The parents of 42 ASD, 18 DLD, and 56 TD filled out the Sensory Processing Measure­Preschool (SPM-P). To gather information on competencies, behaviors, and emotional problems of children, the Child Behavior Checklist 1½-5 (CBCL 1½-5) was also administered. Results: On the SPM-P, ASD and DLD samples generally had scores more compromised than control peers. The contrast between ASD and DLD was reflected in a higher (and highly significant) impairment on the social participation and hearing subscales, suggesting a greater sensitivity and a possible specificity of these scores for ASD. More importantly, linear regression analyses revealed a strong and predictive association for ASD children with SPM total scores explaining more than 50% of the variance of the CBCL 1½-5 total scores (p < 0.001). Conclusions: Our findings reinforce the need to detect the abnormal sensory profiles of ASD already at an early stage and during clinical evaluations. Due to the impact on the emotional and behavioral manifestations, such a procedure has significant clinical and social implications, potentially guiding the development of new interventions relying on multisensory strategies.

Malaria Pigment Hemozoin Impairs GM-CSF Receptor Expression and Function by 4-Hydroxynonenal.

Malarial pigment hemozoin (HZ) generates the lipoperoxidation product 4-hydroxynonenal (4-HNE), which is known to cause dysregulation of the immune response in malaria. The inhibition of granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent differentiation of dendritic cells (DC) by HZ and 4-HNE was previously described in vitro, and the GM-CSF receptor (GM-CSF R) was hypothesised to be a primary target of 4-HNE in monocytes. In this study, we show the functional impact of HZ on GM-CSF R in monocytes and monocyte-derived DC by (i) impairing GM-CSF binding by 50 ± 9% and 65 ± 14%, respectively (n = 3 for both cell types); (ii) decreasing the expression of GM-CSF R functional subunit (CD116) on monocyte's surface by 36 ± 11% (n = 6) and in cell lysate by 58 ± 16% (n = 3); and (iii) binding of 4-HNE to distinct amino acid residues on CD116. The data suggest that defective DC differentiation in malaria is caused by GM-CSF R dysregulation and GM-CSF R modification by lipoperoxidation product 4-HNE via direct interaction with its CD116 subunit.

Could You Give Me the Blue Brick? LEGO®-Based Therapy as a Social Development Program for Children with Autism Spectrum Disorder: A Systematic Review.

LEGO®-based therapy is a social skills development program aimed at children with autism spectrum disorder (ASD). A systematic review of the literature was conducted using PRISMA guidelines. PubMed, Scopus and Web of Science bibliographic databases were searched from their date of inception to August 2020. The review included 19 studies. Studies were classified according to experimental designs (e.g., Randomized Control Trial, Non-Randomized Studies of Interventions and case report and series) and a narrative synthesis of each was provided, along with a critical discussion of the strengths and weaknesses of the available literature on the topic. Although LEGO®-based therapy appears a promising treatment for social interaction in ASD, the findings of LEGO®-based therapy studies should be interpreted and generalized with caution, due to the low quality of the studies and the small sample sizes.

A novel multidimensional questionnaire for the assessment of emotional dysregulation in adolescents: Reactivity, Intensity, Polarity and Stability questionnaire-youth version (RIPoSt-Y).

BACKGROUND: The failure to regulate emotions, namely emotional dysregulation (ED), is a relevant construct in adolescent psychiatry, in terms of prognostic and developmental implications. We developed and validated a novel self-report questionnaire for the assessment of ED, the RIPoSt-Y, both in clinical and non-clinical samples. METHODS: Items selection and subscales construction were conducted on healthy controls (n=374), while test-retest reliability was evaluated in a subsample (n=72); internal consistency was examined both in the control group and in two clinical samples, respectively including patients with Bipolar Spectrum Disorders (BSD; n=44) and ADHD (n=34). Construct, concurrent and convergent validity were also assessed. RESULTS: Thirty-one items were finally retained, and three subscales were identified (Affective Instability, Emotional Reactivity, Interpersonal Sensitivity). Test-retest was significant for each subscale with moderate-to-good correlations, and internal consistency showed good-to-excellent coefficients. Construct validity was supported by significant differences between patients and controls and gender-related differences. Concurrent validity was confirmed through significant associations with two subscales of the CHT-Q, while convergent validity proved to be significant with the CBCL/YSR dysregulation-profile. Cut-offs were also computed to discriminate clinically significant scores of ED. LIMITATIONS: The use of a school-based survey to recruit controls could have biased our results; gender distributions between clinical and non-clinical samples were significantly different. CONCLUSIONS: Our novel questionnaire proved to be a valid and reliable tool able to assess the presence of ED in youths and to characterize this fundamental construct in its multidimensional facets.

Neuropsychological Characterization of Aggressive Behavior in Children and Adolescents with CD/ODD and Effects of Single Doses of Medications: The Protocol of the Matrics_WP6-1 Study.

Aggressive behaviors and disruptive/conduct disorders are some of the commonest reasons for referral to youth mental health services; nevertheless, the efficacy of therapeutic interventions in real-world clinical practice remains unclear. In order to define more appropriate targets for innovative pharmacological therapies for disruptive/conduct disorders, the European Commission within the Seventh Framework Programme (FP7) funded the MATRICS project (Multidisciplinary Approaches to Translational Research in Conduct Syndromes) to identify neural, genetic, and molecular factors underpinning the pathogenesis of aggression/antisocial behavior in preclinical models and clinical samples. Within the program, a multicentre case-control study, followed by a single-blind, placebo-controlled, cross-over, randomized acute single-dose medication challenge, was conducted at two Italian sites. Aggressive children and adolescents with conduct disorder (CD) or oppositional defiant disorder (ODD) were compared to the same age (10-17 y) typically developing controls (TDC) on a neuropsychological tasks battery that included both "cold" (e.g., inhibitory control, decision making) and "hot" executive functions (e.g., moral judgment, emotion processing, risk assessment). Selected autonomic measures (heart rate variability, skin conductance, salivary cortisol) were recorded before/during/after neuropsychological testing sessions. The acute response to different drugs (methylphenidate/atomoxetine, risperidone/aripiprazole, or placebo) was also examined in the ODD/CD cohort in order to identify potential neuropsychological/physiological mechanisms underlying aggression. The paper describes the protocol of the clinical MATRICS WP6-1 study, its rationale, the specific outcome measures, and their implications for a precision medicine approach.

An Exploratory Study of Emotional Dysregulation Dimensions in Youth With Attention Deficit Hyperactivity Disorder and/or Bipolar Spectrum Disorders.

Emotional dysregulation (ED) is currently the most frequently used term to describe children with an impaired regulation of emotional states. Recent research studies speculate whether ED may be a neurodevelopmental disorder itself, a shared risk factor, or a common key feature of several psychiatric disorders, including, among others, attention deficit hyperactivity disorder (ADHD), and bipolar spectrum disorders (BSD). The association between ADHD and ED is one of the main reasons of misconceptions in the definition of boundaries between ADHD and BSD, leading to the frequent misdiagnosis of ADHD as BSD. Since ED is a multidimensional concept, a novel instrument-the Reactivity, Intensity, Polarity and Stability (RIPoSt) scale-was recently developed to assess the different dimensions of ED, which could help in detecting specific ED profiles in clinical youths. Our study included 154 patients, aged 13.8 ± 2.3 years, diagnosed with either ADHD, BSD, or comorbid condition, and a school-based sample of 40 healthy control (HC) adolescents, aged 12.5 ± 1.2 years. The RIPoSt scale and the Child Behavior Checklist were administered to both groups. Our results indicate that affective instability and negative emotionality subscales, as well as negative emotional dysregulation, are higher in BSD, both pure and comorbid with ADHD, while emotional impulsivity is higher in the comorbid condition and similar in the ADHD and BSD alone group; all clinical groups scored higher than HC. Conversely, positive emotionality is similar among clinical groups and within them and HC. Our findings also support the validity of the RIPoSt questionnaire, since the instrument proved to have good-to-excellent internal consistency, and strongly significant positive correlations were found with the CBCL-Dysregulation Profile, which is a commonly used, indirect measure of ED. Hence, the five subscales of the RIPoSt can be reliably used as an effective tool to study the emotional dysregulation in different clinical conditions, to help disentangle the complex relationship between ADHD and juvenile BSD and to provide clinicians with crucial evidence for better diagnostic characterization and therapeutic indications.

Involvement of inflammatory chemokines in survival of human monocytes fed with malarial pigment.

Hemozoin (HZ)-fed monocytes are exposed to strong oxidative stress, releasing large amounts of peroxidation derivatives with subsequent impairment of numerous functions and overproduction of proinflammatory cytokines. However, the histopathology at autopsy of tissues from patients with severe malaria showed abundant HZ in Kupffer cells and other tissue macrophages, suggesting that functional impairment and cytokine production are not accompanied by cell death. The aim of the present study was to clarify the role of HZ in cell survival, focusing on the qualitative and temporal expression patterns of proinflammatory and antiapoptotic molecules. Immunocytochemical and flow cytometric analyses showed that the long-term viability of human monocytes was unaffected by HZ. Short-term analysis by macroarray of a complete panel of cytokines and real-time reverse transcription (RT)-PCR experiments showed that HZ immediately induced interleukin-1ß (IL-1ß) gene expression, followed by transcription of eight additional chemokines (IL-8, epithelial cell-derived neutrophil-activating peptide 78 [ENA-78], growth-regulated oncogene α [GROα], GROß, GROγ, macrophage inflammatory protein 1α [MIP-1α], MIP-1ß, and monocyte chemoattractant protein 1 [MCP-1]), two cytokines (tumor necrosis factor alpha [TNF-α] and IL-1receptor antagonist [IL-1RA]), and the cytokine/chemokine-related proteolytic enzyme matrix metalloproteinase 9 (MMP-9). Furthermore, real-time RT-PCR showed that 15-HETE, a potent lipoperoxidation derivative generated by HZ through heme catalysis, recapitulated the effects of HZ on the expression of four of the chemokines. Intermediate-term investigation by Western blotting showed that HZ increased expression of HSP27, a chemokine-related protein with antiapoptotic properties. Taken together, the present data suggest that apoptosis of HZ-fed monocytes is prevented through a cascade involving 15-HETE-mediated upregulation of IL-1ß transcription, rapidly sustained by chemokine, TNF-α, MMP-9, and IL-1RA transcription and upregulation of HSP27 protein expression.

Plasmodium Impairs Antibacterial Innate Immunity to Systemic Infections in Part Through Hemozoin-Bound Bioactive Molecules.

One complication of malaria is increased susceptibility to invasive bacterial infections. Plasmodium infections impair host immunity to non-Typhoid Salmonella (NTS) through heme-oxygenase I (HO-I)-induced release of immature granulocytes and myeloid cell-derived IL-10. Yet, it is not known if these mechanisms are specific to NTS. We show here, that Plasmodium yoelii 17XNL (Py) infected mice had impaired clearance of systemic Listeria monocytogenes (Lm) during both acute parasitemia and up to 2 months after clearance of Py infected red blood cells that was independent of HO-I and IL-10. Py-infected mice were also susceptible to Streptococcus pneumoniae (Sp) bacteremia, a common malaria-bacteria co-infection, with higher blood and spleen bacterial burdens and decreased survival compared to naïve mice. Mechanistically, impaired immunity to Sp was independent of HO-I, but was dependent on Py-induced IL-10. Splenic phagocytes from Py infected mice exhibit an impaired ability to restrict growth of intracellular Lm, and neutrophils from Py-infected mice produce less reactive oxygen species (ROS) in response to Lm or Sp. Analysis also identified a defect in a serum component in Py-infected mice that contributes to reduced production of ROS in response to Sp. Finally, treating naïve mice with Plasmodium-derived hemozoin containing naturally bound bioactive molecules, excluding DNA, impaired clearance of Lm. Collectively, we have demonstrated that Plasmodium infection impairs host immunity to diverse bacteria, including S. pneumoniae, through multiple effects on innate immunity, and that a parasite-specific factor (Hz+bound bioactive molecules) directly contributes to Plasmodium-induced suppression of antibacterial innate immunity.

Narcissistic traits as predictors of emotional problems in children with oppositional defiant disorder: A longitudinal study.

BACKGROUND: Children's self-views encompass two independent dimensions: self-esteem and narcissism, which recently have received growing attention from researchers and clinicians. The current study sought to test whether these dimensions might predict the developmental course of children with Oppositional Defiant Disorder diagnosis. METHOD: The sample (N = 64, M age = 10.1 years, 57 boys) included children with Oppositional Defiant Disorder diagnosis. We examined longitudinal relationships between self-views (both self-esteem and narcissism) and parent-reported internalizing and externalizing behavioral problems. RESULTS: The study spanned two time-points, spaced 12 months apart. None of the predictors were longitudinally associated with the levels of externalizing behavioral problems in children. However, narcissism predicted the levels of children's internalizing problems at the follow-up, whereas self-esteem did not. LIMITATIONS: The relatively small sample and the lack of assessing causality limit the generalizability of the findings. Results need to be replicated in larger samples. CONCLUSIONS: These findings illustrate the value of taking into account children's narcissistic traits in clinical assessment. By broadening knowledge of narcissistic traits in clinical samples of children, we hope to inform assessment procedures in standard clinical practice, as well as the development of tailored interventions to curb the emergence of later negative outcomes related to childhood narcissism, such as internalizing problems.

[Origins and evaluation of youth narcissism]. / Eziopatogenesi e valutazione dei tratti narcisistici in età evolutiva.

Recently, studies have focused on narcissism as a personality trait, which can be detected during childhood, and can lead to negative outcomes, such as emotional and behavioral problems. After illustrating the main hypotheses on the development of narcissistic traits in children, this paper aims to outline the relation between narcissism, self-esteem and emotional, and behavioral problems in children. Finally, are presented measures for the assessment of narcissistic traits in children and adolescents.