Interplay between liver and blood stages of Plasmodium infection dictates malaria severity via γδ T cells and IL-17-promoted stress erythropoiesis.

Plasmodium replicates within the liver prior to reaching the bloodstream and infecting red blood cells. Because clinical manifestations of malaria only arise during the blood stage of infection, a perception exists that liver infection does not impact disease pathology. By developing a murine model where the liver and blood stages of infection are uncoupled, we showed that the integration of signals from both stages dictated mortality outcomes. This dichotomy relied on liver stage-dependent activation of Vγ4+ γδ T cells. Subsequent blood stage parasite loads dictated their cytokine profiles, where low parasite loads preferentially expanded IL-17-producing γδ T cells. IL-17 drove extra-medullary erythropoiesis and concomitant reticulocytosis, which protected mice from lethal experimental cerebral malaria (ECM). Adoptive transfer of erythroid precursors could rescue mice from ECM. Modeling of γδ T cell dynamics suggests that this protective mechanism may be key for the establishment of naturally acquired malaria immunity among frequently exposed individuals.

A spatiotemporally resolved single-cell atlas of the Plasmodium liver stage.

Malaria infection involves an obligatory, yet clinically silent liver stage1,2. Hepatocytes operate in repeating units termed lobules, exhibiting heterogeneous gene expression patterns along the lobule axis3, but the effects of hepatocyte zonation on parasite development at the molecular level remain unknown. Here we combine single-cell RNA sequencing4 and single-molecule transcript imaging5 to characterize the host and parasite temporal expression programmes in a zonally controlled manner for the rodent malaria parasite Plasmodium berghei ANKA. We identify differences in parasite gene expression in distinct zones, including potentially co-adaptive programmes related to iron and fatty acid metabolism. We find that parasites develop more rapidly in the pericentral lobule zones and identify a subpopulation of periportally biased hepatocytes that harbour abortive infections, reduced levels of Plasmodium transcripts and parasitophorous vacuole breakdown. These 'abortive hepatocytes', which appear predominantly with high parasite inoculum, upregulate immune recruitment and key signalling programmes. Our study provides a resource for understanding the liver stage of Plasmodium infection at high spatial resolution and highlights the heterogeneous behaviour of both the parasite and the host hepatocyte.

Anthracyclines induce DNA damage response-mediated protection against severe sepsis.

Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options in addition to organ support measures. Here we show that the clinically approved group of anthracyclines acts therapeutically at a low dose regimen to confer robust protection against severe sepsis in mice. This salutary effect is strictly dependent on the activation of DNA damage response and autophagy pathways in the lung, as demonstrated by deletion of the ataxia telangiectasia mutated (Atm) or the autophagy-related protein 7 (Atg7) specifically in this organ. The protective effect of anthracyclines occurs irrespectively of pathogen burden, conferring disease tolerance to severe sepsis. These findings demonstrate that DNA damage responses, including the ATM and Fanconi Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis.

A prospective observational study for a Federated Artificial Intelligence solution for moniToring mental Health status after cancer treatment (FAITH): study protocol.

BACKGROUND: Depression is a common condition among cancer patients, across several points in the disease trajectory. Although presenting higher prevalence rates than the general population, it is often not reported or remains unnoticed. Moreover, somatic symptoms of depression are common in the oncological context and should not be dismissed as a general symptom of cancer. It becomes even more challenging to track psychological distress in the period after the treatment, where connection with the healthcare system typically becomes sporadic. The main goal of the FAITH project is to remotely identify and predict depressive symptoms in cancer survivors, based on a federated machine learning (ML) approach, towards optimization of privacy. METHODS: FAITH will remotely analyse depression markers, predicting their negative trends. These markers will be treated in distinct categories, namely nutrition, sleep, activity and voice, assessed in part through wearable technologies. The study will include 300 patients who have had a previous diagnosis of breast or lung cancer and will be recruited 1 to 5 years after the end of primary cancer. The study will be organized as a 12-month longitudinal prospective observational cohort study, with monthly assessments to evaluate depression symptoms and quality of life among cancer survivors. The primary endpoint is the severity of depressive symptoms as measured by the Hamilton Depression Rating Scale (Ham-D) at months 3, 6, 9 and 12. Secondary outcomes include self-reported anxiety and depression symptoms (HADS scale), and perceived quality of life (EORTC questionnaires), at baseline and monthly. Based on the predictive models gathered during the study, FAITH will also aim at further developing a conceptual federated learning framework, enabling to build machine learning models for the prediction and monitoring of depression without direct access to user's personal data. DISCUSSION: Improvements in the objectivity of psychiatric assessment are necessary. Wearable technologies can provide potential indicators of depression and anxiety and be used for biofeedback. If the FAITH application is effective, it will provide healthcare systems with a novel and innovative method to screen depressive symptoms in oncological settings. TRIAL REGISTRATION: Trial ID: ISRCTN10423782 . Date registered: 21/03/2022.

Cold Agglutinins and Cardiac Surgey: a Case Report.

Cold agglutinins (CA) are autoantibodies whose clinical significance depends upon titer and thermal amplitude. Patients, which undergo cardio-pulmonary bypass and especially hypothermic cardioplegia myocardial protection, represent a challenge regarding operative management, as tissue temperature should be maintained above the threshold of agglutination. We report on a case in which the presence of CA was discovered during elective aortic valve replacement surgery, and managed with normothermic cardiopulmonary bypass and continuous retrograde warm blood cardioplegia administration.

The Eastern side of the Westernmost Europeans: Insights from subclades within Y-chromosome haplogroup J-M304.

OBJECTIVES: We examined internal lineages and haplotype diversity in Portuguese samples belonging to J-M304 to improve the spatial and temporal understanding of the introduction of this haplogroup in Iberia, using the available knowledge about the phylogeography of its main branches, J1-M267 and J2-M172. METHODS: A total of 110 males of Portuguese descent were analyzed for 17 Y-chromosome bi-allelic markers and seven Y-chromosome short tandem repeats (Y-STR) loci. RESULTS: Among J1-M267 individuals (n = 36), five different sub-haplogroups were identified, with the most common being J1a2b2-L147.1 (∼72%), which encompassed the majority of representatives of the J1a2b-P58 subclade. One sample belonged to the rare J1a1-M365.1 lineage and presented a core Y-STR haplotype consistent with the Iberian settlement during the fifth century by the Alans, a people of Iranian heritage. The analysis of J2-M172 Portuguese males (n = 74) enabled the detection of the two main subclades at very dissimilar frequencies, J2a-M410 (∼80%) and J2b-M12 (∼20%), among which the most common branches were J2a1(xJ2a1b,h)-L26 (22.9%), J2a1b(xJ2a1b1)-M67 (20.3%), J2a1h-L24 (27%), and J2b2-M241 (20.3%). CONCLUSIONS: While previous inferences based on modern haplogroup J Y-chromosomes implicated a main Neolithic dissemination, here we propose a later arrival of J lineages into Iberia using a combination of novel Portuguese Y-chromosomal data and recent evidence from ancient DNA. Our analysis suggests that a substantial tranche of J1-M267 lineages was likely carried into the Iberian Peninsula as a consequence of the trans-Mediterranean contacts during the first millennium BC, while most of the J2-M172 lineages may be associated with post-Neolithic population movements within Europe.

EARLY MALTREATMENT AND CURRENT QUALITY OF RELATIONAL CARE PREDICT SOCIOEMOTIONAL PROBLEMS AMONG INSTITUTIONALIZED INFANTS AND TODDLERS.

The present study is focused on child socioemotional problems 6 months after institutionalization, by considering the putative predictive role of child maltreatment, of developmental functioning at admission and the following months, and of the quality of institutional relational care. Fifty institutionalized infants and toddlers participated in this study. Child developmental functioning (i.e., cognitive, language, and motor development) was assessed at admission to the institution (Wave 0), and 3 (Wave 1) and 6 months (Wave 2) thereafter. The quality of institutional relational care-operationalized in terms of caregivers' sensitivity and cooperation-was measured at Wave 2. Caregivers reported on the presence of disturbed socioemotional behaviors at Wave 2. Child gestational age, birth weight, age, and stunted growth at admission to the institution served as covariates. Results revealed significant associations between socioemotional difficulties and lower levels of motor development at Waves 0 and 1, child maltreatment, and less sensitive caregiving. A logistic regression showed that child maltreatment and caregiver insensitivity were the only significant predictors of disturbed socioemotional functioning by the end of 6 months of institutionalization.

A Case of Oxalate Nephropathy: When a Single Cause Is Not Crystal Clear.

Hyperoxaluria can result in oxalate nephropathy with intratubular calcium oxalate crystallization and acute tubular injury. Primary inherited enzymatic deficiency or secondary causes such as excessive dietary intake, enteric increased absorption, or high doses of vitamin C, which is metabolized to oxalate, may underlie hyperoxaluria and oxalate nephropathy. We report a case of acute kidney injury due to oxalate nephropathy in a patient using chelating therapy with oral ethylenediamine tetra acetic acid (EDTA), intravenous supplementation with vitamin C, and chronic diarrhea and discuss the potential kidney damage these factors can cause in particular settings. To our knowledge, this is the first report suggesting an association between oral EDTA and oxalate nephropathy.

The Orientalisation of North Africa: New hints from the study of autosomal STRs in an Arab population.

BACKGROUND: Recent genomic analyses suggest that the current North African gene pool was mainly influenced by population flow coming from the East that altered the genetic structure of autochthonous Berber populations. Such genetic flow has not been extensively addressed yet using North African populations of Middle-eastern origin as reference. AIM: To discern the Middle-eastern component in the genetic background of Tunisian Arabs and evaluate the extent of gene flow from the Middle East into North African autochthonous Berber populations. SUBJECTS AND METHODS: This study has examined 113 Tunisians of well-known Arabian origin from Kairouan region, using 15 autosomal Short Tandem Repeats (STRs) loci. RESULTS: No deviations from Hardy-Weinberg equilibrium were observed and all loci presented high levels of heterozygosity. Principal coordinate and STRUCTURE analyses were consistent in clustering together North African and Middle Eastern populations, likely reflecting the recent gene flow from the East dating back to the Arab conquest period. This demographic migration and the Arabisation process that submerged the original Berber language and customs seems to have be accompanied by substantial gene flow and genetic admixture. CONCLUSION: This study represents an additional step to obtain a comprehensive understanding of the complex demographic history of North African populations.

Establishment of murine gammaherpesvirus latency in B cells is not a stochastic event.

Murid γ-herpesvirus-4 (MuHV-4) promotes polyclonal B cell activation and establishes latency in memory B cells via unclear mechanisms. We aimed at exploring whether B cell receptor specificity plays a role in B cell susceptibility to viral latency and how this is related to B cell activation. We first observed that MuHV-4-specific B cells represent a minority of the latent population, and to better understand the influence of the virus on non-MuHV-4 specific B cells we used the SWHEL mouse model, which produce hen egg lysozyme (HEL)-specific B cells. By tracking HEL+ and HEL- B cells, we showed that in vivo latency was restricted to HEL- B cells while the two populations were equally sensitive to the virus in vitro. Moreover, MuHV-4 induced two waves of B cell activation. While the first wave was characterized by a general B cell activation, as shown by HEL+ and HEL- B cells expansion and upregulation of CD69 expression, the second wave was restricted to the HEL- population, which acquired germinal center (GC) and plasma cell phenotypes. Antigenic stimulation of HEL+ B cells led to the development of HEL+ GC B cells where latent infection remained undetectable, indicating that MuHV-4 does not benefit from acute B cell responses to establish latency in non-virus specific B cells but relies on other mechanisms of the humoral response. These data support a model in which the establishment of latency in B cells by γ-herpesviruses is not stochastic in terms of BCR specificity and is tightly linked to the formation of GCs.

Defining immune engagement thresholds for in vivo control of virus-driven lymphoproliferation.

Persistent infections are subject to constant surveillance by CD8+ cytotoxic T cells (CTL). Their control should therefore depend on MHC class I-restricted epitope presentation. Many epitopes are described for γ-herpesviruses and form a basis for prospective immunotherapies and vaccines. However the quantitative requirements of in vivo immune control for epitope presentation and recognition remain poorly defined. We used Murid Herpesvirus-4 (MuHV-4) to determine for a latently expressed viral epitope how MHC class-I binding and CTL functional avidity impact on host colonization. Tracking MuHV-4 recombinants that differed only in epitope presentation, we found little latitude for sub-optimal MHC class I binding before immune control failed. By contrast, control remained effective across a wide range of T cell functional avidities. Thus, we could define critical engagement thresholds for the in vivo immune control of virus-driven B cell proliferation.

Y chromosome diversity in a linguistic isolate (Mirandese, NE Portugal).

OBJECTIVES: The purpose of this study was to genetically characterize the male lineages of people who speak Mirandese, an interesting case of a linguistic relict that can still be found in the municipality of Miranda do Douro, NE Portugal. This region lies within the area of the Leonese dialects, which are remnants of the Romance dialects spoken in the Kingdom of Leon currently grouped in the Astur-Leonese linguistic continuum. We intended to disclose affinities with surrounding populations, namely from Spain where the Astur-Leonese is also spoken. METHODS: Eighty-eight unrelated males (58 from Miranda and 30 from Bragança, the broad Portuguese region where Miranda is located) were genotyped with the combined use of 17 Y chromosome short tandem repeats (Y-STRs) and a high resolution Y chromosome single nucleotide polymorphism (Y-SNPs) strategy. Moreover, 236 males from Miranda and neighboring regions, previously classified as R-M269, were also genotyped. RESULTS: R-P312 was the most frequent haplogroup in the Mirandese, followed by J-12f2.1 and T-M70. The male lineages J-12f2.1 and T-M70 were also well represented, and both were shared with descendants of Sephardic Jews. No signs of diversity reduction were detected. CONCLUSIONS: Mirandese speakers display a Y chromosome gene pool that shows a subtle differentiation from neighboring populations, mainly attributable to the assimilation of lineages ascribed to be of Jewish ancestry. Although not revealing signs of geographic/linguistic isolation, no clear affinities with other Astur-Leonese populations were detected. The results suggest that in Miranda language sharing is not accompanied by significant gene flow between populations from both sides of the political border. Am. J. Hum. Biol. 28:671-680, 2016. © 2016 Wiley Periodicals, Inc.

Y-chromosome analysis in a Northwest Iberian population: unraveling the impact of Northern African lineages.

OBJECTIVES: To provide new clues about the genetic origin, composition and structure of the population of the Spanish province of Zamora, with an emphasis on the genetic impact of the period of Islamic rule in the Iberian Peninsula. METHODS: Polymorphisms in the paternally inherited Y-chromosome, Single Nucleotide Polymorphisms and Short Tandem Repeats, were analyzed in 235 unrelated males born in six different regions in the Zamora province. RESULTS: A relatively homogenous Y-chromosome haplogroup composition was observed in the Zamora province. Haplogroups R1b1-P25 and I-M170, widespread in European populations, accounted for 64.9% of the total sample. Moreover, all of the observed African lineages, accounting for 10.2% of the total variability, belonged to haplogroups having Northwest African origin (E1b1b1b-M81, E1b1b1a-ß-M78, and J1-M267). CONCLUSIONS: No differences between regions or sub-structure due to geographical boundaries were detected. The specific Northwest African male lineages observed contrast with the mitochondrial DNA data, where the majority of African lineages were found to be sub-Saharan. This work made it possible to study the impact of recent historical events in the male gene pool in the province of Zamora in Spain.

Does early family risk and current quality of care predict indiscriminate social behavior in institutionalized Portuguese children?

The current study extends research on the effects of institutionalization, most notably by evaluating the influence of proximal relationship processes over and above prenatal and pre-institutional family experiences. By focusing on current quality of institutional care and the child's early family background, it examines the influence of variations in the institutionalization experience on displays of indiscriminate social behavior, after taking into account potentially confounding pre-admission experiences. Seventy-four Portuguese children (11-30 months) placed in 17 residential institutions and their primary caregivers participated in the study. Children's displays of indiscriminate social behavior were assessed based on an observational measure and a semi-structured interview administered to the child's caregiver. Data on children's physical and mental development were also collected. Three contextual-risk composites of early family behavior - prenatal, family relational, and emotional-neglect--were created. The quality of institutional care was examined in terms of structural, relational characteristics, and, additionally, of the quality of child-caregiver relationship. Current quality of care experienced in the institution, operationalized in terms of the absence (vs. presence) of a preferred caregiver, predicted indiscriminate social behavior over and above prenatal and family risk conditions that preceded the child's institutionalization.

The Bobath concept (NDT) in adult neurorehabilitation: a scoping review of conceptual literature.

PURPOSE: This scoping review aims to describe how Bobath concept is conceptualized, operationalized, and studied in adult neurorehabilitation. METHODS: The Joanna Briggs Institute (JBI) and the Preferred Reporting Items for Scoping Reviews (PRISMA-ScR) guidelines were adopted. Non-scientific and research articles were searched in electronic databases PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, Web of Science, ScienceDirect, and Physiotherapy Evidence Database (PEDro), with the keywords "Bobath" or "Neurodevelopmental Treatment", published in English, Spanish, and Portuguese, between 2013 and 2023. RESULTS: Of the 78 publications identified, 31 articles addressed the conceptual underpinnings of Bobath concept (seven theoretical papers, seven Delphi/surveys/mixed methods studies, four qualitative studies, one scoping review, 10 letters to the editor, and two editorials), comprising five themes: (a) theoretical principles; (b) clinical principles; (c) clinical reasoning; (d) conceptualizing movement; and, current (e) evidence debate. The revised definition and the Model of Bobath Clinical Practice provide a clarification of the unique aspects of Bobath concept. A new clinical skill was identified beyond facilitation - visuospatial kinesthetic perception - as well as how Bobath experts conceptualize movement, which are all integral to clinical reasoning. CONCLUSIONS: This review provides an updated Bobath clinical framework that gathers the theoretical foundations and clinical practice principles that require careful consideration in the design of future intervention studies.Implications for rehabilitationThis scoping review consolidates the clinical and theoretical principles of contemporary Bobath practice, providing a clear framework for clinicians.The Model of Bobath Clinical Practice (MBCP) framework enables detailed documentation of movement analysis and movement diagnosis, guiding clinical reasoning and interventions.This review identifies fundamental principles and practices to inform future Bobath intervention studies, ensuring their clinical relevance.A framework with specific recommendations has been developed to guide Bobath intervention studies, enhancing the integration of clinical practice, education, and research.

Emotion dysregulation and depressive symptoms mediate the association between inhibitory control difficulties and aggressive behaviour in children with ADHD.

Background/objectives: Impulsive aggressive behaviour, although not a core symptom, is often part of the clinical presentation of attention-deficit/hyperactivity disorder (ADHD). Recently, impulsive aggression has been attributed to emotion dysregulation, which is currently conceptualised as a transdiagnostic factor and seems to contribute to the co-occurrence of other problems in ADHD. Thus, this study investigated the presence of impulsive aggressive behaviour and explored whether emotion dysregulation mediates the relationship between inhibitory control difficulties and aggressive behaviour in children with ADHD. Because ADHD may act as a risk factor for the development of other conditions, such as internalising problems, we aimed to understand whether depressive symptoms contribute to this relationship. Methods: Seventy-two children were recruited from a hospital and the community, 38 of whom had ADHD and 34 were typically developing (TD). Parents completed the Child Behaviour Checklist, the Behaviour Rating Inventory of Executive Function, and the Emotion Regulation Checklist. Simple mediation and serial mediation models were performed to test our hypotheses. Results: Aggressive behaviour was significantly higher in ADHD children compared to TD children. Emotion dysregulation fully mediated the relationship between inhibitory control difficulties and aggressive behaviour in ADHD children. Adding depressive symptoms to the model increased the explained variance in aggressive behaviour. Conclusion: The main result of our study supports the role of emotion dysregulation and depressive symptoms in mediating the relationship between inhibitory control difficulties and impulsive aggressive behaviour in children with ADHD. This highlights that aggressive behaviour is, in part, a result of the inability of the child to appropriately regulate their emotions. Future interventions may be tailored to improve emotion regulation skills to address aggressive behaviour.

A new role for erythropoietin in the homeostasis of red blood cells.

The regulation of red blood cell (RBC) homeostasis is widely assumed to rely on the control of cell production by erythropoietin (EPO) and the destruction of cells at a fixed, species-specific age. In this work, we show that such a regulatory mechanism would be a poor homeostatic solution to satisfy the changing needs of the body. Effective homeostatic control would require RBC lifespan to be variable and tightly regulated. We suggest that EPO may control RBC lifespan by determining CD47 expression in newly formed RBCs and SIRP-α expression in sinusoidal macrophages. EPO could also regulate the initiation and intensity of anti-RBC autoimmune responses that curtail RBC lifespan in some circumstances. These mechanisms would continuously modulate the rate of RBC destruction depending on oxygen availability. The control of RBC lifespan by EPO and autoimmunity emerges as a key mechanism in the homeostasis of RBCs.

Familial juvenile hyperuricemic nephropathy: Revisiting the SLC8A1 gene, in a family with a novel terminal gross deletion in the UMOD gene.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) comprises a heterogeneous group of rare hereditary kidney diseases characterized by family history of progressive chronic kidney disease (CKD) with bland urine sediment, absence of significant proteinuria and normal or small-sized kidneys. Current diagnostic criteria require identification of a pathogenic variant in one of five genes - UMOD, MUC1, REN, HNF1ß, SEC61A1. The most prevalent form of ADTKD is uromodulin-associated kidney disease (ADTKD-UMOD). Genetic study of a Portuguese family diagnosed with familial juvenile hyperuricemic nephropathy (FJHN), one of the nosological entities in the spectrum of ADTKD, revealed a previously unreported large deletion in UMOD encompassing the entire terminal exon, which strictly cosegregated with CKD and hyperuricemia/gout, establishing the primary diagnosis of ADTKD-UMOD; as well as an ultra-rare nonsense SLC8A1 variant cosegregating with the UMOD deletion in patients that consistently exhibited an earlier onset of clinical manifestations. Since the terminal exon of UMOD does not encode for any of the critical structural domains or amino acid residues of mature uromodulin, the molecular mechanisms underlying the pathogenicity of its deletion are unclear and require further research. The association of the SLC8A1 locus with FJHN was first indicated by the results of a genome-wide linkage analysis in several multiplex families, but those data have not been subsequently confirmed. Our findings in this family revive that hypothesis.

Diverse physical growth trajectories in institutionalized Portuguese children below age 3: relation to child, family, and institutional factors.

OBJECTIVE: To identify and analyze diverse longitudinal trajectories of physical growth of institutionalized children and their relation to child, family, and institutional factors. METHODS: 49 institutionalized children were studied for 9 months after admission. Weight, height, and head circumference were measured on 4 occasions, beginning at admission. Data were analyzed using latent class analysis, yielding diverse patterns of growth for each feature, and relations with child characteristics, early family risk factors, and institutional relational care were investigated. RESULTS: For each growth feature, 4 classes emerged: "Persistently Low," "Improving," "Deteriorating," and "Persistently High." Younger age at admission was a risk factor for impaired physical growth across all domains. Physical characteristics at birth were associated with trajectories across all domains. Lower prenatal risk and better institutional relational care were associated with Improving weight over time. CONCLUSIONS: Discussion highlights the role of children's physical features at birth, prenatal risk, and caregiver's cooperation with the child in explaining differential trajectories.