Trends in imported infections among migrants and travellers to Spain: a decade of analysis through the +Redivi network (2012-2022).

BACKGROUND: High-speed global travel, increased trade, world population growth, migration, urbanisation and climate change have favoured the emergence and spread of pathogens. We aimed to analyse the evolution of imported infections in Spain during 2012-2022 and the potential impact of some of the abovementioned factors on differential morbidity patterns. METHODS: In this retrospective study (January/2012 to December/2022), we analysed data collected by the +Redivi network across 25 health centres. The network's standardised database records new cases of imported infections, including patient demographics, travel history, pre-travel advice and diagnostic information. To assess outcome rates over time and potential interactions, we constructed penalised weighted models to reduce the bias related to a low event rate and used weighted logistic regression for morbidity outcomes. RESULTS: We recorded 25 632 episodes, comprising 13 913 migrants, 4047 visiting friends and relatives (VFR) immigrants, 392 VFR travellers and 7280 travellers. Most immigrants came from South America (48.3%), Sub-Saharan Africa (28.5%), North Africa (6.6%), South Central Asia (5.4%) and Central America/Caribbean (5.3%). The most common regions visited by travellers were Sub-Saharan Africa (33.5%), South America (24.5%), Central America/Caribbean (13.5%), Southeast Asia (12%) and South Central Asia (10%). The proportion of diagnoses of malaria, strongyloidiasis and unspecified self-limiting febrile syndrome < 3 weeks remained unchanged during the study period. An increased frequency of diagnosis was reported for schistosomiasis, blastocystosis, giardiasis, dengue, diarrhoea, new cases of HIV, latent and pulmonary tuberculosis; a decrease was reported for syphilis, chikungunya fever, Chagas disease and eosinophilia. We detected interactions between time and sex or type of participant across the different diagnoses. CONCLUSIONS: Our study underscores the importance of epidemiological data in understanding infectious diseases dynamics among travellers and migrants, emphasising how demographic shifts, migration trends and healthcare policies affect disease profiles. Comprehensive data play an essential role in enhancing public health policies and travel advice.

Intermediate-Term Clinical Outcomes of High-Density Autologous Chondrocyte Implantation in Patients with Concomitant Anterior Cruciate Ligament Reconstruction and Focal Chondral Lesions.

OBJECTIVE: To investigate intermediate-term clinical results in patients with concomitant anterior cruciate ligament (ACL) reconstruction and chondral defect treated with high-density autologous chondrocyte implantation (HD-ACI) compared to patients without ACL tear but with a chondral lesion and HD-ACI treatment. DESIGN: Forty-eight patients with focal chondral lesions underwent HD-ACI (24 with ACL reconstruction after an ACL injury and 24 with an intact ACL). Follow-up assessments occurred at 6, 12, and 24 months. Patient-reported knee function and symptoms were assessed using the International Knee Documentation Committee (IKDC) questionnaire, pain was measured using the Visual Analog Scale (VAS), and adverse events were monitored. Physical activity was assessed using the Tegner Activity Level Scale, and cartilage healing was evaluated with the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. RESULTS: No significant adverse events occurred during follow-up. Both groups showed significant improvements at 2 years compared to baseline (VAS: 8.0 ± 1.3 to 1.4 ± 2.0 [normal ACL]; 7.4 ± 2.3 to 2.1 ± 2.3 [ACL reconstruction]; IKDC: 39.2 ± 10.6 to 76.1 ± 22.0 [intact ACL]; 35.6 ± 12.1 to 74.6 ± 20.9 [ACL reconstruction]). Patients in both groups exceeded the minimal clinically important difference (MCID) for IKDC scores. The Tegner Activity Level Scale decreased immediately after surgery and increased after 2 years, with 70.6% (normal ACL) and 89.5% (ACL reconstruction) returning to their preinjury activity levels. No significant differences in the MOCART score were observed between the groups. CONCLUSIONS: ACL reconstruction does not appear to reduce the outcomes (at 2 years) of HD-ACI.

The Role of Chaperone-Mediated Autophagy in Tissue Homeostasis and Disease Pathogenesis.

Chaperone-mediated autophagy (CMA) is a selective proteolytic pathway in the lysosomes. Proteins are recognized one by one through the detection of a KFERQ motif or, at least, a KFERQ-like motif, by a heat shock cognate protein 70 (Hsc70), a molecular chaperone. CMA substrates are recognized and delivered to a lysosomal CMA receptor, lysosome-associated membrane protein 2A (LAMP-2A), the only limiting component of this pathway, and transported to the lysosomal lumen with the help of another resident chaperone HSp90. Since approximately 75% of proteins are reported to have canonical, phosphorylation-generated, or acetylation-generated KFERQ motifs, CMA maintains intracellular protein homeostasis and regulates specific functions in the cells in different tissues. CMA also regulates physiologic functions in different organs, and is then implicated in disease pathogenesis related to aging, cancer, and the central nervous and immune systems. In this minireview, we have summarized the most important findings on the role of CMA in tissue homeostasis and disease pathogenesis, updating the recent advances for this Special Issue.

Investigating the impact of physical activity on mitochondrial function in Parkinson's disease (PARKEX): Study protocol for A randomized controlled clinical trial.

Parkinson's disease (PD) is characterized by the progressive dopaminergic neuron degeneration, resulting in striatal dopamine deficiency. Mitochondrial dysfunction and oxidative stress are associated with PD pathogenesis. Physical activity (PA) has been shown to ameliorate neurological impairments and to impede age-related neuronal loss. In addition, skin fibroblasts have been identified as surrogate indicators of pathogenic processes correlating with clinical measures. The PARKEX study aims to compare the effects of two different PA programs, analyzing the impact on mitochondrial function in patients' skin fibroblasts as biomarkers for disease status and metabolic improvement. Early-stage PD patients (n = 24, H&Y stage I to III) will be randomized into three age- and sex-matched groups. Group 1 (n = 8) will undergo basic physical training (BPT) emphasizing strength and resistance. Group 2 (n = 8) will undergo BPT combined with functional exercises (BPTFE), targeting the sensorimotor pathways that are most affected in PD (proprioception-balance-coordination) together with cognitive and motor training (Dual task training). Group 3 (n = 8) will serve as control (sedentary group; Sed). Participants will perform three sessions per week for 12 weeks. Assessment of motor function, quality of life, sleep quality, cognitive aspects and humor will be conducted pre- and post-intervention. Patient skin fibroblasts will be collected before and after the intervention and characterized in terms of metabolic remodeling and mitochondrial bioenergetics. Ethical approval has been given to commence this study. This trial is registered at clinicaltrials.gov (NCT05963425). Trial registration. https://classic.clinicaltrials.gov/ct2/history/NCT05963425.

Cartilage Defect Treatment Using High-Density Autologous Chondrocyte Implantation (HD-ACI).

Hyaline cartilage's inability to self-repair can lead to osteoarthritis and joint replacement. Various treatments, including cell therapy, have been developed for cartilage damage. Autologous chondrocyte implantation (ACI) is considered the best option for focal chondral lesions. In this article, we aimed to create a narrative review that highlights the evolution and enhancement of our chondrocyte implantation technique: High-Density-ACI (HD-ACI) Membrane-assisted Autologous Chondrocyte Implantation (MACI) improved ACI using a collagen membrane as a carrier. However, low cell density in MACI resulted in softer regenerated tissue. HD-ACI was developed to improve MACI, implanting 5 million chondrocytes per cm2, providing higher cell density. In animal models, HD-ACI formed hyaline-like cartilage, while other treatments led to fibrocartilage. HD-ACI was further evaluated in patients with knee or ankle defects and expanded to treat hip lesions and bilateral defects. HD-ACI offers a potential solution for cartilage defects, improving outcomes in regenerative medicine and cell therapy. HD-ACI, with its higher cell density, shows promise for treating chondral defects and advancing cartilage repair in regenerative medicine and cell therapy.

Executive summary consensus statement of imported diseases group (GEPI) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Society of Tropical Medicine and International Health (SETMSI), on the diagnostic and treatment of imported schistosomiasis.

Schistosomiasis is a highly prevalent disease, especially in immigrant populations, and is associated with significant morbidity and diagnostic delays outside endemic areas. For these reasons, the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Society of Tropical Medicine and International Health (SEMTSI) have developed a joint consensus document to serve as a guide for the screening, diagnosis and treatment of this disease outside endemic areas. A panel of experts from both societies identified the main questions to be answered and developed recommendations based on the scientific evidence available at the time. The document was reviewed by the members from both societies for final approval.

Can haematological changes constitute a surrogate diagnostic parameter to detect schistosomiasis in migrants and travellers? - A retrospective analysis.

Background: Earlier studies found characteristic haematological changes in African patients with active schistosomiasis. If consistently present, full blood counts (FBC) may be helpful to diagnose schistosomiasis also in migrants and returning travellers. Methods: A retrospective patient record review was conducted on data from seven European travel clinics, comparing FBC of Schistosoma egg-positive travellers and migrants to reference values. Sub-analyses were performed for children, returned travellers, migrants and different Schistosoma species. Results: Data analysis included 382 subjects (median age 21.0 years [range 2-73]). In returned travellers, decreases in means of haemoglobin particularly in females (ß = -0.82 g/dL, p = 0.005), MCV (ß = -1.6 fL, p = 0.009), basophils, neutrophils, lymphocytes and monocytes (ß = -0.07, p < 0.001; -0.57, p = 0.012; -0.57, p < 0.001 and -0.13 103/µL, p < 0.001, respectively) were observed. As expected, eosinophils were increased (ß = +0.45 103/µL, p < 0.001). In migrants, a similar FBC profile was observed, yet thrombocytes and leukocytes were significantly lower in migrants (ß = -48 103/µL p < 0.001 and ß = -2.35 103/µL, p < 0.001, respectively). Conclusions: Active egg-producing Schistosoma infections are associated with haematological alterations in returned travellers and migrants. However, these differences are discrete and seem to vary among disease stage and Schistosoma species. Therefore, the FBC is unsuitable as a surrogate diagnostic parameter to detect schistosomiasis.

The Consequences of GBA Deficiency in the Autophagy-Lysosome System in Parkinson's Disease Associated with GBA.

GBA gene variants were the first genetic risk factor for Parkinson's disease. GBA encodes the lysosomal enzyme glucocerebrosidase (GBA), which is involved in sphingolipid metabolism. GBA exhibits a complex physiological function that includes not only the degradation of its substrate glucosylceramide but also the metabolism of other sphingolipids and additional lipids such as cholesterol, particularly when glucocerebrosidase activity is deficient. In the context of Parkinson's disease associated with GBA, the loss of GBA activity has been associated with the accumulation of α-synuclein species. In recent years, several hypotheses have proposed alternative and complementary pathological mechanisms to explain why lysosomal enzyme mutations lead to α-synuclein accumulation and become important risk factors in Parkinson's disease etiology. Classically, loss of GBA activity has been linked to a dysfunctional autophagy-lysosome system and to a subsequent decrease in autophagy-dependent α-synuclein turnover; however, several other pathological mechanisms underlying GBA-associated parkinsonism have been proposed. This review summarizes and discusses the different hypotheses with a special focus on autophagy-dependent mechanisms, as well as autophagy-independent mechanisms, where the role of other players such as sphingolipids, cholesterol and other GBA-related proteins make important contributions to Parkinson's disease pathogenesis.

Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology.

Mutations in the GBA gene that encodes the lysosomal enzyme ß-glucocerebrosidase (GCase) are a major genetic risk factor for Parkinson's disease (PD). In this study, we generated a set of differentiated and stable human dopaminergic cell lines that express the two most prevalent GBA mutations as well as GBA knockout cell lines as a in vitro disease modeling system to study the relationship between mutant GBA and the abnormal accumulation of α-synuclein. We performed a deep analysis of the consequences triggered by the presence of mutant GBA protein and the loss of GCase activity in different cellular compartments, focusing primarily on the lysosomal compartment, and analyzed in detail the lysosomal activity, composition, and integrity. The loss of GCase activity generates extensive lysosomal dysfunction, promoting the loss of activity of other lysosomal enzymes, affecting lysosomal membrane stability, promoting intralysosomal pH changes, and favoring the intralysosomal accumulation of sphingolipids and cholesterol. These local events, occurring only at a subcellular level, lead to an impairment of autophagy pathways, particularly chaperone-mediated autophagy, the main α-synuclein degradative pathway. The findings of this study highlighted the role of lysosomal function and lipid metabolism in PD and allowed us to describe a molecular mechanism to understand how mutations in GBA can contribute to an abnormal accumulation of different α-synuclein neurotoxic species in PD pathology.

Coordination of mitochondrial and lysosomal homeostasis mitigates inflammation and muscle atrophy during aging.

Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria (MIT) in muscle could trigger inflammation in the context of aging is still unknown. Here, we demonstrate that BCL2 interacting protein 3 (BNIP3) plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of Toll-like receptor 9 (TLR9)-dependent inflammation and activation of the NLRP3 (nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3) inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age-induced muscle inflammation in mice and humans. Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging.

The Medicalization of the Transsexual: Patient-Physician Narratives in the First Half of the Twentieth Century.

This article explores the history of what the German-American endocrinologist Harry Benjamin labeled in 1966, "the transsexual phenomenon." By mid-century, a growing number of individuals in both Europe and America were approaching physicians such as Benjamin searching for answers and means to change their bodies to match their gender. This phenomenon had started in Europe in the 1930s, when the Danish painter Einar Wegener underwent a series of operations that transformed a body defined at birth as male into the female body of Lili Elbe. The news of Elbe's transformation ignited interest and discussion among physicians as well as the public on the capacity science had to alter bodies to fit their intended selves. The case of Elbe combines the three main aspects studied in this article-the medicalization of the homosexual, the birth of the transsexual, and the physician-patient relationship in transsexual narratives. The study of physician and patient narratives allow us to see how the transsexual phenomenon was in fact created out of the intersection of interests from both physicians and their transsexual patients.

Autophagy and the hallmarks of aging.

Autophagy, an essential cellular process that mediates degradation of proteins and organelles in lysosomes, has been tightly linked to cellular quality control for its role as part of the proteostasis network. The current interest in identifying the cellular and molecular determinants of aging, has highlighted the important contribution of malfunctioning of autophagy with age to the loss of proteostasis that characterizes all old organisms. However, the diversity of cellular functions of the different types of autophagy and the often reciprocal interactions of autophagy with other determinants of aging, is placing autophagy at the center of the aging process. In this work, we summarize evidence for the contribution of autophagy to health- and lifespan and provide examples of the bidirectional interplay between autophagic pathways and several of the so-called hallmarks of aging. This central role of autophagy in aging, and the dependence on autophagy of many geroprotective interventions, has motivated a search for direct modulators of autophagy that could be used to slow aging and extend healthspan. Here, we review some of those ongoing therapeutic efforts and comment on the potential of targeting autophagy in aging.

High-Density Autologous Chondrocyte Implantation as Treatment for Ankle Osteochondral Defects.

PURPOSE: Two-year follow-up to assess efficacy and safety of high-density autologous chondrocyte implantation (HD-ACI) in patients with cartilage lesions in the ankle. DESIGN: Twenty-four consecutive patients with International Cartilage repair Society (ICRS) grade 3-4 cartilage lesions of the ankle were included. Five million chondrocytes per cm2 of lesion were implanted using a type I/III collagen membrane as a carrier and treatment effectiveness was assessed by evaluating pain with the visual analogue scale (VAS) and American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score at baseline, 12-month, and 24-month follow-up, together with dorsal and plantar flexion. Magnetic resonance observation for cartilage repair tissue (MOCART) score was used to evaluate cartilage healing. Histological study was possible in 5 cases. RESULTS: Patients' median age was 31 years (range 18-55 years). Median VAS score was 8 (range 5-10) at baseline, 1.5 (range 0-8) at 12-month follow-up, and 2 (rang e0-5) at 24-month follow-up (P < 0.001). Median AOFAS score was 39.5 (range 29-48) at baseline, 90 (range 38-100) at 12-month follow-up, and 90 (range 40-100) at 24-month follow-up (P < 0.001). Complete dorsal flexion significantly increased at 12 months (16/24, 66.7%) and 24 months (17/24, 70.8%) with regard to baseline (13/24, 54.2%) (P = 0.002). MOCART at 12- and 24-month follow-ups were 73.71 ± 15.99 and 72.33 ± 16.21. Histological study confirmed that neosynthetized tissue was cartilage with hyaline extracellular matrix and numerous viable chondrocytes. CONCLUSION: HD-ACI is a safe and effective technique to treat osteochondral lesions in the talus, providing good clinical and histological results at short- and mid-term follow-ups.

Mutant HTT (huntingtin) impairs mitophagy in a cellular model of Huntington disease.

The precise degradation of dysfunctional mitochondria by mitophagy is essential for maintaining neuronal homeostasis. HTT (huntingtin) can interact with numerous other proteins and thereby perform multiple biological functions within the cell. In this study, we investigated the role of HTT during mitophagy and analyzed the impact of the expansion of its polyglutamine (polyQ) tract. HTT is involved in different mitophagy steps, promoting the physical proximity of different protein complexes during the initiation of mitophagy and recruiting mitophagy receptors essential for promoting the interaction between damaged mitochondria and the nascent autophagosome. The presence of the polyQ tract in mutant HTT affects the formation of these protein complexes and determines the negative consequences of mutant HTT on mitophagy, leading to the accumulation of damaged mitochondria and an increase in oxidative stress. These outcomes contribute to general mitochondrial dysfunction and neurodegeneration in Huntington disease.Abbreviations: AMPK: AMP-activated protein kinase; ATG13: autophagy related 13; BECN1: beclin 1, autophagy related; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chlorophenyl hydrazone; DMEM: Dulbecco's modified eagle medium; EDTA: ethylene-diamine-tetra-acetic acid; EGFP: enhanced green fluorescent protein; EGTA: ethylene glycol bis(2-aminoethyl ether)tetraacetic acid; FUNDC1: FUN14 domain containing 1; HD: Huntington disease; HRP: horseradish peroxidase; HTT: huntingtin; LC3-II: lipidated form of MAP1LC3/LC3; mtDNA: mitochondrial deoxyribonucleic acid; MTDR: MitoTracker Deep Red; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1, autophagy cargo receptor; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; OCR: oxygen consumption rate; OPTN: optineurin; OXPHOS: oxidative phosphorylation; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PINK1: PTEN induced putative kinase 1; PLA: proximity ligation assay; PMSF: phenylmethylsulfonyl fluoride; polyQ: polyglutamine; PtdIns3K: phosphatidylinositol 3-kinase; ROS: reactive oxygen species; Rot: rotenone; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TMRM: tetramethylrhodamine methyl ester; UB: ubiquitin; ULK1: unc-51 like kinase 1.

Ajuste personal y conductas disruptivas en alumnado de primaria / Personal Adjustment and Disruptive Behaviors in Primary School Students

Resumen. Objetivo. Estudiar las relaciones entre variables de ajuste personal y las conductas disruptivas en un grupo de 136 alumnos y alumnas de primaria de entre 9 y 12 años. Método. Estudio de campo observacional, de metodología no experimental y transversal. Se utilizaron varios cuestionarios para medir la autoestima, la personalidad, el estrés y las competencias emocionales de los y las estudiantes, así como un cuestionario ad hoc elaborado para el registro de las conductas disruptivas. Resultados. Los resultados indican relaciones significativas positivas entre conductas disruptivas y estrés escolar, así como negativas con autoestima, estabilidad, competencia y comprensión emocional. Las diferencias son significativas según el género, manifestándose las conductas inadecuadas en menor medida en el caso de las niñas.

Abstract. Objective. This study analyses the relationships between personal adjustment and disruptive behaviors in a group of 136 primary school students between the ages of 9 and 12. Method. This field observation study used a non-experimental, cross-sectional methodology. Several questionnaires were used to measure students' self-esteem, personality, stress, and emotional competencies. Moreover, an ad hoc questionnaire was created to record disruptive behaviors. Results. The results indicate significant positive relationships between disruptive behaviors and school stress, as well as negative ones with self-esteem, stability, competence, and emotional understanding. The differences are significant according to gender, with inappropriate behaviors manifesting to a lesser extent in the case of girls.

The Emerging Role of the Lysosome in Parkinson's Disease.

Lysosomal function has a central role in maintaining neuronal homeostasis, and, accordingly, lysosomal dysfunction has been linked to neurodegeneration and particularly to Parkinson's disease (PD). Lysosomes are the converging step where the substrates delivered by autophagy and endocytosis are degraded in order to recycle their primary components to rebuild new macromolecules. Genetic studies have revealed the important link between the lysosomal function and PD; several of the autosomal dominant and recessive genes associated with PD as well as several genetic risk factors encode for lysosomal, autophagic, and endosomal proteins. Mutations in these PD-associated genes can cause lysosomal dysfunction, and since α-synuclein degradation is mostly lysosomal-dependent, among other consequences, lysosomal impairment can affect α-synuclein turnover, contributing to increase its intracellular levels and therefore promoting its accumulation and aggregation. Recent studies have also highlighted the bidirectional link between Parkinson's disease and lysosomal storage diseases (LSD); evidence includes the presence of α-synuclein inclusions in the brain regions of patients with LSD and the identification of several lysosomal genes involved in LSD as genetic risk factors to develop PD.

Prevalence and Clinical Manifestations of Congenital Cytomegalovirus Infection in a Screening Program in Madrid (PICCSA Study).

BACKGROUND: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Up to 15%-20% of infected newborns will develop long-term sequelae such as hearing loss and neurologic abnormalities. The aim of this study was to investigate the prevalence of congenital CMV infection (cCMV) and associated clinical abnormalities in Spain. METHODS: A prospective screening for cCMV by viral load in saliva was performed. Saliva samples were obtained within the first 72 hours of life in a maternity ward in Madrid (Spain), during a 1-year period. All positive screening tests were confirmed with viral load in urine. Clinical, laboratory, auditory, visual and cerebral imaging assessments were performed in all children with cCMV. RESULTS: Of the 4097 neonates born during the study period, 3190 (78%) were included. CMV viral load in saliva was detectable in 24/3190 (0.75%) children, and congenital infection was confirmed in 15/3190 (0.47%, CI 95%: 0.29%-0.77%). Positive predictive value was 62.5% (CI 95%: 46.5%-76.1%). Two infants presented symptoms at birth. Eight (53.3%) children showed abnormalities in magnetic resonance imaging; most of them isolated white matter abnormalities. Newborns with abnormalities in magnetic resonance imaging showed higher viral loads in blood and saliva (P = 0.04). CONCLUSIONS: One in 200 neonates born in our hospital presented a cCMV infection. CMV viral load in saliva has been shown to be a simple and highly accepted screening method but should be confirmed by CMV detection in urine. In spite of the fact that half of infected children had abnormalities in cerebral imaging, diagnosis during the neonatal period would have been impossible without a screening program in most cases.

Impaired proteasome activity and neurodegeneration with brain iron accumulation in FBXO7 defect.

FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). METHODS: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. RESULTS: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. CONCLUSION: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders.

Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice.

BACKGROUND: The apolipoprotein E (APOE) gene exists in three isoforms in humans: APOE2, APOE3 and APOE4. APOE4 causes structural and functional alterations in normal brains, and is the strongest genetic risk factor of the sporadic form of Alzheimer's disease (LOAD). Research on APOE4 has mainly focused on the neuronal damage caused by defective cholesterol transport and exacerbated amyloid-ß and Tau pathology. The impact of APOE4 on non-neuronal cell functions has been overlooked. Astrocytes, the main producers of ApoE in the healthy brain, are building blocks of neural circuits, and Ca2+ signaling is the basis of their excitability. Because APOE4 modifies membrane-lipid composition, and lipids regulate Ca2+ channels, we determined whether APOE4 dysregulates Ca2+signaling in astrocytes. METHODS: Ca2+ signals were recorded in astrocytes in hippocampal slices from APOE3 and APOE4 gene targeted replacement male and female mice using Ca2+ imaging. Mechanistic analyses were performed in immortalized astrocytes. Ca2+ fluxes were examined with pharmacological tools and Ca2+ probes. APOE3 and APOE4 expression was manipulated with GFP-APOE vectors and APOE siRNA. Lipidomics of lysosomal and whole-membranes were also performed. RESULTS: We found potentiation of ATP-elicited Ca2+responses in APOE4 versus APOE3 astrocytes in male, but not female, mice. The immortalized astrocytes modeled the male response, and showed that Ca2+ hyperactivity associated with APOE4 is caused by dysregulation of Ca2+ handling in lysosomal-enriched acidic stores, and is reversed by the expression of APOE3, but not of APOE4, pointing to loss of function due to APOE4 malfunction. Moreover, immortalized APOE4 astrocytes are refractory to control of Ca2+ fluxes by extracellular lipids, and present distinct lipid composition in lysosomal and plasma membranes. CONCLUSIONS: Immortalized APOE4 versus APOE3 astrocytes present: increased Ca2+ excitability due to lysosome dysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation of Ca2+ responses upon changes in extracellular lipids. Ca2+ hyperactivity associated with APOE4 is found in astrocytes from male, but not female, targeted replacement mice. The study suggests that, independently of Aß and Tau pathologies, altered astrocyte excitability might contribute to neural-circuit hyperactivity depending on APOE allele, sex and lipids, and supports lysosome-targeted therapies to rescue APOE4 phenotypes in LOAD.