Visual and neuropsychological outcomes following paediatric optic pathway glioma

Survival rates for children with brain cancer have dramatically increased in the recent decades, but evidence demonstrates long-term physical impairments, academic difficulties and neuropsychological deficits even among children with non-aggressive tumours and treatments. Children with optic pathway glioma (OPG) are at risk of neuropsychological difficulties due to the resulting visual impairment, the neural damage of the tumour itself and its treatment, and the comorbid neurodevelopmental disorder called Neurofibromatosis Type 1 (NF1). Yet, the literature on the sequelae of OPG beyond vision is scarce. This thesis is a comprehensive evaluation of long-term visual and neuropsychological outcomes in a group of 12 children who were diagnosed with a glioma in optic pathway, who received either chemotherapy or no treatment for their tumour. On the ophthalmic exam, children demonstrated a significant structural and functional damage to the optic pathway in terms of reduced thickness of the retinal nerve fiber layer and as well as poor visual acuity. Visuo-perceptual and visual-motor abilities, which reflect the ability to process of physical and asemantic stimuli, were significantly hindered and half of the sample performed below the level expected for their age in this domain (Chapter 3). On the cognitive assessment, children had preserved reasoning abilities (both verbal and visuospatial), but mild difficulties in working memory and processing speed, similarly to other brain tumour survivors. Core scholastic abilities of reading and maths comprehension were intact, but children had mild problems in writing and oral language. Only a minority of children (mostly with NF1) showed severe problems in these domains (Chapter 4). Significant associations were found among measures of vision and visual perception; cognitive and scholastic abilities were associated with each other, but not with visual perception. Among the risk factors, younger age at diagnosis was associated with poor visual outcomes in the best eye and poor binocular vision had a negative impact on visuoperceptual, cognitive and scholastic abilities that heavily relied on sight. In addition, children with NF1 tended to underperform, unlike children without NF1 (Chapter 5). Finally, participants were examined on a series of abilities (i.e., fine motor control, attention, short-term and working memory, mathematics and English comprehension), using parallel tasks that rely on either visual or auditory input. In comparison to a large group of typically developing children (N = 96), OPG survivors performed overall in line with the level expected for their age in both visual and auditory domains, although some children with NF1 exhibited problems in maths and English comprehension. In addition, strong significant correlations between the two ophthalmic measures and neuropsychological skills indicated that more severe structural and functional damage in the best eye was associated with faster responses on the auditory attention task. This result, in combination with the mild working memory difficulties reported with the standardised assessment, suggests that a compensatory mechanism in the auditory modality might take place in children with OPG, but this does not enable them to develop superior auditory abilities (Chapter 6). Overall, this study demonstrated that children with OPG experience significant visual and visuo-perceptual problems, as well as mild and specific cognitive and scholastic difficulties. About half of the children were at risk of great visuoperceptual problems, while only a minority was specifically at risk of severe underperformance in terms of intellectual and academic functioning. Children with OPG do not develop superior auditory skills to compensate for the loss of sight

Altered Cortical Gyrification in Adults Who Were Born Very Preterm and Its Associations With Cognition and Mental Health

Background: The last trimester of pregnancy is a critical period for the establishment of cortical gyrification, and altered folding patterns have been reported following very preterm birth (\u3c 33 weeks of gestation) in childhood and adolescence. However, research is scant on the persistence of such alterations in adulthood and their associations with cognitive and psychiatric outcomes. Methods: We studied 79 very preterm and 81 age-matched full-term control adults. T1-weighted magnetic resonance images were used to measure a local gyrification index (LGI), indicating the degree of folding across multiple vertices of the reconstructed cortical surface. Group and group-by-sex LGI differences were assessed by means of per-vertex adjustment for cortical thickness and overall intracranial volume. Within-group correlations were also computed between LGI and functional outcomes, including general intelligence (IQ) and psychopathology. Results: Very preterm adults had significantly reduced LGI in extensive cortical regions encompassing the frontal, anterior temporal, and occipitoparietal lobes. Alterations in lateral fronto-temporal-parietal and medial occipitoparietal regions were present in both men and women, although men showed more extensive alterations. In both very preterm and control adults, higher LGI was associated with higher IQ and lower psychopathology scores, with the spatial distribution of these associations substantially differing between the two groups. Conclusions: Very preterm adults’ brains are characterized by significant and widespread local hypogyria, and these alterations might be implicated in cognitive and psychiatric outcomes. Gyrification reflects an early developmental process and provides a fingerprint for very preterm birth

Caring for children with brain tumors in an oncology ward: a phenomenologic-hermeneutic study

Brain tumors are the most common form of solid tumors in childhood and are characterized by an uncertain prognosis, often meaning tumor invasive surgical procedures in the first steps of the patient’s treatment. In a Pediatric Oncology Ward, children with brain tumors are considered a challenge for health professionals, due to the nature of the relationship between the child, the parents, and the health care providers in the initial phase of the patient’s illness. Here we present a phenomenologic-hermeneutic study, developed in the Oncology Ward of a Hospital in Southern Spain. All the caregivers of the Ward underwent interviews concerning their experience in caring for children with brain tumors. Interviews were recorded and transcribed with the consent of the participants and were analyzed by content themes. In the present paper, we focus on the experiences concerning the first meeting of the professionals with the children and their families and the principal critical issues related to the communication of the diagnosis

Neuropsychological outcomes of children with Optic Pathway Glioma

Optic Pathway Glioma (OPG) is a relatively common brain tumour in childhood; however, there is scarce understanding of neuropsychological sequelae in these survivors. In this study, 12 children with diagnosis of OPG before 6 years of age received a comprehensive standardised assessment of visual perception, general intelligence and academic achievement, using adjustments to visual materials of the tests, to examine the extent of concurrent impairment in these functional domains. Information about vision, clinical and sociodemographic factors were extracted from medical records to assess the associations of neuropsychological outcomes with clinical and socio-demographic factors. Children with OPG exhibited high within-patient variability and moderate group-level impairment compared to test norms. Visual perception was the most impaired domain, while scholastic progression was age-appropriate overall. For cognition, core verbal and visuo-spatial reasoning skills were intact, whereas deficits were found in working memory and processing speed. Visual function was associated with tasks that rely on visual input. Children with OPG are at moderate risk of neuropsychological impairment, especially for visual perception and cognitive proficiency. Future research should elucidate further the relative contribution of vision loss and neurofibromatosis type 1 co-diagnosis within a large sample

Associations between Learning and Behavioral Difficulties in Second-Grade Children

Learning and behavioral difficulties often emerge during the first years of primary school and are one of the most important issues of concern for families and schools. The study was aimed at investigating the co-occurrence of difficulties between academic learning and emotional-behavioral control in typically developing school children and the moderating role of sex. A sample of 640 second-grade school children participated in the study. This study used the Strengths and Difficulties Questionnaire to measure the emotional and behavioral difficulties and a battery of objective and standardized tests to evaluate the learning skills in children. In this sample 7% to 16% of children performed below the normal range in reading and/or arithmetic tests. Mixed models showed that children's hyperactive behaviors were positively related to both reading and math difficulties, and emotional problems correlated negatively with reading accuracy. The more children displayed behavioral difficulties, the more they were exposed to the risk of worsening reading and math performance, especially for girls. The result that among different emotional-behavioral problems within the school setting, hyperactivity behaviors and emotional difficulties are related to learning difficulties with a moderate effect of sex, needs to be taken into account in screening and prevention programs for learning difficulties in order to not disregard the complexity of the associated profiles

Formyl-peptide Receptor Agonists and Amorphous SiO2-NPs Synergistically and Selectively Increase the Inflammatory Responses of Human Monocytes and PMNs

We tested whether amorphous SiO2-NPs and formyl-peptide receptor (FPRs) agonists synergistically activate human monocytes and neutrophil polymorphonuclear granulocytes (PMNs). Peptide ligands specifically binding to FPR1 (f-MLP) and to FPR2 (MMK-1, WKYMVM and WKYMVm) human isoforms did not modify the association of SiO2-NPs to both cell types or their cytotoxic effects. Similarly, the extent of CD80, CD86, CD83, ICAM-1 and MHCII expression in monocytes treated with SiO2-NPs was not significantly altered by any FPRs agonist. However, FPR1 stimulation with f-MLP strongly increased the secretion of IL-1β, IL-6 and IL-8 by human monocytes, and of IL-8 by PMNs in the presence of SiO2-NPs, due to the synergic stimulation of gene transcription. FPR2 agonists also up-modulated the production of IL-1β induced by monocytes treated with SiO2-NPs. In turn, SiO2-NPs increased the chemotaxis of PMNs toward FPR1-specific ligands, but not toward FPR2-specific ones. Conversely, the chemotaxis of monocytes toward FPR2-specific peptides was inhibited by SiO2-NPs. NADPH-oxidase activation triggered by FPR1- and FPR2-specific ligands in both cell types was not altered by SiO2-NPs. Microbial and tissue danger signals sensed by FPRs selectively amplified the functional responses of monocytes and PMNS to SiO2-NPs, and should be carefully considered in the assessment of the risk associated with nanoparticle exposure

Antibodies from multiple sclerosis patients preferentially recognize hyperglucosylated adhesin of non-typeable Haemophilus influenzae

In autoimmune diseases, there have been proposals that exogenous "molecular triggers", i.e., specific this should be 'non-self antigens' accompanying infectious agents, might disrupt control of the adaptive immune system resulting in serious pathologies. The etiology of the multiple sclerosis (MS) remains unclear. However, epidemiologic data suggest that exposure to infectious agents may be associated with increased MS risk and progression may be linked to exogenous, bacterially-derived, antigenic molecules, mimicking mammalian cell surface glycoconjugates triggering autoimmune responses. Previously, antibodies specific to a gluco-asparagine (N-Glc) glycopeptide, CSF114(N-Glc), were identified in sera of an MS patient subpopulation. Since the human glycoproteome repertoire lacks this uniquely modified amino acid, we turned our attention to bacteria, i.e., Haemophilus influenzae, expressing cell-surface adhesins including N-Glc, to establish a connection between H. influenzae infection and MS. We exploited the biosynthetic machinery from the opportunistic pathogen H. influenzae (and the homologous enzymes from A. pleuropneumoniae) to produce a unique set of defined glucosylated adhesin proteins. Interestingly we revealed that a hyperglucosylated protein domain, based on the cell-surface adhesin HMW1A, is preferentially recognized by antibodies from sera of an MS patient subpopulation. In conclusion the hyperglucosylated adhesin is the first example of an N-glucosylated native antigen that can be considered a relevant candidate for triggering pathogenic antibodies in MS

Di-(2-ethylhexyl) phthalate and autism spectrum disorders

ASDs (autism spectrum disorders) are a complex group of neurodevelopment disorders, still poorly understood, steadily rising in frequency and treatment refractory. Extensive research has been so far unable to explain the aetiology of this condition, whereas a growing body of evidence suggests the involvement of environmental factors. Phthalates, given their extensive use and their persistence, are ubiquitous environmental contaminants. They are EDs (endocrine disruptors) suspected to interfere with neurodevelopment. Therefore they represent interesting candidate risk factors for ASD pathogenesis. The aim of this study was to evaluate the levels of the primary and secondary metabolites of DEHP [di-(2-ethylhexyl) phthalate] in children with ASD. A total of 48 children with ASD (male: 36, female: 12; mean age: 11±5 years) and age- and sex-comparable 45 HCs (healthy controls; male: 25, female: 20; mean age: 12±5 years) were enrolled. A diagnostic methodology, based on the determination of urinary concentrations of DEHP metabolites by HPLC-ESI-MS (HPLC electrospray ionization MS), was applied to urine spot samples. MEHP [mono-(2-ethylhexenyl) 1,2-benzenedicarboxylate], 6-OH-MEHP [mono-(2-ethyl-6-hydroxyhexyl) 1,2-benzenedicarboxylate], 5-OH-MEHP [mono-(2-ethyl-5-hydroxyhexyl) 1,2-benzenedicarboxylate] and 5-oxo-MEHP [mono-(2-ethyl-5-oxohexyl) 1,2-benzenedicarboxylate] were measured and compared with unequivocally characterized, pure synthetic compounds (>98%) taken as standard. In ASD patients, significant increase in 5-OH-MEHP (52.1%, median 0.18) and 5-oxo-MEHP (46.0%, median 0.096) urinary concentrations were detected, with a significant positive correlation between 5-OH-MEHP and 5-oxo-MEHP (rs = 0.668, P<0.0001). The fully oxidized form 5-oxo-MEHP showed 91.1% specificity in identifying patients with ASDs. Our findings demonstrate for the first time an association between phthalates exposure and ASDs, thus suggesting a previously unrecognized role for these ubiquitous environmental contaminants in the pathogenesis of autism