Healthy Siblings Research Articles

Fecal Myeloperoxidase Levels Reflect Disease Activity in Children With Crohn's Disease.

Crohn's disease (CD) is a major form of inflammatory bowel disease (IBD) which has relapsing and remitting symptoms. Better ways to detect and monitor active disease are required for early diagnosis and optimal outcomes. We assessed fecal myeloperoxidase (fMPO), a neutrophil-derived enzyme that produces hypochlorous acid, as a marker of disease activity in children with CD. This observational study assessed myeloperoxidase (MPO) levels in fecal samples from children aged <17 years with CD (51 with active or 42 inactive disease) measured by enzyme-linked immunosorbent assay (ELISA) and compared to controls (35 healthy siblings and 15 unrelated well children). Results were correlated with fecal calprotectin, serum C-reactive protein, urinary glutathione sulfonamide (a biomarker of hypochlorous acid), and disease activity scores. Differences between groups were assessed by analysis of variance. Receiver-operating-characteristic curves were used to assess how biomarkers predicted disease and disease activity. Fecal myeloperoxidase activity and fMPO protein correlated with fecal calprotectin (r = 0.78, P < .0001, and r = 0.81, P < .0001, respectively). Fecal myeloperoxidase activity and protein levels were significantly higher (P ≤ .0001) in individuals with active disease compared to healthy sibling controls, unrelated well children, and those with inactive disease. A 9.7 µg/g fMPO protein cutoff distinguished inactive from active disease (sensitivity = 75%, specificity = 76%). Urinary GSA was elevated in children with active disease (P < .0001) and correlated with fMPO protein (r = 0.43, P = .0002) in a subset of 72 children with IBD and controls. Fecal myeloperoxidase may be superior to fCal at reflecting disease severity in children with CD and produces the damaging oxidant hypochlorous acid during active inflammation.

No Conflicting Loyalties in Parents When Their Healthy Child Donates Stem Cells to a Severely Ill Sibling: An Interview Study.

Background: When a potential stem cell donor to a seriously ill child is a healthy sibling below 18 years, Swedish parents have the legal right and obligation to decide on behalf of the donor child. However, there are potentially conflicting loyalties when parents have one severely ill child in need for a cure and one healthy child who will be subjected to medical procedures. This study explored parents' experiences related to their decision on stem cell donation, as well as ethical considerations in the donation process where outcomes are uncertain. Method: Individual interviews were performed with 18 parents of 13 minor donors after successful hematopoietic stem cell transplantations. Interviews were analyzed using inductive Reflexive Thematic Analysis. Results: The parents were living with the threat of losing a child, and in this context, the main theme No conflicting loyalties was found and included four subthemes; Focus on the ill child, Sibling as the preferred donor, Obvious that the healthy child should donate, and Keep on keeping on. Conclusion: When a healthy child is a potential donor to an ill sibling, their parents' main focus is on the cure for the ill child. The lack of obvious conflicting loyalties among parents highlights the need to secure an ethical process for healthy minor donors and the importance of a separate donor advocate for these minor donors.

Substantial elevation of telomeric oxidized bases in childhood autism

BackgroundThe underlying molecular mechanisms responsible for the etiology of autism and its sex-biased prevalence remain largely elusive. We have previously shown that children with non-syndromic low-functioning idiopathic autism exhibit a sexually dimorphic pattern of relative telomere length (RTL), with autistic male children having significantly shorter RTL than autistic female children, healthy controls, and paired siblings. By contrast, a number of autistic girls had longer RTLs than healthy controls. Here, we investigated levels of telomeric oxidized base (TelOB) lesions among the same study subjects and groups. MethodsEmploying a quantitative PCR (qPCR)-based method, which combines DNA digestion targeting oxidized bases and telomere measurement, TelOB lesions were measured using genomic DNA extracted from saliva samples collected from 24 children (14 male and 10 female) with autism, 10 paired siblings, and 24 sex, age, and location-matched typically-developing controls. ResultsOur findings show that both male and female autistic children exhibit substantially higher TelOB lesions at their telomeres than healthy controls and paired siblings. Interestingly, these elevated levels of TelOBs show a direct correlation with RTL values in autistic children but not in healthy controls. However, TelOB levels do not show any association with age either in the autistic children or the healthy control group. ConclusionsOur findings open a fresh angle into autism spectrum disorders (ASD), raise new questions, and lay the foundation for further research into telomere biology and underlying molecular mechanisms involved in ASD. TelOB levels are likely set during early development and may serve as biomarkers for childhood autism.

Mitigating and minimising at-home illness-related stress of well-siblings through school support

Living with a chronic health condition in the home can have a debilitating effect on the psychosocial and psychoaffective wellbeing of the entire family. This is particularly the case for healthy school aged siblings. This research investigated the perceptions and experiences of at-school support for well-siblings to evaluate its effectiveness in mitigating and minimising the at-home illness-related stress effect. Seven siblings (both primary and secondary age) whose brothers had received treatment for a chronic illness (e.g. cancer) were interviewed, as were their mothers, six schoolteachers, and two principals. Responses were analysed thematically, and the findings revealed that the chronic illness of a sibling bears strongly on how well-siblings feel about themselves: their very identity is challenged; and they lose their sense of belonging, worth, and self. Findings identified that inconsistencies in at-school support are linked with a lack of an overarching mandate for support, emphasising the need for urgent remediation in policy development and process reform.

Evaluation of Body Composition and Biochemical Parameters in Adult Phenylketonuria

Background/Objectives: Phenylketonuria is a hereditary metabolic disorder characterized by a deficiency of phenylalanine hydroxylase. The main treatment for PKU is a phenylalanine-restricted diet. The exclusion of protein rich natural foods and inclusion of low-Phe substitutes may give rise to an imbalanced diet, and the increased risk of overweight and obesity in PKU is a cause for concern. We aimed to evaluate the body composition and nutritional biochemical biomarkers in adult PKU patients who are on Phe-restricted and essential amino acid-supplemented nutrition therapy and to investigate the relationships between these parameters and patient gender, adherence to dietary therapy, and disease type, defined as mild or classic PKU. Methods: The study group comprised 37 PKU patients and 26 healthy siblings as controls. The participants were assessed based on an analysis of anthropometric parameters, body composition, and biochemical test results. Results: PKU patients do not have a higher incidence of overweight and obesity than healthy controls, the proportion of energy derived from carbohydrates in their diets was below the recommended level, and their total energy intake was below the recommended daily allowance. It was remarkable that patients with a treatment adherence ratio of &lt;50% displayed a higher prevalence of overweight and abdominal obesity in comparison to those with a more favorable treatment adherence ratio. Conclusions: In view of the growing prevalence of overweight in the general population, PKU patients should be kept under close long-term follow-up. Particularly in the group with low treatment compliance, more caution should be taken in terms of adverse outcomes.

HLA-A, -B, -C and -DRB1 Association with Autism Spectrum Disorder Risk: A Sex-Related Analysis in Italian ASD Children and Their Siblings.

Autism Spectrum disorders (ASD) are diagnosed more often in males than in females, by a ratio of about 3:1; this is likely to be due to a difference in risk burden between the sexes and/or to "compensatory skills" in females, that may delay the diagnosis of ASD. Identifying specific risk factors for ASD in females may be important in facilitating early diagnosis. We investigated whether HLA- class I: -A, -B, -C and class II -DRB1 alleles, which have been suggested to play a role in the development of ASD, can be considered as sex-related risk/protective markers towards the ASD. We performed HLA allele genotyping in 178 Italian children with ASD, 94 healthy siblings, and their parents. HLA allele distribution was compared between children with ASD, sex-matched healthy siblings, and a cohort of healthy controls (HC) enrolled in the Italian bone marrow donor registry. Allele transmission from parents to children with ASD and their siblings was also assessed. Our findings suggest that HLA-A*02, B*38, and C*12 alleles are more frequently carried by females with ASD compared to both HC and healthy female siblings, indicating these alleles as potential risk factors for ASD in females. Conversely, the HLA-A*03 allele was more commonly transmitted to healthy female siblings, suggesting it might have a protective effect. Additionally, the HLA-B*44 allele was found to be more prevalent in boys with ASD, indicating it is a potential risk factor for male patients. This is the first Italian study of sex-related HLA association with ASD. If confirmed, these results could facilitate early ASD diagnosis in female patients, allowing earlier interventions, which are crucial in the management of neurodevelopmental disorders.

Dose-dependent cranial irradiation associations with brain structures and neuropsychological outcomes in children with posterior fossa brain tumors.

Posterior fossa irradiation with or without whole brain irradiation results in high doses of radiation to the thalamus, hippocampus, and putamen, structures critical to cognitive functioning. As a result, children with brain tumors treated with cranial irradiation (CRT) may experience significant cognitive late effects. We sought to determine the effect of radiation to those structures on neuropsychological outcome. Forty-seven children with a history of posterior fossa tumor (17 treated with surgery; 11 with surgery and chemotherapy; and 19 with surgery, chemotherapy, and CRT) underwent neuroimaging and neuropsychological assessment at a mean of 4.8 years after treatment, along with 17 healthy sibling controls. The putamen, thalamus, and hippocampus were segmented on each participant's magnetic resonance imaging for diffusion indices and volumes, and in the radiation treatment group, radiation dose to each structure was calculated. Performance on visuoconstruction and spatial learning and memory was lower in patient groups than controls. Volume of the thalamus, when controlling for age, was smaller in the patient group treated with CRT than other groups. Higher radiation doses to the putamen correlated with higher fractional anisotropy in that structure. Higher radiation dose to the hippocampus correlated with lower spatial learning, and higher dose to thalami and putamina to lower verbal and nonverbal reasoning. All children with posterior fossa tumors, regardless of treatment modality, had cognitive deficits compared to their sibling controls. Posterior fossa irradiation may affect thalamic volume and aspects of verbal and nonverbal cognitive functioning.

Feasibility and Potential Diagnostic Value of Noncontrast Brain MRI in Nonsedated Children With Sturge-Weber Syndrome and Healthy Siblings.

Postcontrast magnetic resonance imaging (MRI), obtained under anesthesia, is often used to evaluate brain parenchymal and vascular abnormalities in young children, including those with Sturge-Weber syndrome. However, anesthesia and contrast administration may carry risks. We explored the feasibility and potential diagnostic value of a noncontrast, nonsedate MRI acquisition in Sturge-Weber syndrome children and their siblings with a wide range of cognitive and behavioral functioning. Twenty children (10 with Sturge-Weber syndrome and 10 healthy siblings; age: 0.7-13.5 years) underwent nonsedate 3-tesla (T) brain MRI acquisition with noncontrast sequences (including susceptibility-weighted imaging) prospectively along with neuropsychology assessment. All images were evaluated for quality, and MRI abnormalities identified in the Sturge-Weber syndrome group were compared to those identified on previous clinical pre- and postcontrast MRI. Nineteen participants (95%) completed the MRI with good (n = 18) or adequate (n = 1) quality, including all children with Sturge-Weber syndrome and all 5 children ≤5 years of age. The Sturge-Weber syndrome group had lower cognitive functions than the controls, and both groups had several children with behavioral issues, without an apparent effect on the success and quality of the MR images. Susceptibility-weighted imaging detected key venous vascular abnormalities and calcifications and, along with the other noncontrast sequences, provided diagnostic information comparable to previous clinical MRI performed with contrast administration under anesthesia. This study demonstrates the feasibility and the potential diagnostic value of a nonsedate, noncontrast MRI acquisition protocol in young children including those with cognitive impairment and/or behavioral concerns. This approach can facilitate clinical trials in children where safe serial MRI is warranted.

Rheumatoid arthritis patients harbour aberrant enteric bacteriophages with autoimmunity-provoking potential: a paired sibling study

ObjectivesViruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed...

The Nutritional Burden of Cancer: Nutritional Status and Body Composition Differences Between Children with Acute Lymphoblastic Leukemia and their Siblings in Guatemala

During treatment, children with acute lymphoblastic leukemia (ALL) gain fat mass and lose skeletal muscle mass. The great majority live in low- and middle-income countries with few studies of their body composition and none addressing the hypothesis that the disease itself contributes to nutritional morbidity. At diagnosis, children with ALL were compared to their siblings on socioeconomic status (SES). Nutritional status was assessed by mid-upper arm circumference (MUAC)-for-age Z scores and body composition by dual energy x-ray absorptiometry (DXA). Median SES scores for the patients (47.5) and their siblings (47.0) were very similar (P = 0.5). MUAC Z scores for patients aged >5 years were lower than for siblings (P < 0.001). On DXA siblings had a higher mean appendicular lean mass index Z score, a surrogate of skeletal muscle mass, than patients (P = 0.019). A logistic model to estimate the odds ratio (OR) of being severely/moderately under-nourished (classified by MUAC Z score) by SES revealed that, compared with siblings (n = 49), children with ALL (n = 60) had a higher probability of being under-nourished (OR 5.25, 95% CI 1.44–25.95, P = 0.02). The results support the hypothesis that children at diagnosis of ALL in Guatemala are more nutritionally depleted than their apparently healthy siblings.

Novel splicing variant and gonadal mosaicism in DYRK1A gene identified by whole-genome sequencing in multiplex autism spectrum disorder families.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with considerable genetic heterogeneity. The disorder is clinically diagnosed based on DSM-5 criteria, featuring deficits in social communication and interaction, along with restricted and repetitive behaviours. Here, we performed whole-genome sequencing (WGS) on four individuals with ASD from two multiplex families (MPX), where more than one individual is affected, to identify potential single nucleotide variants (SNVs) and structural variants (SVs) in coding and non-coding regions. A rigorous bioinformatics pipeline was employed for variant detection, followed by segregation analysis. Our investigation revealed an unreported splicing variant in the DYRK1A gene (c.-77 + 2T > C; IVS1 + 2T > C; NM_001396.5), in heterozygote form in two affected children in one of the families (family B), which was absent in the healthy parents and siblings. This finding suggests the presence of gonadal mosaicism in one of the parents, representing the first documented instance of such inheritance for a variant in the DYRK1A gene associated with ASD. Furthermore, we identified a 50bp deletion in intron 9 of the DLG2 gene in two affected patients from the same family, confirmed by PCR and Sanger sequencing. In Family A, we identified potential candidate variants associated with ASD shared by the two patients. These findings enhance our understanding of the genetic landscape of ASD, particularly in MPX families, and highlight the utility of WGS in uncovering novel genetic contributions to neurodevelopmental disorders.

Exploring health-related quality of life, exercise and alcohol use in adolescents with sickle cell disease and healthy siblings

Objective This study explored the health-related quality of life (HRQL) and health behaviours of adolescents with sickle cell disease (SCD) and healthy siblings, drawing on Gap theory which suggests HRQL is the discrepancy between current and ideal selves. Design Twenty-three adolescents with SCD and 21 healthy siblings aged 13 to 17 years participated in eight focus groups. Results Thematic analysis identified three themes: learning to accept SCD, coping with SCD and influences on health behaviours. Adolescents appear to have normalised and adapted to SCD. Adolescents with SCD have learnt effective coping strategies, such as moderating engagement in exercise. Unlike heathy siblings, they were not encouraged to exercise by parents but were content with their level of participation. Both groups were influenced to exercise by role models or wanting to socialise, and influenced to drink alcohol by peers, but there was limited understanding of the potential negative impacts of alcohol on SCD. Conclusion There does not appear to be a discrepancy between adolescents’ current and ideal selves, providing optimism about their HRQL. Further consideration of engaging in healthy behaviours is needed, but it is important to strike a balance so that modifications to lifestyle do not impair HRQL.

Investigation of Siblings of Patients Diagnosed with Substance-Induced Psychotic Disorder in terms of Cognitive Functions and Clinical High-Risk State for Psychosis

Objective: This study aimed to investigate the influence of familial predisposition on substance-induced psychosis among healthy siblings of patients diagnosed with substance-induced psychotic disorder, who themselves lack any family history of psychotic disorders. Additionally, the study aimed to explore clinical high-risk states for psychosis, schizotypal features, and neurocognitive functions in comparison to a healthy control group. Method: The study compared healthy siblings of 41 patients diagnosed with substance-induced psychotic disorder with 41 healthy volunteers without a family history of psychotic disorders, matching age, gender, and education. Sociodemographic and clinical characteristics of participants were obtained using data collection forms. The Comprehensive Assessment of At-Risk Mental States (CAARMS) and the Structured Interview for Schizotypy-Revised Form (SIS-R) scales were utilized to assess clinical high risk for psychosis. Neurocognitive functions were evaluated with digit span test (DST), trail making test part A-B (TMT), verbal fluency test (VFT), and Stroop test (ST). Results: Analysis using the CAARMS scale revealed that 39% of siblings and 7.3% of the control group were at clinically high risk for psychosis, indicating a significant difference in rates of psychotic vulnerability. Comparison between siblings and the control group showed significant differences in mean SIS-R subscale scores, including social behavior, hypersensitivity, referential thinking, suspiciousness, illusions, and overall oddness, as well as in mean neurocognitive function scores, including errors in TMT-A, TMT-B, and VFT out-of-category errors, with siblings exhibiting poorer performance. Conclusion: Our study suggests that healthy siblings of patients with substance-induced psychosis exhibit more schizotypal features and have a higher risk of developing psychosis compared to healthy controls. Additionally, siblings demonstrate greater impairment in attention, response inhibition, and executive functions compared to healthy controls, indicating the potential role of genetic predisposition in the development of substance-induced psychotic disorder.

Comparison of the Quality of Life of Mentally and Physically Disabled Children and Their Healthy Siblings

Comparison of the Quality of Life of Mentally and Physically Disabled Children and Their Healthy Siblings

Comparison of Serum Neurofilament Light Chain and Tau Protein Levels in Cases with Autism Spectrum Disorder and Their Healthy Siblings and Healthy Controls.

: There is a growing interest among clinicians and researchers in identifying potential biomarkers associated with autism. Neurofilament light chain (NfL) and Tau protein, which are proteins associated with neurodegeneration and neuroaxonal degeneration, are particularly promising potential biomarker candidates in this field. : In this study, we compared serum NfL (sNfL) and serum Tau (sTau) levels in Autism spectrum disorder (ASD) patients, their healthy siblings (HS), and healthy controls (HC), aimed to investigate their relationship with ASD severity. Our study included 43 ASD-diagnosed participants, 43 HS participants and 42 HC participants. Clinical characteristics of the participants were assesed by Kiddie Schedule for Affective Disorders and Schizophrenia, Childhood Autism Rating Scale, Aberrant Behavior Checklist, and Strengths and Difficulties Questionnaire. Serum samples were subjected to analysis via enzyme-linked immunosorbent assay to quantitatively measure the levels of NfL and Tau protein. : sNfL levels in the ASD group were significantly higher than both of the control groups. Regarding sTau levels, no significant difference was found between study and control groups. In addition, NfL and Tau levels were not significantly correlated with ASD symptom severity. : Our findings may indicate that the sNfl levels associated with neuroaxonal damage may constitue a potential clinical biomarker rather than being an endophenotype phenomena.

Monocytes in type 1 diabetes families exhibit high cytolytic activity and subset abundances that correlate with clinical progression.

Monocytes are immune regulators implicated in the pathogenesis of type 1 diabetes (T1D), an autoimmune disease that targets insulin-producing pancreatic β cells. We determined that monocytes of recent onset (RO) T1D patients and their healthy siblings express proinflammatory/cytolytic transcriptomes and hypersecrete cytokines in response to lipopolysaccharide exposure compared to unrelated healthy controls (uHCs). Flow cytometry measured elevated circulating abundances of intermediate monocytes and >2-fold more CD14+CD16+HLADR+KLRD1+PRF1+ NK-like monocytes among patients with ROT1D compared to uHC. The intermediate to nonclassical monocyte ratio among ROT1D patients correlated with the decline in functional β cell mass during the first 24 months after onset. Among sibling nonprogressors, temporal decreases were measured in the intermediate to nonclassical monocyte ratio and NK-like monocyte abundances; these changes coincided with increases in activated regulatory T cells. In contrast, these monocyte populations exhibited stability among T1D progressors. This study associates heightened monocyte proinflammatory/cytolytic activity with T1D susceptibility and progression and offers insight to the age-dependent decline in T1D susceptibility.

Gut Microbiota in Autism Spectrum Disorder: A Systematic Review

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with stereotyped behavior and deficits in communication and social interaction. There is increasing evidence of the implication of gut microbiota in ASD. We conducted a systematic review to summarize previously published data to compare the profile of gut microbiota between autistic and neurotypical subjects. The outcomes of interventions such as prebiotics, probiotics, and microbiota transplantation therapy to overcome the symptomatology of ASD were also discussed. The current review allows us to associate gut microbiota dysbiosis and ASD. To date, there is still little consensus on which bacterial species are consistently altered in individuals with autism. Further studies are required to obtain stronger evidence of the relationship between gut microbiota and the severity of ASD conjointly with the effectiveness of dietary/probiotic interventions in reducing autistic behaviors compared to their healthy siblings.

The role of bipolar disorder and family wealth in choosing creative occupations

Research in psychology and medicine has linked mental health disorders, and particularly bipolar disorder (BD), to employment in creative professions. Little is known, however, about the mechanisms for this link, which could be due to biology (primarily through a person’s genes) or environmental (through socioeconomic status). Using administrative data on mental health diagnoses and occupations for the population of Denmark, we find that people with BD are more likely to be musicians than the population, but less likely to hold other creative jobs. Yet, we also show that healthy siblings of people with BD are significantly more likely to work in creative professions. Notably, people from wealthy families are consistently more likely to work in creative professions, and access to family wealth amplifies the likelihood that siblings of people with BD pursue creative occupations. Nevertheless, family wealth explains only a small share of the correlation between BD and creative employment.

Elevated Cathepsin S Serum Levels in New-Onset Type 1 Diabetes and Autoantibody-Positive Siblings.

Accumulating data suggest a role for the lysosomal protease cathepsin S (CTSS) in type 1 diabetes. Circulating CTSS is increased in type 1 diabetes; however, whether CTSS has protective or deleterious effects is unclear. The study's objectives were to examine the biomarker potential of CTSS in new-onset type 1 diabetes, and to investigate the expression and secretion of CTSS in human islets and β cells. The CTSS level was analyzed in serum from children with new-onset type 1 diabetes and autoantibody-positive and -negative siblings by ELISA. The expression and secretion of CTSS were evaluated in isolated human islets and EndoC-βH5 cells by real-time qPCR, immunoblotting, and ELISA. The CTSS serum level was elevated in children with new-onset type 1 diabetes and positively associated with autoantibody status in healthy siblings. Human islets and EndoC-βH5 cells demonstrated induction and secretion of CTSS after exposure to pro-inflammatory cytokines, a model system of islet inflammation. Analysis of publicly available single-cell RNA sequencing data on human islets showed that elevated CTSS expression was exclusive for the β cells in donors with type 1 diabetes as compared to non-diabetic donors. These findings suggest a potential of CTSS as a diagnostic biomarker in type 1 diabetes.

N-glycosylation of immunoglobulin A in children and adults with type 1 diabetes mellitus

AimsTo identify N-glycan structures on immunoglobulin A related to type 1 diabetes mellitus among children at the disease onset and adults with type 1 diabetes mellitus. MethodsHuman polyclonal IgA N-glycans were profiled using hydrophilic interaction ultra performance liquid chromatography in two cohorts. The first cohort consisted of 62 children at the onset of type 1 diabetes mellitus and 86 of their healthy siblings. The second cohort contained 84 adults with the disease and 84 controls. Associations between N-glycans and type 1 diabetes mellitus were tested using linear mixed model for the paediatric cohort, or general linear model for the adult cohort. False discovery rate was controlled by Benjamini-Hochberg method modified by Li and Ji. ResultsIn children, an increase in a single oligomannose N-glycan was associated with type 1 diabetes mellitus (B = 0.529, p = 0.0067). N-glycome of the adults displayed increased branching (B = 0.466, p = 0.0052), trigalactosylation (B = 0.466, p = 0.0052), trisialylation (B = 0.629, p < 0.001), and mannosylation (B = 0.604, p < 0.001). The strongest association with the disease was a decrease in immunoglobulin A core fucosylation (B = −0.900, p < 0.001). ConclusionsChanges in immunoglobulin N-glycosylation patterns in type 1 diabetes point to disruptions in immunoglobulin A catabolism and dysregulated inflammatory capabilities of the antibody, potentially impacting immune responses and inflammation.