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Journal of Affective Disorders Jun 2024Carbonyl stress, a metabolic state characterized by elevated production of reactive carbonyl compounds (RCCs), is closely related to oxidative stress and has been...
BACKGROUND
Carbonyl stress, a metabolic state characterized by elevated production of reactive carbonyl compounds (RCCs), is closely related to oxidative stress and has been implicated in various diseases. This study aims to investigate carbonyl stress parameters in drug-free bipolar disorder (BD) patients compared to healthy controls, explore their relationship with clinical features, and assess the effect of treatment on these parameters.
METHODS
Patients with a primary diagnosis of a manic episode of BD and healthy controls were recruited. Exclusion criteria included intellectual disability, presence of neurological diseases, chronic medical conditions such as diabetes mellitus and metabolic syndrome, and clinical signs of inflammation. Levels of serum carbonyl stress parameters were determined using high-performance liquid chromatography.
RESULTS
Levels of glyoxal (GO) and methylglyoxal (MGO) did not differ between pre- and post-treatment patients, but malondialdehyde (MDA) levels decreased significantly post-treatment. Pre-treatment MGO and MDA levels were higher in patients compared to controls, and these differences persisted post-treatment. After adjusting for BMI and waist circumference, only MDA levels remained significantly higher in patients compared to controls.
LIMITATIONS
The study's limitations include the exclusion of female patients, which precluded any assessment of potential gender differences, and the lack of analysis of the effect of specific mood stabilizers or antipsychotic drugs.
CONCLUSIONS
This study is the first to focus on carbonyl stress markers in BD, specifically GO, MGO, and MDA. MDA levels remained significantly higher in patients, suggesting a potential role in BD pathophysiology. MGO levels were influenced by metabolic parameters, indicating a potential link to neurotoxicity in BD. Further research with larger cohorts is needed to better understand the role of RCCs in BD and their potential as therapeutic targets.
PubMed: 38944288
DOI: 10.1016/j.jad.2024.06.112 -
Epilepsia Jun 2024This study was undertaken to analyze whether the rate of breakthrough seizures in patients taking antiseizure medication (ASM) who have been seizure-free for at least...
OBJECTIVE
This study was undertaken to analyze whether the rate of breakthrough seizures in patients taking antiseizure medication (ASM) who have been seizure-free for at least 12 months varies among different types and etiologies of epilepsy. Given the relative ease of achieving seizure freedom with ASM in patients with post-ischemic stroke epilepsy, we hypothesized that this etiology is associated with a reduced risk of breakthrough seizures.
METHODS
We defined a breakthrough seizure as an unprovoked seizure occurring while the patient was taking ASM after a period of at least 12 months without seizures. Data were analyzed retrospectively from a tertiary epilepsy outpatient clinic. Patients were eligible for inclusion if they either had a breakthrough seizure at any time or a seizure-free interval of at least 2 years. Our primary endpoint was rate of breakthrough seizures. We conducted univariable and multivariable analyses to identify variables associated with breakthrough seizures.
RESULTS
Of 521 patients (53% females, median age = 49 years) included, 29% had a breakthrough seizure, which occurred after a median seizure-free interval of 34 months (quartiles = 22, 62). When controlling for clinically relevant covariates, breakthrough seizures were associated with post-ischemic stroke epilepsy (odds ratio [OR] = .267, 95% confidence interval [CI] = .075-.946), genetic generalized epilepsy (OR = .559; 95% CI = .319-.978), intellectual disability (OR = 2.768, 95% CI = 1.271-6.031), and the number of ASMs previously and currently tried (OR = 1.203, 95% CI = 1.056-1.371). Of the 151 patients with breakthrough seizures, 34.3% did not reachieve terminal 12-month seizure freedom at the last visit.
SIGNIFICANCE
This is the first study to show an association between type and etiology of epilepsy and risk of breakthrough seizures. Our data suggest that epilepsies in which seizure freedom can be obtained more easily also exhibit a lower risk of breakthrough seizures. These findings may help to better counsel seizure-free patients on their further seizure prognosis.
PubMed: 38943516
DOI: 10.1111/epi.18048 -
Nature Communications Jun 2024Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and...
Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome.
Topics: Down Syndrome; Humans; Chromosomes, Human, Pair 21; Female; Transcriptome; Male; Child; Child, Preschool; Adult; Gene Expression Profiling; Proteome; Adolescent
PubMed: 38942750
DOI: 10.1038/s41467-024-49781-1 -
ENeuro Jun 2024Acetylcholine (ACh) neurons in the central nervous system are required for the coordination of neural network activity during higher brain functions, such as attention,...
Acetylcholine (ACh) neurons in the central nervous system are required for the coordination of neural network activity during higher brain functions, such as attention, learning, and memory, as well as locomotion. Disturbed cholinergic signaling has been described in many neurodevelopmental and neurodegenerative disorders. Furthermore, co-transmission of other signaling molecules, such as glutamate and GABA, with ACh has been associated with essential roles in brain function or disease. However, it is unknown when ACh neurons become cholinergic during development. Thus, understanding the timeline of how the cholinergic system develops and becomes active in the healthy brain is a crucial part of understanding brain development. To study this, we used transgenic mice to selectively label ACh neurons with tdTomato. We imaged serial sectioned brains and generated whole-brain reconstructions at different time points during pre- and postnatal development. We found three crucial time windows - two in the prenatal and one in the postnatal brain - during which most ACh neuron populations become cholinergic in the brain. We also found that cholinergic gene expression is initiated in cortical ACh interneurons, while the cerebral cortex is innervated by cholinergic projection neurons from the basal forebrain. Taken together, we show that ACh neuron populations are present and become cholinergic before postnatal day 12, which is the onset of major sensory processes, such as hearing and vision. We conclude that birth of ACh neurons and initiation of cholinergic gene expression are temporally separated during development but highly coordinated by brain anatomical structure. Acetylcholine (ACh) neurons are required for higher brain functions and locomotion. Disturbed cholinergic signaling was observed in neurodevelopmental disorders and intellectual disability. While the role of ACh release in neural circuit function is well understood, it is unknown when ACh neurons become cholinergic. We labelled ACh neurons to investigate when ACh neurons become cholinergic in the developing brain and performed reconstructions of serial sectioned brains. Here, we show that ACh neuron populations become cholinergic during three time windows pre- and postnatally. ACh neurons become cholinergic following the caudorostral direction of brain formation. In cortex and hippocampus, activation of cholinergic gene expression in ACh interneurons coincides with cholinergic innervation from the basal forebrain. We highlight that brain ACh neurons are cholinergic before P12, the onset of major sensory functions, such as hearing and vision.
PubMed: 38942474
DOI: 10.1523/ENEURO.0542-23.2024 -
Journal of AAPOS : the Official... Jun 2024Terminal deletions of chromosome 3q are associated with a heterogenous clinical phenotype, which includes growth restriction, developmental delay, and intellectual...
Terminal deletions of chromosome 3q are associated with a heterogenous clinical phenotype, which includes growth restriction, developmental delay, and intellectual disability. However, little has been published on the ophthalmic impacts of chromosome 3q deletions. We report a 9-year-old boy with a 1.4 megabase deletion of 3q27.1q27.2 whose ocular morbidities included retinal detachment in one eye, vitreous hemorrhage in the other eye, and foveal hypoplasia in both eyes that required acute care and continuous ophthalmologic follow-up.
PubMed: 38942230
DOI: 10.1016/j.jaapos.2024.103960 -
Seizure Jun 2024The purpose of this study was to describe intellectual disability and its association with epilepsy and brain imaging, in a population-based group of children with...
PURPOSE
The purpose of this study was to describe intellectual disability and its association with epilepsy and brain imaging, in a population-based group of children with hemiplegic (unilateral) cerebral palsy, previously investigated and published in 2020.
MATERIALS AND METHODS
Forty-seven children of school age in northern Stockholm, fulfilling the Surveillance of Cerebral Palsy in Europe-criteria of hemiplegic (unilateral spastic) cerebral palsy, were invited to participate in the study. Twenty-one children consented to participate. A WISC (Wechsler Intelligence Scale for Children)-test was performed by an experienced psychologist.
RESULTS
In the study population of twenty-one children, 57 % (n 12) displayed uneven cognitive profiles, 38 % (n 8) intellectual disability and 62 % (n 13) had a normal IQ. 43 % (n 9) developed epilepsy. Children with extensive brain lesions had more severe intellectual disability.
CONCLUSIONS
In this study intellectual disability and/or epilepsy were associated with the type and extent of the underlying brain lesion. Intellectual disability and uneven cognitive profiles were common. We therefore recommend individual cognitive assessment to ensure an optimal school start.
PubMed: 38941801
DOI: 10.1016/j.seizure.2024.06.012 -
Research in Developmental Disabilities Jun 2024In Saudi Arabia, students with intellectual disabilities (ID) receive some of their education through textbooks. However, using textbooks with students with ID...
BACKGROUND/AIMS
In Saudi Arabia, students with intellectual disabilities (ID) receive some of their education through textbooks. However, using textbooks with students with ID contradicts the principles of providing services based on individuals with ID needs personalized plans to develop their individual abilities. This study aimed to investigate family and teacher perceptions of middle and high school curricula for students with ID in Saudi Arabia. This study focused specifically on the extent to which these curricula contribute to the development of academic and life skills among these students.
METHOD AND PROCEDURE
A 21-item scale was used to measure the perceptions of family members and teachers of individuals with intellectual disability. The scale validity and reliability were examined and supported. The sample comprised of 113 family members and 111 teachers of students with ID.
OUTCOMES AND RESULTS
Family members and teachers both expressed low satisfaction regarding the improvement in academic and life skills of students as a result of the current curricular in the surveyed programs. Additionally, they conveyed dissatisfaction with the overall outcomes of services provided for individuals with intellectual disabilities.
CONCLUSIONS AND IMPLICATIONS
This study highlights the inadequacies of a one-size-fits-all approach to designing curricula for students with ID. There is a need to improve and enhance curriculum content to meet the diverse learning needs of these individuals.
PubMed: 38941691
DOI: 10.1016/j.ridd.2024.104785 -
Health and Social Care Delivery Research Jun 2024People with learning disabilities are living longer. Despite government policy to encourage people to lead supported lives in their community, family carers often...
BACKGROUND
People with learning disabilities are living longer. Despite government policy to encourage people to lead supported lives in their community, family carers often maintain support due to dissatisfaction with services. This can lead to people moving from the family home in a crisis.
OBJECTIVES
(1) Find out what is known about health needs and resources for older people with learning disabilities (aged ≥ 40 years); (2) identify exemplars of good services for older people with learning disabilities; (3) explore service exemplars through ethnographic case studies; (4) evaluate support for older people with learning disabilities and their families through co-producing and testing future planning tools and (5) co-produce recommendations and resources.
DESIGN AND METHODS
Work package 1 rapid scoping reviews - three reviews focused on the health and social care needs of older people with learning disabilities and 'behaviours that challenge others', and family carers, and the co-ordination of support for this group. Work package 2 scoping and mapping exemplars of good practice - analysis of published service standards to assess excellence criteria, by mapping services, interviews ( = 30), survey ( = 9) and informal discussion with commissioners. Work package 3 ethnography of case studies of exemplar provision; independent supported living ( = 4); residential/nursing home ( = 2); day activities ( = 1), Shared Lives ( = 2). Fieldwork (20 days per model), interviews ( = 77) with older people with learning disabilities, family carers, support staff and commissioners. Work package 4 - co-producing and testing resources for older people with learning disabilities and their families involved interviews and focus groups with 36 people with learning disabilities, parents, and siblings, and experience-based co-design with 11 participants. Eight families evaluated the resources. Work package 5 - three stakeholder workshops co-produced service recommendations.
FINDINGS
The reviews confirmed an inadequate evidence base concerning the experiences and support of family carers and older people with learning disabilities and 'behaviours that challenge others'. Criteria of excellence were produced, and a shortlist of 15 services was identified for consideration in work package 3. The ethnographic work found that environmental, organisational and social factors were important, including supporting independence and choice about who people live with, matching staff to people, consistent relationships and adapting to ageing. Practices of institutionalisation were observed. In work package 4, we found that families were worried about the future and unsupported to explore options. 'Planning Ahead' cards and a booklet to record discussions were produced, and the evaluation was positively rated. Finally, formative discussion informed recommendations. Outputs include training packages, a carers' forum, a film, a podcast and academic papers.
CONCLUSIONS
There is little focus on older people with learning disabilities and family carers. Services vary in their approach to planning for older-age support. Families are unsupported to plan, leaving people without choice. 'Behaviours that challenge others' was found to be unhelpful terminology. Recommendations: A new strategy is recommended for older people with learning disabilities and family carers that encompasses commissioning practices, professional input and peer learning, proactive support in ageing well and excellent service design.
LIMITATIONS
The COVID-19 pandemic created recruitment challenges. Reliance on providers for recruitment resulted in a lack of diversity in work package 3. Families' plans, and therefore change, may be frustrated by insufficient service resources.
FUTURE WORK
Given the lack of focus in this area, there is a range of future work to consider: experiences of older people with learning disabilities from diverse ethnic backgrounds; supporting people to age and die 'in place'; best practice regarding designing/commissioning services, including housing; the role of social workers; access to nature; accessing mainstream support; and evaluation of the 'Planning Ahead' cards.
TRIAL REGISTRATION
This trial is registered as ISRCTN74264887.
FUNDING
This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR129491) and is published in full in ; Vol. 12, No. 16. See the NIHR Funding and Awards website for further award information.
Topics: Humans; Caregivers; Aged; Learning Disabilities; Female; Male; Middle Aged; Adult; Social Support; Qualitative Research; Aged, 80 and over; Anthropology, Cultural; Health Services Needs and Demand
PubMed: 38940476
DOI: 10.3310/MTHW2644 -
Bioinformatics (Oxford, England) Jun 2024Artificial intelligence (AI) is increasingly used in genomics research and practice, and generative AI has garnered significant recent attention. In clinical...
Artificial intelligence (AI) is increasingly used in genomics research and practice, and generative AI has garnered significant recent attention. In clinical applications of generative AI, aspects of the underlying datasets can impact results, and confounders should be studied and mitigated. One example involves the facial expressions of people with genetic conditions. Stereotypically, Williams (WS) and Angelman (AS) syndromes are associated with a "happy" demeanor, including a smiling expression. Clinical geneticists may be more likely to identify these conditions in images of smiling individuals. To study the impact of facial expression, we analyzed publicly available facial images of approximately 3500 individuals with genetic conditions. Using a deep learning (DL) image classifier, we found that WS and AS images with non-smiling expressions had significantly lower prediction probabilities for the correct syndrome labels than those with smiling expressions. This was not seen for 22q11.2 deletion and Noonan syndromes, which are not associated with a smiling expression. To further explore the effect of facial expressions, we computationally altered the facial expressions for these images. We trained HyperStyle, a GAN-inversion technique compatible with StyleGAN2, to determine the vector representations of our images. Then, following the concept of InterfaceGAN, we edited these vectors to recreate the original images in a phenotypically accurate way but with a different facial expression. Through online surveys and an eye-tracking experiment, we examined how altered facial expressions affect the performance of human experts. We overall found that facial expression is associated with diagnostic accuracy variably in different genetic conditions.
Topics: Humans; Facial Expression; Deep Learning; Artificial Intelligence; Genetics, Medical; Williams Syndrome
PubMed: 38940144
DOI: 10.1093/bioinformatics/btae239 -
Biochemistry Research International 2024Eg5 is a protein encoded by KIF11 gene and is primarily involved in correct mitotic cell division. It is also involved in nonmitotic processes such as polypeptide... (Review)
Review
Eg5 is a protein encoded by KIF11 gene and is primarily involved in correct mitotic cell division. It is also involved in nonmitotic processes such as polypeptide synthesis, protein transport, and angiogenesis. The scientific literature sheds light on the ubiquitous functions of KIF11 and its involvement in the onset and progression of different pathologies. This review focuses attention on two main points: (1) the correlation between Eg5 and cancer and (2) the involvement of Eg5 in noncancerous conditions. Regarding the first point, several tumors revealed an overexpression of this kinesin, thus pushing to look for new Eg5 inhibitors for clinical practice. In addition, the evaluation of Eg5 expression represents a crucial step, as its overexpression could predict a poor prognosis for cancer patients. Referring to the second point, in specific pathological conditions, the reduced activity of Eg5 can be one of the causes of pathological onset. This is the case of Alzheimer's disease (AD), in which A and Tau work as Eg5 inhibitors, or in acquired immune deficiency syndrome (AIDS), in which Tat-mediated Eg5 determines the loss of CD T-lymphocytes. Reduced Eg5 activity, due to mutations of KIF11 gene, is also responsible for pathological conditions such as microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability (MCLRI) and familial exudative vitreous retinopathy (FEVR). In conclusion, this review highlights the double impact that overexpression or loss of function of Eg5 could have in the onset and progression of different pathological situations. This emphasizes, on one hand, a possible role of Eg5 as a potential biomarker and new target in cancer and, on the other hand, the promotion of Eg5 expression/activity as a new therapeutic strategy in different noncancerous diseases.
PubMed: 38939361
DOI: 10.1155/2024/3649912