Fragile X cortex is characterized by decreased parvalbumin-expressing interneurons.

Fragile X syndrome is a genetic neurodevelopmental disorder caused by a mutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene in the X chromosome. Many fragile X syndrome cases present with autism spectrum disorder and fragile X syndrome cases account for up to 5% of all autism spectrum disorder cases. The cellular composition of the fragile X syndrome cortex is not well known. We evaluated alterations in the number of Calbindin, Calretinin, and Parvalbumin expressing interneurons across 5 different cortical areas, medial prefrontal cortex (BA46), primary somatosensory cortex (BA3), primary motor cortex (BA4), superior temporal cortex (BA22), and anterior cingulate cortex (BA24) of fragile X syndrome and neurotypical brains. Compared with neurotypical cases, fragile X syndrome brains displayed a significant reduction in the number of PV+ interneurons in all areas and of CR+ interneurons in BA22 and BA3. The number of CB+ interneurons did not differ. These findings are the first to demonstrate that fragile X syndrome brains are characterized by cortical wide PV+ interneuron deficits across multiple cortical areas. These add to the idea that deficits in PV+ interneurons could disrupt the cortical balance and promote clinical deficits in fragile X syndrome patients and help to develop novel therapies for neurodevelopmental disorders like fragile X syndrome and autism spectrum disorder.

Triple enzymatic immunochemistry for interneuron populations in postmortem human cerebral cortex.

Immunostaining is an antibody-based tool used to visualize proteins in tissue. Enzymes or fluorochromes conjugated to antibodies are used to detect proteins of interests. Fluorescent immunostaining can be used in human tissue, however due to the high autofluorescence of non-perfused human tissue, enzymatic immunostaining is better suited. Enzymes produce a colored product that is detectable by light microscopes. Here we describe a successful triple immunochemistry protocol to enzymatically label three distinct populations of interneurons (Parvalbumin+, Calbindin+, and Calretinin + interneurons) in non-perfused formalin fixed human brain cerebral cortex. Signal was achieved using a combination of horseradish peroxidase (HRP) and Alkaline Phosphatase (AP) enzymes and color was generated using the insoluble chromogens: 3,3'- Diaminobenzidine (DAB, Brown), Vector Blue (Blue), and Vector VIP (Pink). There were no noticeable background and minimal signal overlap between the different colors. We were able to successfully stain human cortical tissue and distinguish morphological properties of the three interneuron (IN) populations.

Brain Metabolomics in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).

The course of pathophysiological mechanisms involved in fragile X-associated tremor/ataxia syndrome (FXTAS) remains largely unknown. Previous proteomics and metabolomics studies conducted in blood samples collected from FMR1 premutation carriers with FXTAS reported abnormalities in energy metabolism, and precursors of gluconeogenesis showed significant changes in plasma expression levels in FMR1 premutation carriers who developed FXTAS. We conducted an analysis of postmortem human brain tissues from 44 donors, 25 brains with FXTAS, and 19 matched controls. We quantified the metabolite relative abundance in the inferior temporal gyrus and the cerebellum using untargeted mass spectrometry (MS)-based metabolomics. We investigated how the metabolite type and abundance relate to the number of cytosine-guanine-guanine (CGG) repeats, to markers of neurodegeneration, and to the symptoms of FXTAS. A metabolomic analysis identified 191 primary metabolites, the data were log-transformed and normalized prior to the analysis, and the relative abundance was compared between the groups. The changes in the relative abundance of a set of metabolites were region-specific with some overlapping results; 22 metabolites showed alterations in the inferior temporal gyrus, while 21 showed differences in the cerebellum. The relative abundance of cytidine was decreased in the inferior temporal gyrus, and a lower abundance was found in the cases with larger CGG expansions; oleamide was significantly decreased in the cerebellum. The abundance of 11 metabolites was influenced by changes in the CGG repeat number. A histological evaluation found an association between the presence of microhemorrhages in the inferior temporal gyrus and a lower abundance of 2,5-dihydroxypyrazine. Our study identified alterations in the metabolites involved in the oxidative-stress response and bioenergetics in the brains of individuals with FXTAS. Significant changes in the abundance of cytidine and oleamide suggest their potential as biomarkers and therapeutic targets for FXTAS.

Improvement of sensory deficits in fragile X mice by increasing cortical interneuron activity after the critical period.

Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to the pathophysiology of neurodevelopmental disorders. Using all-optical in vivo approaches, we find that parvalbumin (PV) INs and their immature precursors are hypoactive and transiently decoupled from excitatory neurons in postnatal mouse somatosensory cortex (S1) of Fmr1 KO mice, a model of fragile X syndrome (FXS). This leads to a loss of parvalbumin INs (PV-INs) in both mice and humans with FXS. Increasing the activity of future PV-INs in neonatal Fmr1 KO mice restores PV-IN density and ameliorates transcriptional dysregulation in S1, but not circuit dysfunction. Critically, administering an allosteric modulator of Kv3.1 channels after the S1 critical period does rescue circuit dynamics and tactile defensiveness. Symptoms in FXS and related disorders could be mitigated by targeting PV-INs.

Distinct patterns of GABAergic interneuron pathology in autism are associated with intellectual impairment and stereotypic behaviors.

LAY ABSTRACT: Autism spectrum disorder is a neurodevelopmental condition characterized by deficits in sociability and communication and the presence of repetitive behaviors. How specific pathological alterations of the brain contribute to the clinical profile of autism spectrum disorder remains unknown. We previously found that a specific type of inhibitory interneuron is reduced in number in the autism spectrum disorder prefrontal cortex. Here, we assessed the relationship between interneuron reduction and autism spectrum disorder symptom severity. We collected clinical records from autism spectrum disorder (n = 20) and assessed the relationship between the severity of symptoms and interneuron number. We found that the reduced number of inhibitory interneurons that we previously reported is linked to specific symptoms of autism spectrum disorder, particularly stereotypic movements and intellectual impairments.

Health and wellbeing implications of adaptation to flood risk.

Adaptation strategies to ameliorate the impacts of climate change are increasing in scale and scope around the world, with interventions becoming a part of daily life for many people. Though the implications of climate impacts for health and wellbeing are well documented, to date, adaptations are largely evaluated by financial cost and their effectiveness in reducing risk. Looking across different forms of adaptation to floods, we use existing literature to develop a typology of key domains of impact arising from interventions that are likely to shape health and wellbeing. We suggest that this typology can be used to assess the health consequences of adaptation interventions more generally and argue that such forms of evaluation will better support the development of sustainable adaptation planning.

Parvalbumin and parvalbumin chandelier interneurons in autism and other psychiatric disorders.

Parvalbumin (PV) is a calcium binding protein expressed by inhibitory fast-spiking interneurons in the cerebral cortex. By generating a fast stream of action potentials, PV+ interneurons provide a quick and stable inhibitory input to pyramidal neurons and contribute to the generation of gamma oscillations in the cortex. Their fast-firing rates, while advantageous for regulating cortical signaling, also leave them vulnerable to metabolic stress. Chandelier (Ch) cells are a type of PV+ interneuron that modulate the output of pyramidal neurons and synchronize spikes within neuron populations by directly innervating the pyramidal axon initial segment. Changes in the morphology and/or function of PV+ interneurons, mostly of Ch cells, are linked to neurological disorders. In ASD, the number of PV+ Ch cells is decreased across several cortical areas. Changes in the morphology and/or function of PV+ interneurons have also been linked to schizophrenia, epilepsy, and bipolar disorder. Herein, we review the role of PV and PV+ Ch cell alterations in ASD and other psychiatric disorders.

Opportunities and Challenges in Developing Technology-Based Social Skills Interventions for Adolescents with Autism Spectrum Disorder: A Qualitative Analysis of Parent Perspectives.

Interest continues to be high in technology-based interventions for individuals with autism spectrum disorder (ASD). Understanding the preferences and challenges of technology use among individuals with ASD can inform the design of such interventions. Through 18 interviews with parents, we used an iterative inductive-deductive approach to qualitative analysis and explored uses of technology for social skills development among adolescents with ASD. Our findings include parents' observations about their adolescent's preferences in types of technology devices and digital content, as well as both positive and negative effects of technology use on mood and behavior. Parents highlighted several avenues of technological preferences and risks that may inform intervention design, enhance user engagement, and capitalize on users' strengths while buttressing areas for growth.

Case Report: Coexistence of Alzheimer-Type Neuropathology in Fragile X-Associated Tremor Ataxia Syndrome.

This case documents the co-occurrence of the fragile X-associated tremor ataxia syndrome (FXTAS) and Alzheimer-type neuropathology in a 71-year-old premutation carrier with 85 CGG repeats in the fragile X mental retardation 1 (FMR1) gene, in addition to an apolipoprotein E (APOE) ε4 allele. FXTAS and Alzheimer's Disease (AD) are late-onset neurodegenerative diseases that share overlapping cognitive deficits including processing speed, working memory and executive function. The prevalence of coexistent FXTAS-AD pathology remains unknown. The clinical picture in this case was marked with rapid cognitive decline between age 67 and 71 years in addition to remarkable MRI changes. Over the 16 months between the two clinical evaluations, the brain atrophied 4.12% while the lateral ventricles increased 26.4% and white matter hyperintensities (WMH) volume increased 15.6%. Other regions atrophied substantially faster than the whole brain included the thalamus (-6.28%), globus pallidus (-10.95%), hippocampus (-6.95%), and amygdala (-7.58%). A detailed postmortem assessment included an MRI with confluent WMH and evidence of cerebral microbleeds (CMB). The histopathological study demonstrated FXTAS inclusions in neurons and astrocytes, a widespread presence of phosphorylated tau protein and, amyloid ß plaques in cortical areas and the hippocampus. CMBs were noticed in the precentral gyrus, middle temporal gyrus, visual cortex, and brainstem. There were high amounts of iron deposits in the globus pallidus and the putamen consistent with MRI findings. We hypothesize that coexistent FXTAS-AD neuropathology contributed to the steep decline in cognitive abilities.

Explaining inequalities in fruit and vegetable intake in Europe: The role of capabilities, opportunities and motivations.

People who do not eat enough fruit and vegetables (F&V) have incremental health risks. Most Europeans do not comply with health recommendations relating to F&V consumption and this is especially true for those with lower-level education, which reinforces structural inequalities in health and wellbeing among Europeans. This study investigated the role of key behavioural triggers - capabilities, opportunities and motivation (in the COM-B model) - as pathways for educational differentials in F&V intake in Europe. A cross-sectional survey-based study was conducted in five European countries differing widely in their consumption habits, wealth, and climatic conditions. A structural equation model was designed to study how capabilities (diet perceived knowledge, health purchase criteria), opportunities (financial availability, social norms), and motivations (health value, habits strength) affect educational inequalities in the intake of F&V (5 portions a day) as mediators. Multi-group comparisons assessed country differences. People with higher levels of education were more likely to eat the recommended diet, i.e., at least 5 portions of F&V a day. Countries in the sample vary significantly in the percentage of people complying with the recommendation, but not significantly in terms of relative education differentials. The educational gap in the intake of F&V is mainly explained by education differentials in financial availability, diet knowledge, and habits in inserting F&V in main meals. Policies targeting dietary inequalities should address behavioural triggers affecting dietary intake, for example by subsidising F&V, developing targeted dietary awareness campaigns, or by intervening in mass catering contexts to facilitate the implementation of healthy habits.

Cerebral Microbleeds in Fragile X-Associated Tremor/Ataxia Syndrome.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disease of late onset developed by carriers of the premutation in the fragile x mental retardation 1 (FMR1) gene. Pathological features of neurodegeneration in fragile X-associated tremor/ataxia syndrome include toxic levels of FMR1 mRNA, ubiquitin-positive intranuclear inclusions, white matter disease, iron accumulation, and a proinflammatory state. OBJECTIVE: The objective of this study was to analyze the presence of cerebral microbleeds in the brains of patients with fragile X-associated tremor/ataxia syndrome and investigate plausible causes for cerebral microbleeds in fragile X-associated tremor/ataxia syndrome. METHODS: We collected cerebral and cerebellar tissue from 15 fragile X-associated tremor/ataxia syndrome cases and 15 control cases carrying FMR1 normal alleles. We performed hematoxylin and eosin, Perls and Congo red stains, ubiquitin, and amyloid ß protein immunostaining. We quantified the number of cerebral microbleeds, amount of iron, presence of amyloid ß within the capillaries, and number of endothelial cells containing intranuclear inclusions. We evaluated the relationships between pathological findings using correlation analysis. RESULTS: We found intranuclear inclusions in the endothelial cells of capillaries and an increased number of cerebral microbleeds in the brains of those with fragile X-associated tremor/ataxia syndrome, both of which are indicators of cerebrovascular dysfunction. We also found a suggestive association between the amount of capillaries that contain amyloid ß in the cerebral cortex and the rate of disease progression. CONCLUSION: We propose microangiopathy as a pathologic feature of fragile X-associated tremor/ataxia syndrome. © 2021 International Parkinson and Movement Disorder Society.

A Predictive Multimodal Framework to Alert Caregivers of Problem Behaviors for Children with ASD (PreMAC).

Autism Spectrum Disorder (ASD) impacts 1 in 54 children in the US. Two-thirds of children with ASD display problem behavior. If a caregiver can predict that a child is likely to engage in problem behavior, they may be able to take action to minimize that risk. Although experts in Applied Behavior Analysis can offer caregivers recognition and remediation strategies, there are limitations to the extent to which human prediction of problem behavior is possible without the assistance of technology. In this paper, we propose a machine learning-based predictive framework, PreMAC, that uses multimodal signals from precursors of problem behaviors to alert caregivers of impending problem behavior for children with ASD. A multimodal data capture platform, M2P3, was designed to collect multimodal training data for PreMAC. The development of PreMAC integrated a rapid functional analysis, the interview-informed synthesized contingency analysis (IISCA), for collection of training data. A feasibility study with seven 4 to 15-year-old children with ASD was conducted to investigate the tolerability and feasibility of the M2P3 platform and the accuracy of PreMAC. Results indicate that the M2P3 platform was well tolerated by the children and PreMAC could predict precursors of problem behaviors with high prediction accuracies.

Vasculitis reumatoide: estudio de 41 casos / Rheumatoid vasculitis: study of 41 cases

OBJETIVO: Analizar las características clínicas, tratamiento y evolución de la vasculitis reumatoide. MÉTODOS: Estudio retrospectivo (1975-2017). Pacientes con vasculitis reumatoide diagnosticados en 2 servicios de reumatología. RESULTADOS: Se incluyó a 41 pacientes: 17 (41,5%) varones y 24 (58,5%) mujeres; con una edad media al diagnóstico de 67 ± 9 años y una duración de la artritis reumatoide de 10 ± 8,3 años. La artritis fue erosiva en 33 (80%) pacientes. Tanto el factor reumatoide como los anticuerpos antipéptido citrulinados fueron positivos en todos los casos. Los síntomas constitucionales se presentaron en 30 pacientes (73%) y las manifestaciones extrarticulares en 17 (41%). Las manifestaciones clínicas más frecuentes fueron: cutáneas 28 (68%) y neuropatía periférica 26 (63%). Todos los pacientes fueron tratados con glucocorticoides. En 24 pacientes (58%) se asoció a un inmunosupresor y 5 (12%) pacientes fueron tratados con fármacos biológicos. La mortalidad a los 2 años de seguimiento fue del 33%. Las principales causas de muerte fueron: la infección y la progresión de la vasculitis reumatoide. La frecuencia de la vasculitis reumatoide disminuyó en la última década. CONCLUSIONES: Las manifestaciones clínicas de la vasculitis reumatoide en España son similares a las descritas. La frecuencia disminuye; sin embargo, el cuadro clínico y la gravedad se mantienen invariables

AIM: To describe the clinical manifestations, evolution and treatment of patients with rheumatoid vasculitis. METHODS: Retrospective study (1975-2017) of all patients diagnosed with rheumatoid vasculitis in 2 Rheumatology Services. RESULTS: A total of 41 patients were included, 17 (41.5%) males and 24 (58.5%) females; mean age at diagnosis: 67 ± 9 years; duration of rheumatoid arthritis: 10 ± 8.3 years. Most patients had erosive disease, 33 (80%). Rheumatoid factor and anticitrullinated antibodies were positive in all patients. Constitutional symptoms were present in 30 (73%) patients and extra-articular manifestations in 17 (41%) patients. The clinical manifestations of rheumatoid vasculitis were mainly: cutaneous 28 (68%), and polyneuritis 26 (63%). All patients were treated with glucocorticoids. An immunosuppressant was associated in 24 (58.5%) patients. Five (12%) patients were treated with the association of glucocorticoids and a biologic treatment. The mortality after 2years of follow-up was 33%, the most common causes being infection and progression of the vasculitis. The frequency of rheumatoid vasculitis has decreased over the last decade. CONCLUSION: The clinical manifestations of rheumatoid vasculitis were similar to previous studies. The frequency of rheumatoid vasculitis seems to decrease. However, the clinical picture and severity remains invariable

Rheumatoid vasculitis: study of 41 cases. / Vasculitis reumatoide: estudio de 41 casos.

AIM: To describe the clinical manifestations, evolution and treatment of patients with rheumatoid vasculitis. METHODS: Retrospective study (1975-2017) of all patients diagnosed with rheumatoid vasculitis in 2 Rheumatology Services. RESULTS: A total of 41 patients were included, 17 (41.5%) males and 24 (58.5%) females; mean age at diagnosis: 67 ± 9 years; duration of rheumatoid arthritis: 10 ± 8.3 years. Most patients had erosive disease, 33 (80%). Rheumatoid factor and anticitrullinated antibodies were positive in all patients. Constitutional symptoms were present in 30 (73%) patients and extra-articular manifestations in 17 (41%) patients. The clinical manifestations of rheumatoid vasculitis were mainly: cutaneous 28 (68%), and polyneuritis 26 (63%). All patients were treated with glucocorticoids. An immunosuppressant was associated in 24 (58.5%) patients. Five (12%) patients were treated with the association of glucocorticoids and a biologic treatment. The mortality after 2years of follow-up was 33%, the most common causes being infection and progression of the vasculitis. The frequency of rheumatoid vasculitis has decreased over the last decade. CONCLUSION: The clinical manifestations of rheumatoid vasculitis were similar to previous studies. The frequency of rheumatoid vasculitis seems to decrease. However, the clinical picture and severity remains invariable.

[18F] FDG PET/CT may be a useful adjunct in diagnosis of eosinophilic fasciitis / [18F] FDG PET/CT puede ser un complemento útil en el diagnóstico de fasciitis eosinofílica

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Ten Lessons for Good Practice for the INHERIT Triple Win: Health, Equity, and Environmental Sustainability.

The world's challenges of climate change, damage to ecosystems, and social and health inequalities require changes in human behaviours at every level of organisation, among governments, business, communities, and individuals. An important question is how behaviour change can be enabled and supported at the scale and speed required. The research reported in this paper describes important lessons for good practice in changing contexts to modify behaviours for a triple win for health, equity and environmental sustainability. Authors synthesised learning from qualitative, quantitative and cost benefit evaluations of 15 case studies conducted in 12 countries in Europe. The case studies address ways of living (green spaces and energy efficient housing), moving (active transport) and consuming (healthy and sustainable diets) that support the triple win. Ten lessons for good practice were identified. These include bringing a triple win mindset to policy and practice in planning interventions, with potential to improve environmental sustainability, health and equity at the same time. The lessons for good practice are intended to support governmental and non-governmental actors, practitioners and researchers planning to work across sectors to achieve mutual benefits for health and environmental sustainability and in particular to benefit poorer and more socio-economically disadvantaged groups.

Urban Green Space: Creating a Triple Win for Environmental Sustainability, Health, and Health Equity through Behavior Change.

Urbanization, costs of green space maintenance, and diminishing connection between people and nature all exert pressures on urban green space. This is regrettable as green space has the potential to create wins for environmental sustainability, health, and health equity. This paper explores this potential triple win and investigates how to increase the use of urban green space through behavior change. A narrative literature review was conducted and was supplemented with literature suggested by experts. Results show that creating well-designed green spaces and stimulating people to use them can indeed deliver this triple win. Providing accessible, attractive, well-maintained green space with room for socialization, and where people feel safe, may increase the opportunity and motivation of people to use it more often. Informing and educating people and organizing activities may increase capability (and motivation) to use green space. Since the use of green space depends on life stage, lifestyle factors and individual values, it is important to involve potential users in its design. We recommend a specific focus on those groups who may benefit most from the use of green space. More evaluation is needed to inform effective green space interventions and to assess related economic, social, and environmental benefits.

Effectiveness and safety of rituximab for the treatment of refractory systemic sclerosis associated calcinosis: A case series and systematic review of the literature.

OBJECTIVE: To analyze the effectiveness and safety of rituximab (RTX) for the treatment of refractory systemic sclerosis (SSc)-associated calcinosis. METHODS: We undertook an observational study of patients with this complication treated with 1 or more cycles of RTX (1 g × 2 weeks) and evaluated for at least 12 months after RTX treatment in a single center. The primary outcome measures of the study were the improvement of calcinosis symptoms (pain, signs of local inflammation, and new episodes of skin ulceration) and the radiologic evolution of the calcification(s). RESULTS: We treated 8 patients with refractory SSc-related calcinosis with RTX (off-label use). The main indications for RTX were complicated calcinosis unresponsive to previous therapies with concomitant arthritis in 2 patients and refractory arthritis or interstitial lung fibrosing disease in the remaining 6 patients. The mean number of RTX cycles administered was 3.12 ±â€¯2.1 (range, 1-7), the median duration of RTX treatment was 9 months (interquartile range [IQR], 7.5-36 months), and the median follow-up after the first infusion of RTX dose was 19 months (IQR, http://catsalut.gencat.cat/web/.content/minisite/catsalut/proveidors_professionals/medicaments_farmacia/phf_mhda/informes_camse/esclerosi_sistemica/Dictamen-CAMS_-ES_-web.pdf (n.d.) 5-45 months). Four patients (50%) had a significant improvement in clinical symptoms (sustained improvement in the visual analog scale for pain of at least 50% and no new episodes of local inflammation or skin ulceration). Two of these patients (25%) also had a complete resolution or significant reduction in the size of the calcification(s) on X-ray, according with the radiographical scoring system for calcinosis developed by the Scleroderma Clinical Trials Consortium. In the remaining 4 patients (50%), RTX did not provide any significant clinical or radiologic benefit for calcinosis. The frequency of adverse effects was low, occurring in only 1 patient (12.5%), who developed upper respiratory tract infections not requiring hospitalization. CONCLUSION: Our preliminary data suggest that RTX may be helpful as a rescue therapy in selected cases of severe and refractory SSc-related calcinosis.

A Technological Scenario for a Healthier, More Equitable and Sustainable Europe in 2040: Citizen Perceptions and Policy Implications.

This article aims at exploring, understanding and comparing European citizens' insights and perceptions towards "My life between realities", a positive future scenario which depicts a narrative of reaching healthier, more equitable and sustainable societies by 2040 with the support of technology and technological solutions. It responds to the need for gathering and incorporating more citizen insights into future policy developments and strategic actions to tackle the global challenge of unsustainable development. Citizens of five European countries-the Czech Republic, Germany, North Macedonia, Spain and the United Kingdom-have been consulted through focus groups. The exercise has uncovered citizens' preferences and attitudes towards four main lifestyle areas; namely, green spaces, energy efficient housing, active mobility and (food) consumption. The technological attributes of the scenario led to citizens expressing diametrically opposed and critical perceptions and attitudes. Given the prospects of technology in driving sustainable development, based on these insights, policy recommendations for the better integration and acceptance of technological advances by the public are discussed herein.