How best to support parents in the management of standing frame usage in home settings: A mixed methods study.

BACKGROUND: An improved understanding of the current practice of standing frame use may have implications for supporting parents in managing standing frames. We aimed to investigate how parents of children with cerebral palsy perceive and manage standing frame use in home settings. METHODS: We conducted a mixed methods study with an explanatory sequential design, first collecting and analysing quantitative questionnaire data and then using these results to inform a qualitative follow-up phase to explain them. The questionnaire was answered by 103 parents of children with cerebral palsy across five countries, Denmark, Norway, Great Britain, Canada and the United States, and 12 Danish families participated in the subsequent interviews. A descriptive analysis was conducted using the questionnaire data. The qualitative data were analysed using a directed content analysis, enabling integration of the quantitative and qualitative data. RESULTS: The quantitative analysis showed that 89% of the parents felt confident with their child's standing frame, and 82% felt they had sufficient knowledge about how their child's standing frame could/should be used. However, the qualitative analysis showed that even when feeling confident, the parents experienced insecurity regarding whether their child was positioned correctly, and being responsible for positioning was challenging. CONCLUSION: Our study implies a need for providing educational materials to assist the parents in ensuring optimal positioning of their child in the standing frame to decrease insecurity. Additionally, our study suggests a need to provide more thorough information about the benefits of using a standing frame and ensure alignment of expectations in relation to the child's prognosis of functional independence.

Brain-targeting autoantibodies in patients with dementia.

Autoantibodies against proteins in the brain are increasingly considered as a potential cause of cognitive decline, not only in subacute autoimmune encephalopathies but also in slowly progressing impairment of memory in patients with classical neurodegenerative dementias. In this retrospective cohort study of 161 well-characterized patients with different forms of dementia and 34 controls, we determined the prevalence of immunoglobulin (Ig) G and IgA autoantibodies to brain proteins using unbiased immunofluorescence staining of unfixed murine brain sections. Autoantibodies were detected in 21.1% of dementia patients and in 2.9% of gender-matched controls, with higher frequencies in vascular dementia (42%), Alzheimer's disease (30%), dementia of unknown cause (25%), and subjective cognitive impairment (16.7%). Underlying antigens involved glial fibrillary acidic protein (GFAP), glycine receptor, and Rho GTPase activating protein 26 (ARHGAP26), but also a range of yet undetermined epitopes on neurons, myelinated fiber tracts, choroid plexus, glial cells, and blood vessels. Antibody-positive patients were younger than antibody-negative patients but did not differ in the extent of cognitive impairment, epidemiological and clinical factors, or comorbidities. Further research is needed to understand the potential contribution to disease progression and symptomatology, and to determine the antigenic targets of dementia-associated autoantibodies.

KCNA2 IgG autoimmunity in neuropsychiatric diseases.

BACKGROUND: Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their diagnostic and pathophysiological role is currently unknown, imposing challenges to medical practice. DESIGN / METHODS: We retrospectively collected comprehensive clinical and paraclinical data of 35 patients with KCNA2 IgG autoantibodies detected in cell-based and tissue-based assays. Patients' sera and cerebrospinal fluid (CSF) were used for characterization of the antigen, clinical-serological correlations, and determination of IgG subclasses. RESULTS: KCNA2 autoantibody-positive patients (n = 35, median age at disease onset of 65 years, range of 16-83 years, 74 % male) mostly presented with cognitive impairment and/or epileptic seizures but also ataxia, gait disorder and personality changes. Serum autoantibodies belonged to IgG3 and IgG1 subclasses and titers ranged from 1:32 to 1:10,000. KCNA2 IgG was found in the CSF of 8/21 (38 %) patients and in the serum of 4/96 (4.2 %) healthy blood donors. KCNA2 autoantibodies bound to characteristic anatomical areas in the cerebellum and hippocampus of mammalian brain and juxtaparanodal regions of peripheral nerves but reacted exclusively with intracellular epitopes. A subset of four KCNA2 autoantibody-positive patients responded markedly to immunotherapy alongside with conversion to seronegativity, in particular those presenting an autoimmune encephalitis phenotype and receiving early immunotherapy. An available brain biopsy showed strong immune cell invasion. KCNA2 autoantibodies occurred in less than 10 % in association with an underlying tumor. CONCLUSION: Our data suggest that KCNA2 autoimmunity is clinically heterogeneous. Future studies should determine whether KCNA2 autoantibodies are directly pathogenic or develop secondarily. Early immunotherapy should be considered, in particular if autoantibodies occur in CSF or if clinical or diagnostic findings suggest ongoing inflammation. Suspicious clinical phenotypes include autoimmune encephalitis, atypical dementia, new-onset epilepsy and unexplained epileptic seizures.

Psychosocial patient perspectives following major lower-limb amputation due to vascular aetiology: a protocol for a systematic meta-aggregation study.

INTRODUCTION: Persistent psychosocial problems in people with lower-limb amputation due to vascular aetiology indicate a great need for long-lasting holistic rehabilitation. An in-depth understanding of the psychosocial problems is essential for the guidance of health professionals in meeting and normalising patients' experiences and emotions. Furthermore, identifying the psychological problems may help develop effective rehabilitation and counselling programmes. This meta-aggregation study aims to explore the psychosocial perspectives of individuals who have undergone a major lower-limb amputation due to vascular aetiology during the post-discharge rehabilitation phase. METHODS AND ANALYSIS: A systematic meta-aggregation study will be performed to identify full-text, peer-reviewed journal articles reporting on patients' psychosocial perspectives on major lower-limb amputation due to vascular aetiology from post-discharge to several years afterward. The databases Embase, CINAHL Ultimate, APA PsycInfo, PubMed and Scopus will be searched with no limitations regarding the publication year. Studies that satisfy the eligibility criteria will be critically appraised using an acknowledged checklist and synthesised using the Joanna Briggs Institute three-phase approach for the synthesis of meta-aggregation studies. The GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation- Confidence in Evidence from Reviews of Qualitative research) tool will be used to determine the level of confidence in the qualitative evidence, and the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) reporting guidelines will be followed throughout the review process. ETHICS AND DISSEMINATION: Ethical approval is not required for the study, as the review is built on pre-existing available data in the literature. Findings from the review will be disseminated through publication in a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42022377114.

Synapsin autoantibodies during pregnancy are associated with fetal abnormalities.

Anti-neuronal autoantibodies can be transplacentally transferred during pregnancy and may cause detrimental effects on fetal development. It is unclear whether autoantibodies against synapsin-I, one of the most abundant synaptic proteins, are associated with developmental abnormalities in humans. We recruited a cohort of 263 pregnant women and detected serum synapsin-I IgG autoantibodies in 13.3% using cell-based assays. Seropositivity was strongly associated with abnormalities of fetal development including structural defects, intrauterine growth retardation, amniotic fluid disorders and neuropsychiatric developmental diseases in previous children (odds ratios of 3-6.5). Autoantibodies reached the fetal circulation and were mainly of IgG1/IgG3 subclasses. They bound to conformational and linear synapsin-I epitopes, five distinct epitopes were identified using peptide microarrays. The findings indicate that synapsin-I autoantibodies may be clinically useful biomarkers or even directly participate in the disease process of neurodevelopmental disorders, thus being potentially amenable to antibody-targeting interventional strategies in the future.

Quality of life and symptom burden after rectal cancer surgery: a randomised controlled trial comparing patient-led versus standard follow-up.

PURPOSE: After curatively intended rectal cancer (RC) surgery, new follow-up strategies are warranted, seeking more individualised care and targeting health-related quality of life (HRQoL) and functional outcomes. The FURCA trial aimed to investigate the effect of patient-led follow-up on HRQoL and symptom burden 3 years after surgery. METHODS: RC patients from four Danish centres were randomised 1:1 to intervention (patient-led follow-up with patient education and self-referral to a specialist nurse) or control (standard follow-up with five routine doctor visits). Patients in both groups had a computed tomography (CT) at 1 and 3 years. The primary outcome (HRQoL) was assessed by the Functional Assessment of Cancer Therapy - colorectal (FACT-C) score (Ward et al. in Qual Life Res. 8(3):181-95, 18). Secondary outcomes were functional measures, patient involvement and satisfaction and cancer recurrence at 3 years. RESULTS: From Feb 2016 to Aug 2018, 336 patients were included of whom 248 completed 3 years of follow-up. Between-group differences were found neither for the primary endpoint, nor for functional outcomes. The recurrence rate did not differ between the groups. Patient involvement and satisfaction were higher in the intervention group with statistical significance in almost half of the items. CONCLUSIONS: We found no effect on HRQoL and symptom burden from patient-led follow-up, although it may improve patient-perceived involvement and satisfaction. IMPLICATIONS FOR CANCER SURVIVORS: The findings in this study suggest that patient-led follow-up is a more tailored approach to meet cancer survivors' needs and might improve their ability to cope with survivorship. GOV IDENTIFIER: R97-A6511-14-S23.

Maternal synapsin autoantibodies are associated with neurodevelopmental delay.

Maternal autoantibodies can be transmitted diaplacentally, with potentially deleterious effects on neurodevelopment. Synapsin 1 (SYN1) is a neuronal protein that is important for synaptic communication and neuronal plasticity. While monoallelic loss of function (LoF) variants in the SYN1 gene result in X-linked intellectual disability (ID), learning disabilities, epilepsy, behavioral problems, and macrocephaly, the effect of SYN1 autoantibodies on neurodevelopment remains unclear. We recruited a clinical cohort of 208 mothers and their children with neurologic abnormalities and analyzed the role of maternal SYN1 autoantibodies. We identified seropositivity in 9.6% of mothers, and seropositivity was associated with an increased risk for ID and behavioral problems. Furthermore, children more frequently had epilepsy, macrocephaly, and developmental delay, in line with the SYN1 LoF phenotype. Whether SYN1 autoantibodies have a direct pathogenic effect on neurodevelopment or serve as biomarkers requires functional experiments.

Association of cerebrospinal fluid brain-binding autoantibodies with cognitive impairment in post-COVID-19 syndrome.

BACKGROUND: Neurological symptoms, in particular cognitive deficits, are common in post-COVID-19 syndrome (PCS). There is no approved therapy available, and the underlying disease mechanisms are largely unknown. Besides others, autoimmune processes may play a key role. DESIGN: We here present data of a prospective study conducted between September 2020 and December 2021 and performed at two German University hospitals with specialized Neurology outpatient clinics. Fifty patients with self-reported cognitive deficits as main complaint of PCS and available serum and CSF samples were included. Cell-based assays and indirect immunofluorescence on murine brain sections were used to detect autoantibodies against intracellular and surface antigens in serum and CSF and analyzed for associations with cognitive screening assessment. RESULTS: Clearly abnormal cognitive status (MoCA ≤ 25/30 points) was only seen in 18/50 patients with self-reported cognitive deficits. Most patients (46/50) had normal routine CSF parameters. anti-neuronal autoantibodies were found in 52 % of all patients: n = 9 in serum only, n = 3 in CSF only and n = 14 in both, including those against myelin, Yo, Ma2/Ta, GAD65 and NMDA receptor, but also a variety of undetermined epitopes on brain sections. These included cerebral vessel endothelium, Purkinje neurons, granule cells, axon initial segments, astrocytic proteins and neuropil of basal ganglia or hippocampus as well as a formerly unknown perinuclear rim pattern. Pathological MoCA results were associated with the presence of anti-neuronal antibodies in CSF (p = 0.0004). CONCLUSIONS: Autoantibodies targeting brain epitopes are common in PCS patients and strongly associate with pathological cognitive screening tests, in particular when found in CSF. Several underlying autoantigens still await experimental identification. Further research is needed to inform on the clinical relevance of these autoantibodies, including controlled studies that explore the potential efficacy of antibody-depleting immunotherapy in PCS.

Spectrum of Novel Anti-Central Nervous System Autoantibodies in the Cerebrospinal Fluid of 119 Patients With Schizophreniform and Affective Disorders.

BACKGROUND: Autoimmune psychosis may be caused by well-characterized anti-neuronal autoantibodies, such as those against the NMDA receptor. However, the presence of additional anti-central nervous system (CNS) autoantibodies in these patients has not been systematically assessed. METHODS: Serum and cerebrospinal fluid (CSF) from patients with schizophreniform and affective syndromes were analyzed for immunoglobulin G anti-CNS autoantibodies using tissue-based assays with indirect immunofluorescence on unfixed murine brain tissue as part of an extended routine clinical practice. After an initial assessment of patients with red flags for autoimmune psychosis (n = 30), tissue-based testing was extended to a routine procedure (n = 89). RESULTS: Based on the findings from all 119 patients, anti-CNS immunoglobulin G autoantibodies against brain tissue were detected in 18% (n = 22) of patients (serum 9%, CSF 18%) following five principal patterns: 1) against vascular structures, most likely endothelial cells (serum 3%, CSF 8%); 2) against granule cells in the cerebellum and/or hippocampus (serum 4%, CSF 6%); 3) against myelinated fibers (serum 2%, CSF 2%); 4) against cerebellar Purkinje cells (serum 0%, CSF 2%); and 5) against astrocytes (serum 1%, CSF 1%). The patients with novel anti-CNS autoantibodies showed increased albumin quotients (p = .026) and white matter changes (p = .020) more frequently than those who tested negative for autoantibodies. CONCLUSIONS: The study demonstrates five novel autoantibody-binding patterns on brain tissue of patients with schizophreniform and affective syndromes. CSF yielded positive findings more frequently than serum analysis. The frequency and spectrum of autoantibodies in these patient groups may be broader than previously thought.

SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Beta variant of concern (VOC) resists neutralization by major classes of antibodies from COVID-19 patients and vaccinated individuals. In this study, serum of Beta-infected patients revealed reduced cross-neutralization of wild-type virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of VOC-specific clonotypes and accommodation of mutations present in Beta and Omicron into a major antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with wild type-elicited antibodies, including a public VH1-58 clonotype that targets the RBD ridge. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift, with implications for design of next-generation vaccines and therapeutics.

Measurement of physical activity in children and adolescents with cerebral palsy: a scoping review protocol.

OBJECTIVE: The objective of this scoping review is to identify and map subjective instruments that have been developed for children and adolescents with cerebral palsy from birth to 18 years to measure physical activity and sedentary behavior. INTRODUCTION: Children and adolescents with cerebral palsy often do not meet the recommended levels of physical activity, even though regular physical activity is an important determinant of good health. Considering the importance of physical activity, there is a need for systematic collection of data on daily activity and sedentary behavior of children and adolescents with cerebral palsy. Subjective instruments with clinical utility for use in quality registers are needed to evaluate interventions and investigate the relationship between activity and health outcomes. INCLUSION CRITERIA: This review will consider studies that include children and adolescents from birth to 18 years with cerebral palsy across levels I to V of the Gross Motor Function Classification System. Specifically, this scoping review will report on subjective instruments used to measure physical activity and sedentary behavior and that distinguish between physical activity performance and physical activity capability. METHODS: This scoping review will be conducted in accordance with the JBI methodology for scoping reviews and will search the following databases: MEDLINE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, JBI Evidence Synthesis, Embase, and PEDro, as well as specific journals relating to physical activity assessment.

Impact of Metronidazole Treatment and Dientamoeba Fragilis Colonization on Gut Microbiota Diversity.

OBJECTIVES: The intestinal parasite Dientamoeba fragilis is a common colonizer of children in Denmark. Metronidazole has been used to reduce gastrointestinal symptoms in children colonized with D fragilis. We aimed to identify gut microbiota changes associated with D fragilis carrier status and metronidazole treatment of D fragilis-positive children. METHODS: The fecal microbiota of 275 fecal samples from children treated with metronidazole (n = 48) or placebo (n = 48) were characterized by ribosomal DNA sequencing. Samples collected before (T1), 2 weeks after (T2), and 8 weeks (T5) after treatment were included. Seventy fecal samples from 70 age-matched parasite-negative children served as controls. RESULTS: The abundance of 24 bacterial genera differed significantly according to D fragilis carrier status, with Flavonifractor being remarkably more abundant in children testing negative for D fragilis. Eight bacterial genera changed significantly in abundance in children losing versus keeping D fragilis after metronidazole treatment. Of these, 7 returned to pretreatment (T1) levels at T5. Meanwhile, the abundance of Flavonifractor continued to differ at T5, whereas for Ruminococcus the abundance only remained high in children who were D fragilis-negative at T2 and T5. Increases in Hungatella, Sutterella, and Streptococcus abundances observed at T2 were specific to metronidazole exposure and hence independent of D fragilis colonization. CONCLUSIONS: This study revealed that specific bacterial genera were associated with D fragilis colonization. Metronidazole treatment had a short-term impact on the abundance of some bacterial genera, with most of these reverting to pretreatment levels 8 weeks after completed treatment.

Effectiveness of instrumented gait analysis in interdisciplinary interventions on parents' perception of family-centered service and on gross motor function in children with cerebral palsy: a randomized controlled trial.

BACKGROUND: Children with cerebral palsy often exhibit an altered gait pattern; however, it is uncertain whether the use of an instrumented gait analysis in interdisciplinary interventions affects the perceived experience of family-centered service (FCS) and/or gross motor function. The aim of this study is to investigate whether individually tailored interdisciplinary interventions, based on an instrumented gait analysis report, has a superior effectiveness on perceived FCS and gross motor function in children with cerebral palsy, compared to 'care as usual' without the use of instrumented gait analysis. Furthermore, to investigate potential associations between perceived FCS and gross motor function improvement with the goal of improving future therapy on gross motor function. METHOD: This is a sequel analysis on tertiary outcome measures from a prospective, single blind, randomized, parallel group study including two groups of 30 children aged 5-8 years with spastic cerebral palsy at Gross Motor Function Classification System levels I-II (n = 60). The intervention group underwent a three-dimensional gait analysis, from which a clinical report was written with recommendations on interdisciplinary interventions, such as physical therapy, orthopedic surgery, orthotics or spasticity management. To assess effectiveness on perceived FCS and gross motor function, at baseline, 26 weeks and 52 weeks, the five domains in the Measure of Processes of Care (MPOC-20) (Enabling and partnership, Providing general information, Providing specific information about the child, Respectful and supportive service, and Coordinated and comprehensive care) and the Gross Motor Function Measurement (GMFM-66) were used as outcome measures. RESULTS: No significant differences in between-group change scores in any of the five MPOC-20 domains were observed (p = 0.40-0.97). In favor of the intervention group a significantly higher between-group change score in GMFM-66 (mean difference: 3.05 [95%CI: 1.12-4.98], p = 0.003) after 52 weeks was observed. CONCLUSION: The addition of an instrumented gait analysis report to 'care as usual' did not improve the parents' perceptions of FCS in treatment of children with cerebral palsy. However, superior improvement in the GMFM-66 was observed in the intervention group, suggesting meaningful gross motor function improvement. TRIAL REGISTRATION: Clinical Trials, NCT02160457 . Registered June 10th 2014.

Gait analysis for individually tailored interdisciplinary interventions in children with cerebral palsy: a randomized controlled trial.

AIM: To test the hypothesis that improvements in gait and function following individualized interdisciplinary interventions consisting of physical therapy, orthotics, spasticity management, and orthopaedic surgery using instrumented gait analysis are superior to 'usual care' in children with cerebral palsy (CP). METHOD: This was a prospective, single-blind, parallel-group, randomized controlled trial investigating the effectiveness of interventions based on the use of gait analysis. Primary outcome was gait (Gait Deviation Index) and secondary outcomes were walking and patient-reported outcome measures of function, disability, and health-related quality of life. Follow-ups were done at 26 weeks (questionnaires) and at the primary end point of 52 weeks (all outcomes). RESULTS: Sixty participants with CP (39 males, 21 females, mean age 6y 10mo, standard deviation 1y 3mo, range 5y-9y 1mo) in Gross Motor Function Classification System levels I or II, were randomized to interventions with or without gait analysis. No significant or clinically relevant between-group differences in change scores of the primary or secondary outcomes were found. The recommended categories of interventions were dominated by non-surgical interventions and were applied in 36% to 86% of the participants. INTERPRETATION: Interventions using gait analysis were not superior to 'usual care' on gait, walking, or patient-reported outcomes in a sample of relatively young and independently walking children with CP not expected to need surgery. WHAT THIS PAPER ADDS: Gait analysis in children with cerebral palsy in Gross Motor Function Classification System levels I or II recommends interdisciplinary interventions. Compliance to interventions recommended after gait analysis was low. No statistically significant advantages were identified for the intervention group versus the control group.

ANÁLISIS DE MARCHA PARA LA INTERVENCIÓN INTERDISCIPLINARIA ADAPTADA INDIVIDUALMENTE EN NIÑOS CON PARÁLISIS CEREBRAL: ENSAYO CONTROLADO RANDOMIZADO: OBJETIVO: Comprobar la hipótesis que las mejoras en la marcha y la función luego de las intervenciones interdisciplinarias individualizadas de terapia física, ortésis, tratamiento antiespástico, y cirugía ortopédica son superiores que "tratamiento convencional" en parálisis cerebral (PC) utilizando un análisis de marcha instrumentada METODO: Este fue un ensayo randomizado controlado, prospectivo, ciego, con grupo paralelo que investigó la efectividad de intervenciones basada en el uso de análisis de marcha. El resultado primario fue la marcha (Índice de Desviación de la Marcha) y los resultados secundarios fueron el paso y los resultados reportados por los pacientes de función, discapacidad y calidad de vida relacionada a la salud. Los seguimientos se realizaron a las 26 semanas (cuestionarios) y el punto de fin primario de 52 semanas (todos los resultados). RESULTADOS: Sesenta participantes con PC (39 masculinos, 21 femeninos, edad media de 6 años 10 meses, desviación estándar de 1 años y 3 meses, rango 5 años 0 meses- 9 años y 1 mes) con niveles de GMFCS I o II, fueron asignados al azar intervenciones con y sin análisis de marcha. No se encontraron diferencias significativas o clínicamente relevantes entre los grupos en cuanto a los cambios de los resultados primarios y secundarios. INTERPRETACION: Las intervenciones que usaron análisis de marcha no fueron superiores al tratamiento convencional sobre el paso, la marcha o resultados reportados por los pacientes en una muestra de niños con PC relativamente jóvenes y de marcha independiente que no se espera que necesiten cirugía.

ANÁLISE DE MARCHA PARA INTERVENÇÕES INDIVIDUALMENTE PLANEJADAS EM CRIANÇAS COM PARALISIA CEREBRAL: UM ENSAIO CONTROLADO RANDOMIZADO: OBJETIVO: Testar a hipótese de que melhoras na marcha e função após intervenções interdisciplinares individualizadas consistindo de fisioterapia, órteses, manejo da espasticidade, e cirurgia ortopédica usando análise de marcha instrumentalizada são superiors comparadas ao "cuidado usual" em crianças com paralisia cerebral (PC). MÉTODO: Este foi um estudo randomizado controlado prospectivo, único cego, com grupos paralelos, investigando a efetividade de intervenções baseadas no uso da análise de marcha. O desfecho primário foi a marcha (Índice de Desvio da Marcha) e os desfechos secundários foram o caminhar e medidas relatadas pelo paciente da função, incapacidade, e qualidade de vida relacionada à saúde. Acompanhamentos foram feitos com 26 semanas (questionários) e o encerramento primário foi 52 semanas (todos os resultados). RESULTADOS: Sessenta participantes com PC (39 do sexo masculino, 21 do sexo feminino, média de idade 6a 10 m, desvio padrão 1a 3 m, variação 5a 0 m- 9a 1 m) nos níveis do Sistema de Classificação da Função Motora Grossa (GMFCS) I ou II foram fandomizados para intervenções com ou sem análise de marcha. Nenhuma diferença significativa ou clinicamente relevante entre grupos nos escores de mudança dos desfechos primários e secundários foram encontradas. As categorias de intervenção recomendadas foram dominadas pelas intervenções não-cirúrgicas e foram aplicadas em 36% a 86% dos participantes. INTERPRETAÇÃO: Intervenções usando análise de marcha não foram superiores ao "cuidado usual" para a marcha, o caminhar, ou resultados reportados por pacientes em ma amostra de crianças com PC relativamente jovens e com deambulação indepente, para a qual não se espera a necessidade de cirurgia.

Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases.

Dimethyl fumarate (DMF) has been applied for decades in the treatment of psoriasis and now also multiple sclerosis. However, the mechanism of action has remained obscure and involves high dose over long time of this small, reactive compound implicating many potential targets. Based on a 1.9 Å resolution crystal structure of the C-terminal kinase domain of the mouse p90 Ribosomal S6 Kinase 2 (RSK2) inhibited by DMF we describe a central binding site in RSKs and the closely related Mitogen and Stress-activated Kinases (MSKs). DMF reacts covalently as a Michael acceptor to a conserved cysteine residue in the αF-helix of RSK/MSKs. Binding of DMF prevents the activation loop of the kinase from engaging substrate, and stabilizes an auto-inhibitory αL-helix, thus pointing to an effective, allosteric mechanism of kinase inhibition. The biochemical and cell biological characteristics of DMF inhibition of RSK/MSKs are consistent with the clinical protocols of DMF treatment.

Threshold values of ankle dorsiflexion and gross motor function in 60 children with cerebral palsy.

Background and purpose - Threshold values defining 3 categories of passive range of motion are used in the Cerebral Palsy follow-Up Program to guide clinical decisions. The aim of this study was to investigate the threshold values by testing the hypothesis that passive range of motion in ankle dorsiflexion is associated with gross motor function and that function differs between the groups of participants in each category. Patients and methods - We analyzed data from 60 ambulatory children (aged 5-9 years) with spastic cerebral palsy. Outcomes were passive range of motion in ankle dorsiflexion with flexed and extended knee and gross motor function (Gait Deviation Index, Gait Variable Score of the ankle, peak dorsiflexion during gait, 1-minute walk, Gross Motor Function Measure, the Pediatric Quality of Life Inventory Cerebral Palsy Module, and Pediatric Outcomes Data Collection Instrument). Results - Significant (p < 0.05) and moderate correlations were documented for range of motion versus Gait Variable Score of the ankle (r = -0.37 and r = -0.37) and range of motion versus peak dorsiflexion (r = 0.49 and r = 0.55). Differences between the groups formed by the categories were shown for Gait Variable Score of the ankle and peak dorsiflexion (p < 0.05). No other significant correlations or differences between the categories were observed. Interpretation - The results suggest that threshold values for ankle dorsiflexion used in the Cerebral Palsy follow-Up Program are of limited clinical value in assessing overall gross motor function, but may be used to identify deviations in ankle-specific gait function.

Sortilin-Related Receptor Expression in Human Neural Stem Cells Derived from Alzheimer's Disease Patients Carrying the APOE Epsilon 4 Allele.

Alzheimer's disease (AD) is the most common form of dementia in the elderly; important risk factors are old age and inheritance of the apolipoprotein E4 (APOE4) allele. Changes in amyloid precursor protein (APP) binding, trafficking, and sorting may be important AD causative factors. Secretase-mediated APP cleavage produces neurotoxic amyloid-beta (Aß) peptides, which form lethal deposits in the brain. In vivo and in vitro studies have implicated sortilin-related receptor (SORL1) as an important factor in APP trafficking and processing. Recent in vitro evidence has associated the APOE4 allele and alterations in the SORL1 pathway with AD development and progression. Here, we analyzed SORL1 expression in neural stem cells (NSCs) from AD patients carrying null, one, or two copies of the APOE4 allele. We show reduced SORL1 expression only in NSCs of a patient carrying two copies of APOE4 allele with increased Aß/SORL1 localization along the degenerated neurites. Interestingly, SORL1 binding to APP was largely compromised; this could be almost completely reversed by γ-secretase (but not ß-secretase) inhibitor treatment. These findings may yield new insights into the complex interplay of SORL1 and AD pathology and point to NSCs as a valuable tool to address unsolved AD-related questions in vitro.

An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer's Disease Patients.

Alzheimer's disease (AD) is the most common cause of dementia and is likely caused by defective amyloid precursor protein (APP) trafficking and processing in neurons leading to amyloid plaques containing the amyloid-ß (Aß) APP peptide byproducts. Understanding how APP is targeted to selected destinations inside neurons and identifying the mechanisms responsible for the generation of Aß are thus the keys for the advancement of new therapies. We previously developed a mouse model with a mutation at tyrosine (Tyr) 682 in the C-terminus of APP. This residue is needed for APP to bind to the coating protein Clathrin and to the Clathrin adaptor protein AP2 as well as for the correct APP trafficking and sorting in neurons. By extending these findings to humans, we found that APP binding to Clathrin is decreased in neural stem cells from AD sufferers. Increased APP Tyr phosphorylation alters APP trafficking in AD neurons and it is associated to Fyn Tyr kinase activation. We show that compounds affecting Tyr kinase activity and counteracting defects in AD neurons can control APP location and compartmentalization. APP Tyr phosphorylation is thus a potential therapeutic target for AD.

The Danish Cerebral Palsy Follow-up Program.

AIM OF DATABASE: The Danish Cerebral Palsy Follow-up Program is a combined follow-up program and national clinical quality database that aims to monitor and improve the quality of health care for children with cerebral palsy (CP). STUDY POPULATION: The database includes children with CP aged 0-15 years and children with symptoms of CP aged 0-5 years. MAIN VARIABLES: In the follow-up program, the children are offered examinations throughout their childhood by orthopedic surgeons, physiotherapists, occupational therapists, and pediatricians. Examinations of gross and fine motor function, manual ability, muscle tone, passive range of motion, use of orthotics, and assistive devices are performed once a year; radiographic examination of the hips is planned based on the child's age and gross motor function; and the diagnosis is performed once before the age of 5 years. Six indicators were developed based on scientific literature and consensus in the steering committee, and their calculation is based on the following four main variables: radiographic examination of the hip, gross motor function, manual ability, and diagnosis. DESCRIPTIVE DATA: The 2014 annual report includes results of the quality indicators in three of five regions in Denmark comprising 432 children with CP, corresponding to a coverage of 82% of the expected population. CONCLUSION: The Danish Cerebral Palsy Follow-up Program is currently under development as a national clinical quality database in Denmark. The database holds potential for research in prevalence, clinical characteristics of the population, and the effects of prevention and treatment.

Comparison of sensitivity and specificity of 4 methods for detection of Giardia duodenalis in feces: immunofluorescence and PCR are superior to microscopy of concentrated iodine-stained samples.

For decades, microscopy of feces after formol-ethylacetate (FEA) concentration and iodine staining has been the routine test for intestinal protozoa. Lately, polymerase chain reaction or fluorescence-labeled parasite-specific antibodies have been introduced, but their place in everyday routine diagnostics has not yet been established. We compared FEA and salt-sugar flotation (SSF) concentration followed by microscopy of iodine-stained concentrate and immunofluorescence assay (IFA) and real-time polymerase chain reaction (qPCR) for detection of Giardia duodenalis in human feces. The median number of Giardia cysts found by FEA in 19 Giardia-positive samples was 50 cysts per gram (CPG), by SSF 350 CPG, by IFA 76,700 CPG, and by qPCR 316,000 CPG. We next tested 455 consecutive samples for presence of Giardia cysts. Using IFA as reference, qPCR had a sensitivity of 91%, specificity of 95.1%, a false-positive rate of 50%, a false-negative rate of 0.48%, a positive predictive value of 50%, and a negative predictive value of 99.5%. In conclusion, qPCR and IFA were significantly more sensitive than microscopy of iodine-stained concentrates using either FEA or SSF. We suggest, when using qPCR, that positive samples are verified by IFA to prevent false-positive results.