Histomorphometric Analysis of 38 Giant Cell Tumors of Bone after Recurrence as Compared to Changes Following Denosumab Treatment.

Giant cell tumor of bone (GCTB) is an osteolytic tumor driven by an H3F3A-mutated mononuclear cell with the accumulation of osteoclastic giant cells. We analyzed tissue from 13 patients with recurrence and 25 patients with denosumab therapy, including two cases of malignant transformation. We found a decrease in the total number of cells (p = 0.03), but not in the individual cell populations when comparing primary and recurrence. The patients treated with denosumab showed induction of osteoid formation increasing during therapy. The total number of cells was reduced (p < 0.0001) and the number of H3F3A-mutated tumor cells decreased (p = 0.0001), while the H3F3A wild-type population remained stable. The KI-67 proliferation rate dropped from 10% to 1% and Runx2- and SATB2-positive cells were reduced. The two cases of malignant transformation revealed a loss of the H3F3A-mutated cells, while the KI-67 rate increased. Changes in RUNX2 and SATB2 expression were higher in one sarcoma, while in the other RUNX2 was decreased and SATB2-positive cells were completely lost. We conclude that denosumab has a strong impact on the morphology of GCTB. KI-67, RUNX2 and SATB2 expression differed depending on the benign or malignant course of the tumor under denosumab therapy.

Epigenetic lockdown of CDKN1A (p21) and CDKN2A (p16) characterises the neoplastic spindle cell component of giant cell tumours of bone.

Giant cell tumour of bone (GCTB) comprises the eponymous osteoclastic multinucleated giant cells eliciting bone lysis, an H3F3A-mutated neoplastic mononucleated fibroblast-like cell population, and H3F3A wild-type mononucleated stromal cells. In this study, we characterised four new cell lines from GCTB. Furthermore, we compared the genome-wide DNA methylation profile of 13 such tumours and three further cell lines with giant cell-rich lesions comprising three H3F3B-mutated chondroblastomas, three USP6-rearranged aneurysmal bone cysts, three non-ossifying fibromas, two hyperparathyroidism-associated brown tumours as well as mesenchymal stem cells, osteoblasts, and osteoclasts. In an unsupervised analysis, we delineated GCTB and chondroblastomas from the other analysed tumour entities. Using comparative methylation analysis, we demonstrated that the methylation pattern of the cell lines approximately equals that of H3F3A-mutated stromal cells in tissue. These patterns more resemble that of osteoblasts than that of mesenchymal stem cells, which argues for the osteoblast as the cell of origin of giant cell tumours of bone. Using enrichment analysis, we detected distinct hypermethylated clusters containing histone and collagen genes as well as target genes of the tumour suppressor p53. We found that the promotor regions of CDKN1A, CDKN2A, and IGFBP3 are methylated more strongly in GCTB than in the other giant cell-containing lesions, mesenchymal stem cells, osteoblasts, and osteoclasts (p < 0.001). This hypermethylation correlates with the lower gene expression at the mRNA level for these three genes in the cell lines, the lack of p16 and p21 in these cell lines, and the lower expression of p16 and p21 in GCTB. Overall, our analysis reveals characteristic DNA methylation patterns of giant cell tumours of bone and chondroblastomas and shows that cell lines of giant cell tumours of bone are a valid model for further analysis of H3F3A-mutated tumour cells. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

How Pause Duration Influences Impressions of English Speech: Comparison Between Native and Non-native Speakers.

The purpose of this study was to investigate how the subjective impression of English speech would change when pause duration at punctuation marks was varied. Two listening experiments were performed in which written English speech segments were rated on a variety of evaluation items by both native-English speakers and non-native speakers (native-Chinese speakers and native-Japanese speakers). The ratings were then subjected to factor analysis. In the first experiment, the pauses in three segments were made into the same durations, from 0.075 to 4.8 s. Participants rated the segments on 23 evaluation items on a rating scale from 1 to 10. A varimax rotation after PCA (principal component analysis) led to two factors that were related to speech style. These two factors could be interpreted as representing speech naturalness and speech rate. Speech segments with a pause duration of 0.6 s received the highest naturalness evaluation, while perceived speech rate decreased as the physical pause duration increased, without any changes in utterance segments. In the second experiment, a full-factorial design of pause durations (0.15, 0.3, 0.6, 1.2, and 2.4 s) within and between sentences, i.e., for commas and for periods, was implemented in two speech segments. The original speech segments and speech segments without any pauses were also included as control conditions. From ratings on 12 evaluation items, similar to Experiment 1, two factors representing speech naturalness and speech rate were obtained. The results showed again that the perceived speech rate decreased with an increase only in pause duration. As for speech naturalness, the highest evaluations occurred when pause durations were 0.6 s within sentences, and either 0.6 or 1.2 s between sentences. This recommends fixing all pause durations to 0.6 s as a practical way to train non-native speakers to make their spoken English appear more natural.

Attention deficit hyperactivity disorder (ADHD) symptoms, comorbid psychopathology, behaviour problems and gastrointestinal symptoms in children and adolescents with autism spectrum disorder.

OBJECTIVES: The study aims to investigate attention deficit hyperactivity disorder (ADHD) symptoms, gastrointestinal (GI) symptoms, comorbid psychopathology and behaviour problems in children and adolescents with autism spectrum disorder (ASD). METHODS: Parents of 147 children and adolescents with ASD aged 6-18 years completed the Conners 3 Parent-Short Form, Gastrointestinal Symptom Inventory, Behavior Problems Inventory-Short Form and Autism Spectrum Disorder-Comorbid for Children. RESULTS: Fifty-six per cent of children and adolescents had a comorbid diagnosis of ADHD, yet over 70% presented with clinically significant ADHD symptoms. Forty per cent of participants received a diagnosis of ADHD before ASD and 25.6% received a diagnosis of ASD first. Relationships were found between ADHD symptoms and comorbid psychopathology, GI symptoms, and behaviour problems. CONCLUSIONS: The outcomes suggest that ADHD is being underestimated as a comorbid disorder of ASD. This may have implications on treatment and interventions for children and adolescents who have a diagnosis of both ASD and ADHD.

Quality of life, gastrointestinal symptoms, sleep problems, social support, and social functioning in adults with autism spectrum disorder.

BACKGROUND: The purpose of this study was to investigate the relationship between sleep problems, gastrointestinal symptoms, social functioning, autism traits, and social support on quality of life (QoL) in 107 adults with autism spectrum disorder (ASD). METHOD: Questionnaires included the Autism Spectrum Quotient-10 (Adult), Multidimensional Scale of Perceived Social Support, Social Functioning Questionnaire, Pittsburgh Sleep Quality Index, Gastrointestinal Symptom Inventory, and World Health Organization Quality of Life-BREF. RESULTS: GI symptoms were a common comorbidity with 86 % of participants presenting with them. Sleep problems were also frequent issues with 89 % of participants being classified as poor sleepers. Greater sleep problems were correlated with poorer QoL in the physical health and environment domains. Specifically, the sleep problem of daytime dysfunction was correlated with poorer QoL in physical health. Daytime dysfunction and sleep duration were correlated with poorer QoL in the environment domain. Better social support was correlated with greater QoL in the psychological, social and environment domains. Poorer social functioning was correlated with poorer QoL in each of the four domains. CONCLUSION: This research indicated that GI symptoms and sleep problems are common comorbid conditions in the adult ASD population. This paper expanded upon the existing literature by highlighting unexplored factors influencing QoL in adults with ASD.

Complex Comorbid Presentations are Associated with Harmful Behavior Problems among Children and Adolescents with Cerebral Palsy.

Aim: Frequency and relationship between gastrointestinal symptoms, sleep problems, internalizing and externalizing symptoms, behavior problems and autism spectrum disorder (ASD) symptoms, and predictors of behavior problems were examined in children and adolescents with Cerebral Palsy (CP). Method: Parents of 104 children and adolescents with CP completed the Gastrointestinal Symptom Inventory, Children's Sleep Habits Questionnaire, Child Behavior Checklist, Social Communication Questionnaire and the Behavior Problem Inventory-Short Form. Results: High frequency of behavior problems (88.5%), gastrointestinal symptoms (81.7%), sleep problems (81%) ASD symptoms (48%) and internalizing and externalizing symptoms (31.7%) were found. Relationships were found between gastrointestinal symptoms and sleep problems, and gastrointestinal symptoms and internalizing and externalizing symptoms. Relationships were found between sleep problems and behavior problems. Intellectual disability, sleep problems, internalizing and externalizing symptoms, and ASD symptoms predicted behavior problems. Conclusion: Findings highlights the frequency of comorbidities that exist in CP and how these comorbidities affect one another.

Relationship between parent-reported gastrointestinal symptoms, sleep problems, autism spectrum disorder symptoms, and behavior problems in children and adolescents with 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q) is a chromosome disorder, where a segment of chromosome 22, located at q11.2, is missing. This study aims to investigate the relationship between a number of parent-reported comorbid conditions including gastrointestinal symptoms, sleep problems, autism spectrum disorder (ASD) symptoms and behavior problems in children and adolescents with 22q deletion syndrome. METHOD: The Gastrointestinal Symptom Inventory, Children's Sleep Habits Questionnaire, Behavior Problem Inventory-Short Form and the Social Communication Questionnaire were completed by parents of 149 children and adolescents aged 3-18 years with a diagnosis of 22q. RESULTS: A series of correlations and hierarchical multiple regressions were conducted to examine the relationships between GI symptoms, sleep problems and behavior problems in children and adolescents with 22q deletion syndrome. A significant moderate relationship was found between GI symptoms and sleep problems. Gender and ASD symptoms predicted GI symptoms. Significant small relationships were found between GI symptoms and self-injurious behavior. Significant small to moderate relationships were found between sleep problems and self-injurious behavior, aggressive/destructive behavior, and sterotyped behavior. Sleep problems predicted challenging behavior. CONCLUSIONS: This research demonstrated the importance of studying the relationship between comorbidities, including gastrointestinal symptoms, sleep problems, and behavior problems and how they shape the phenotype of 22q deletion syndrome.

The Arcuate Fasciculus Network and Verbal Deficits in Psychosis.

BACKGROUND: Verbal learning (VL) and fluency (VF) are prominent cognitive deficits in psychosis, of which the precise neuroanatomical contributions are not fully understood. We investigated the arcuate fasciculus (AF) and its associated cortical regions to identify structural abnormalities contributing to these verbal impairments in early stages of psychotic illness. METHODS: Twenty-six individuals with recent-onset psychosis and 27 healthy controls underwent cognitive testing (MATRICS Consensus Cognitive Battery) and structural/diffusion-weighted MRI. Bilaterally, AF anisotropy and cortical thickness, surface area and volume of seven cortical regions were investigated in relation to VL and VF performance in both groups. RESULTS: Reduced right superior temporal gyrus surface area and volume related to better VF in controls. In psychosis, greater right pars opercularis volume and reduced left lateralization of this region related to better VL, while greater right long AF fractional anisotropy and right pars orbitalis volume related to better VF, these findings not present in controls. Psychosis had reduced right pars orbitalis thickness compared to controls. CONCLUSION: Anatomical substrates for normal processing of VL and VF appear altered in recent-onset psychosis. A possible aberrant role of the right hemisphere arcuate fasciculus and fronto-temporal cortical regions in psychosis may contribute to deficits in VL and VF.

Cognitive course in first-episode psychosis and clinical correlates: A 4 year longitudinal study using the MATRICS Consensus Cognitive Battery.

While cognitive impairments are prevalent in first-episode psychosis, the course of these deficits is not fully understood. Most deficits appear to remain stable, however there is uncertainty regarding the trajectory of specific cognitive domains after illness onset. This study investigates the longitudinal course of cognitive deficits four years after a first-episode of psychosis and the relationship of performance with clinical course and response to treatment. Twenty three individuals with psychotic illness, matched with 21 healthy volunteers, were assessed using the MATRICS Consensus Cognitive Battery at illness onset and 4 years later. We also investigated the relationship between cognitive deficits and quality of life and clinical indices. Verbal learning and two measures of processing speed had marked poorer trajectory over four years compared to the remaining cognitive domains. Processing speed performance was found to contribute to the cognitive deficits in psychosis. Poorer clinical outcome was associated with greater deficits at illness onset in reasoning and problem solving and social cognition. Cognitive deficits did not predict quality of life at follow-up, nor did diagnosis subtype differentiate cognitive performance. In conclusion, an initial psychotic episode may be associated with an additional cost on verbal learning and two measures of processing speed over a time spanning at least four years. Moreover, processing speed, which has been manipulated through intervention in previous studies, may represent a viable therapeutic target. Finally, cognition at illness onset may have a predictive capability of illness course.

Radical protection in the visible and infrared by a hyperforin-rich cream--in vivo versus ex vivo methods.

The formation of radicals plays an important role in the development of atopic eczema or barrier-disrupted skin. We evaluated the radical scavenging effect of a cream containing a Hypericum perforatum extract rich in hyperforin in a double-blind placebo-controlled study on 11 healthy volunteers. Electron paramagnetic resonance spectroscopy was applied to determine radical formation during VIS/NIR irradiation of the inner forearm. The results were compared to ex vivo investigations on excised porcine ear skin after a single application of the creams. The non-treated skin was measured as control. The absolute values and the kinetics are not comparable for ex vivo and in vivo radical formation. Whereas in vivo, the radical production decreases with time, it remains stable ex vivo over the investigated timescale. Nevertheless, ex vivo methods could be developed to estimate the protection efficiency of creams. In vivo as well as ex vivo, the radical formation could be reduced by almost 80% when applying the hyperforin-rich cream onto the skin, whereas placebo resulted in about 60%. In vivo, a daylong protection effect could be validated after a 4-week application time of the cream indicating that a regular application is necessary to obtain the full effect.