How available to European children and young people with cerebral palsy are features of their environment that they need?

Publication date: December 2017
Source:Research in Developmental Disabilities, Volume 71
Author(s): Sandra Martina Espín-Tello, Allan Colver
BackgroundThe UN Convention on the Rights of Persons with Disabilities requires accessibility to the physical and social environments. However, individuals with cerebral palsy (CP) have many difficulties in accessing the environment they need for functional independence and social inclusion.AimsTo examine the availability of environmental features which children with CP need for optimal participation, and whether availability changed for them between ages 8–12 and 13–17 years.MethodsThe sample is the 594 children with CP, born 31/07/1991–01/04/1997, who took part in the SPARCLE study at age 8–12 (SPARCLE 1) and again at 13–17 years (SPARCLE 2). Participants were randomly sampled from population registers of children with CP in eight European regions; one further region recruited from multiple sources. Data about environment were captured with the European Child Environment Questionnaire (60 items). Differences in availability of environmental features between childhood and adolescence were assessed using McNemar's test; differences between regions were assessed by ranking regions. Differences in availability between regions were assessed by ranking regions.ResultsFor seven environmental features significantly (p<0.01) fewer individuals needed the feature in SPARCLE 2 than in SPARCLE 1, whilst for two features more individuals needed the feature. Nine features in SPARCLE 1 and six features in SPARCLE 2 were available to less than half the participants who needed them. Eight features showed significantly (p<0.01) higher availability in SPARCLE 2 than in SPARCLE 1 (enlarged rooms, adapted toilet, modified kitchen and hoists at home, adapted toilets and lifts at school, an adequate vehicle, grants for home modifications) while none showed significantly lower availability. The relative rankings of the better and less good regions persisted from the age 8–12year age group to the 13–17year age group.ConclusionsNeeded environmental features are unavailable to many children at ages 8–12 and 13–17 years. This lack of availability is more pronounced in some regions than others, which probably results from their policy, legislative and statutory frameworks.



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The bouba-kiki effect and its relation to the Autism Quotient (AQ) in autistic adolescents

Publication date: December 2017
Source:Research in Developmental Disabilities, Volume 71
Author(s): Rinat Gold, Osnat Segal
The bouba-kiki effect refers to the correspondence between arbitrary visual and auditory stimuli. Previous studies indicate ASD persons' reduced bouba-kiki effect compared to controls.This study examines the relation between ASD symptomology and performance on the bouba-kiki task. Twenty ASD participants and 20 matched controls were presented the bouba-kiki task. Autism-Quotient (AQ) scores and several cognitive measures were obtained for all participants. Results demonstrate that among all measures, only AQ scores were significantly correlated to the performance on the bouba-kiki task in the ASD group.Results thus support the existence of a relation between autism symptoms and performance on the bouba-kiki task, and are discussed in light of current theories.



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The effect of asymmetrical limited hip flexion on seating posture, scoliosis and windswept hip distortion

Publication date: December 2017
Source:Research in Developmental Disabilities, Volume 71
Author(s): Atli Ágústsson, Þórarinn Sveinsson, Elisabet Rodby-Bousquet
BackgroundPostural asymmetries with seating problems are common in adults with cerebral palsy.AimsTo analyse the prevalence of asymmetrical limited hip flexion (<90°) in adults with CP, and to evaluate the association between asymmetrical limited hip flexion and postural asymmetries in the sitting position.Methods and proceduresCross-sectional data of 714 adults with CP, 16–73 years, GMFCS level I–V, reported to CPUP, the Swedish cerebral palsy national surveillance program and quality registry, from 2013 to 2015. Hip range of motion was analysed in relation to pelvic obliquity, trunk asymmetry, weight distribution, scoliosis and windswept hip distortion.Outcomes and resultsThe prevalence of asymmetrical limited hip flexion increased as GMFCS level decreased. Of adults at GMFCS level V, 22% had asymmetrical limited hip flexion (<90°). The odds of having an oblique pelvis (OR 2.6, 95% CI:1.6–2.1), an asymmetrical trunk (OR 2.1, 95% CI:1.1–4.2), scoliosis (OR 3.7, 95% CI:1.3–9.7), and windswept hip distortion (OR 2.6, 95% CI:1.2–5.4) were higher for adults with asymmetrical limited hip flexion compared with those with bilateral hip flexion>90°.Conclusions and implicationsAsymmetrical limited hip flexion affects the seating posture and is associated with scoliosis and windswept hip distortion.



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Effectiveness of cognitive orientation to (daily) occupational performance (CO-OP) on children with cerebral palsy: A mixed design

Publication date: December 2017
Source:Research in Developmental Disabilities, Volume 71
Author(s): Neda Ghorbani, Mehdi Rassafiani, Sara Izadi-Najafabadi, Farzaneh Yazdani, Nazila Akbarfahimi, Naser Havaei, Soraya Gharebaghy
BackgroundCerebral palsy (CP) is the most common cause of physical disabilities during childhood. Therapeutic interventions mainly focus on impairment reduction to address motor-based difficulties. In contrast, Cognitive Orientation to daily Occupational Performance (CO-OP) is a cognitive approach, providing intervention at the level of activity and participation.AimsThis study aims to determine whether the CO-OP approach improves motor skills and achievement in motor-based occupational performance goals in children with CP.Methods and proceduresIn this mixed design research (i.e., a multiple baseline single case experimental design and a one-group pretest-posttest design), five children with CP participated in 12 CO-OP intervention sessions. Repeated measures of motor skills for the multiple baseline single case experimental design were taken using the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP); pre- and post-measures of parent/child perception of performance and satisfaction were identified using the Canadian Occupational Performance Measure (COPM); level of achievement was identified using Goal Attainment Scaling (GAS).Outcomes and resultsAccording to the BOTMP results, all children were able to engage in the CO-OP intervention to improve motor performance. Significant differences after treatment were found in both performance and performance satisfaction ratings using the COPM as rated by parents and children. The GAS results showed progress in achievement levels for all children; all goals were achieved or exceeded.Conclusions and implicationsCO-OP intervention can be helpful in improving motor skills and achieving self-identified, motor-based goals in children with CP.



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An evaluation of the production effects of video self-modeling

Publication date: December 2017
Source:Research in Developmental Disabilities, Volume 71
Author(s): Roderick D. O'Handley, Keith D. Allen
A multiple baseline across tasks design was used to evaluate the production effects of video self-modeling on three activities of daily living tasks of an adult male with Autism Spectrum Disorder and Intellectual Disability. Results indicated large increases in task accuracy after the production of a self-modeling video for each task, but before the video was viewed by the participant. Results also indicated small increases when the participant was directed to view the same video self-models before being prompted to complete each task.



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IFC-EDITORIAL BOARD

Publication date: December 2017
Source:Research in Developmental Disabilities, Volume 71





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Best seating condition in children with spastic cerebral palsy: One type does not fit all

Publication date: December 2017
Source:Research in Developmental Disabilities, Volume 71
Author(s): Mattana Angsupaisal, Linze-Jaap Dijkstra, Sacha la Bastide-van Gemert, Jessika F. van Hoorn, Karine Burger, Carel G.B. Maathuis, Mijna Hadders-Algra
BackgroundThe effect of forward-tilting of the seat surface and foot-support in children with spastic cerebral palsy (CP) is debated.AimTo assess the effect of forward-tilting of the seat surface and foot-support in children with CP on kinematic head stability and reaching.MethodsNineteen children functioning at Gross Motor Function Classification System levels I–III participated [range 6–12y; ten unilateral spastic CP (US-CP) and nine bilateral spastic CP (BS-CP)]. Kinematic data were recorded of head sway and reaching with the dominant arm in four sitting conditions: a horizontal and a 15° forward (FW) tilted seat surface, each with and without foot-support.ResultsSeating condition did not affect head stability during reaching, but did affect kinematic reaching quality. The major reaching parameters, i.e., the proportion of reaches with one movement unit (MU) and the size of the transport MU, were not affected by foot-support. Forward-tilting had a positive effect on these parameters in children with US-CP, whereas the horizontal condition had this effect in children with BS-CP.ImplicationsA 15° forward-tilted seating and foot-support do not affect head stability. Reaching in children with US-CP profits from forward-tilting; in children with BS-CP forward-tilting worsens reaching − effects that are independent of foot-support.



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Survival benefit of postoperative radiation in papillary meningioma: Analysis of the National Cancer Data Base

Publication date: November–December 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 6
Author(s): Whitney A. Sumner, Arya Amini, Todd C. Hankinson, Nicholas K. Foreman, Laurie E. Gaspar, Brian D. Kavanagh, Sana D. Karam, Chad G. Rusthoven, Arthur K. Liu
Aim/BackgroundPapillary meningioma represents a rare subset of World Health Organization (WHO) Grade III meningioma that portends an overall poor prognosis. There is relatively limited data regarding the benefit of postoperative radiation therapy (PORT). We used the National Cancer Data Base (NCDB) to compare overall survival (OS) outcomes of surgically resected papillary meningioma cases undergoing PORT compared to post-operative observation.Materials and methodsThe NCDB was queried for patients with papillary meningioma, diagnosed between 2004 and 2013, who underwent upfront surgery with or without PORT. Overall survival (OS) was determined using the Kaplan–Meier method. Univariate (UVA) and multivariate (MVA) analyses were performed.ResultsIn total, 190 patients were identified; 89 patients underwent PORT, 101 patients were observed. Eleven patients received chemotherapy (6 with PORT, 5 without). 2-Year OS was significantly improved with PORT vs. no PORT (93.0% vs. 74.4%), as was 5-year OS (78.5% vs. 62.5%) (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.27–0.85; p=0.01). On MVA, patients receiving PORT had improved OS compared to observation (HR, 0.41; 95% CI, 0.22–0.76; p=0.005). On subset analysis by age group, the benefit of PORT vs. no PORT was significant in patients ≤18 years (n=13), with 2-year OS of 85.7% vs. 50.0% (HR, 0.08; 95% CI, 0.01–0.80; p=0.032) and for patients >18 years (n=184), with 2-year OS of 94.7% vs. 76.1% (HR, 0.55; 95% CI, 0.31–1.00; p=0.049), respectively.ConclusionsIn this large contemporary analysis, PORT was associated with improved survival for both adult and pediatric patients with papillary meningioma. PORT should be considered in those who present with this rare, aggressive tumor.



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Structural insights into the interaction of a monoclonal antibody and Nodal peptides by STD-NMR spectroscopy

Publication date: Available online 28 October 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Luisa Calvanese, Annalia Focà, Annamaria Sandomenico, Giuseppina Focà, Andrea Caporale, Nunzianna Doti, Emanuela Iaccarino, Antonio Leonardi, Gabriella D'Auria, Menotti Ruvo, Lucia Falcigno
Nodal is a growth factor expressed during early embryonic development, but reactivated in several advanced-stage cancers. Targeting of Nodal signaling, which occurs via the binding to Cripto-1 co-receptor, results in inhibition of cell aggressiveness and reduced tumor growth. The Nodal binding region to Cripto-1 was identified and targeted with a high affinity monoclonal antibody (3D1).By STD-NMR technique, we investigated the interaction of Nodal fragments with 3D1 with the aim to elucidate at atomic level the interaction surface.Data indicate with high accuracy the antibody-antigen contact atoms and confirm the information previously obtained by immune-enzymatic methods. Main residues contacted by 3D1 are P46, V47, E49 and E50, which belong to the Nodal loop involved in the interaction with the co-receptor.

Graphical abstract

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Bioactive natural products

Publication date: 15 November 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
Author(s): Mathias Christmann




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Natural products and morphogenic activity of γ-Proteobacteria associated with the marine hydroid polyp Hydractinia echinata

Publication date: 15 November 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
Author(s): Huijuan Guo, Maja Rischer, Martin Sperfeld, Christiane Weigel, Klaus Dieter Menzel, Jon Clardy, Christine Beemelmanns
Illumina 16S rRNA gene sequencing was used to profile the associated bacterial community of the marine hydroid Hydractinia echinata, a long-standing model system in developmental biology. 56 associated bacteria were isolated and evaluated for their antimicrobial activity. Three strains were selected for further in-depth chemical analysis leading to the identification of 17 natural products. Several γ-Proteobacteria were found to induce settlement of the motile larvae, but only six isolates induced the metamorphosis to the primary polyp stage within 24h. Our study paves the way to better understand how bacterial partners contribute to protection, homeostasis and propagation of the hydroid polyp.

Graphical abstract

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Editorial board

Publication date: 15 November 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22





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Anti-tuberculosis activity and structure–activity relationships of oxygenated tricyclic carbazole alkaloids and synthetic derivatives

Publication date: 15 November 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
Author(s): Carsten Börger, Christian Brütting, Konstanze K. Julich-Gruner, Ronny Hesse, V. Pavan Kumar, Sebastian K. Kutz, Marika Rönnefahrt, Claudia Thomas, Baojie Wan, Scott G. Franzblau, Hans-Joachim Knölker
A series of 49 oxygenated tricyclic carbazole derivatives has been tested for inhibition of the growth of Mycobacterium tuberculosis and a mammalian cell line (vero cells). From this series, twelve carbazoles showed a significant anti-TB activity. The four most active compounds were the naturally occurring carbazole alkaloids clauszoline-M (45), murrayaline-C (41), carbalexin-C (27), and the synthetic carbazole derivative 22 with MIC90 values ranging from 1.5 to 3.7μM. The active compounds were virtually nontoxic for the mammalian cell line in the concentration range up to 50μM.

Graphical abstract

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Heterocycles: versatile control elements in bioactive macrocycles

Publication date: Available online 27 October 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Harjeet S. Soor, Solomon D. Appavoo, Andrei K. Yudin
The potential of macrocyclic peptides as therapeutics has garnered much attention over the last several years. Unlike their linear counterparts, macrocycles have higher resistance to enzymatic degradation and often display improved bioavailability. However, macrocycles are typically not lipophilic enough for cellular membrane penetration, which prevents them from interacting with intracellular targets. Methods to increase cellular permeability have involved the incorporation of bicyclic scaffolds, D-amino acids and N-methylation of amides. These modifications exert their effect through conformational control of macrocycles and have been well studied in the literature. In contrast, the structural consequences of heterocycle incorporation into macrocyclic rings has not been as exhaustively investigated. In this mini-review we discuss key examples in which heterocycles influence the conformational stability and other properties of macrocycles.

Graphical abstract

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Tumour Lateralization in Cushing's disease by Inferior Petrosal Sinus Sampling with desmopressin

Abstract

Background

Bilateral inferior petrosal sinus sampling (IPSS) with corticotropin-releasing hormone (CRH) is currently the gold standard in the diagnosis of Cushing's disease (CD) and has also been used in tumour lateralization. Our objective was to determine the diagnostic value and lateralization accuracy of IPSS with desmopressin.

Methods

We retrospectively analyzed 91 patients with Cushing's syndrome who had either negative findings on pituitary dynamic enhanced magnetic resonance imaging (MRI) or non-suppressed high dose dexamethasone suppression tests (HDDST). Thin-slice thoracoabdominal computed tomography (CT) and octreotide receptor imaging of whole body were also negative to rule out ectopic adrenocorticotropin hormone (ACTH) syndrome. All patients went through IPSS with desmopressin. Afterwards, transsphenoidal pituitary surgery, light microscope pathology and immunohistological staining for ACTH were performed in all patients.

Results

1. Diagnosis of CD. Among the 91 patients included, 90 were confirmed with CD, of whom 89 had positive IPSS findings, therefore the sensitivity was 98.9%. The one patient who was negative for CD also had negative IPSS findings, therefore the specificity was 100%. 2. Tumour lateralization. Among the 51 patients who were ultimately diagnosed with CD and whose lateralization by IPSS and surgery was either left or right, 37 had IPSS lateralization in concordance with surgery, therefore the concordance rate was 72.5%. Patients in the concordant group had a higher frequency of right lateralization by surgery.

Conclusions

IPSS with desmopressin is a sensitive approach in the diagnosis of CD and has moderate accuracy in tumour lateralization, making it an alternative choice to IPSS with CRH.

This article is protected by copyright. All rights reserved.

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Combination chemotherapy with irinotecan and gemcitabine for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancer: a multicenter phase I/II trial (GOGO-Ov 6)

Abstract

Purpose

To develop a new therapeutic strategy for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers, we evaluated the feasibility and efficacy of irinotecan and gemcitabine combination chemotherapy.

Methods

Patients with taxane/platinum-resistant/refractory cancer received escalating doses of irinotecan and gemcitabine (level 1: 80 and 800 mg/m², respectively; level 2: 100 and 1000 mg/m²) on days 1 and 8 on a 21-day cycle. Genotyping for UGT1A1*6 and *28 polymorphisms was performed for possible adverse irinotecan sensitivity.

Results

A total of 35 patients were enrolled. The recommended dose was defined as 100 mg/m² irinotecan and 1000 mg/m² gemcitabine (level 2). The observed common grade 3/4 toxicities were neutropenia (60%), anemia (17.1%), diarrhea (8.6%), thrombocytopenia (5.7%) and nausea (5.7%). Groups homozygous for UGT1A1*6 or *28 were associated with grade 3/4 neutropenia and diarrhea. Objective responses were 20%, including one complete response and six partial responses. In 29 patients treated with the recommended dose, the median progression-free survival and overall survival were 3.8 months (95% CI 2.1–6.0 months) and 17.4 months (95% CI 9.9–21.9 months), respectively, while the 1-year survival rate was 58.6%.

Conclusions

Combination chemotherapy with irinotecan and gemcitabine represents a safe and effective treatment combination for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers.

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Apoptosis during arenavirus infection: mechanisms and evasion strategies

Publication date: Available online 28 October 2017
Source:Microbes and Infection
Author(s): Bjoern Meyer, Allison Groseth
In recent years there has been a greatly increased interest in the interactions of arenaviruses with the apoptotic machinery, and particularly the extent to which these interactions may be an important contributor to pathogenesis. Here we summarize the current state of our knowledge on this subject and address the potential for interplay with other immunological mechanisms known to be regulated by these viruses. We also compare and contrast what is known for arenavirus-induced apoptosis with observations from other segmented hemorrhagic fever viruses.



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Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study

Abstract

Purpose

Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects.

Methods

Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted.

Results

No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10 ms at all timepoints and at supratherapeutic C _max. Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful.

Conclusions

Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval.

Clinicaltrials.gov

NCT02271438.

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Epidermal growth factor receptor mutation predicts favorable outcomes in non-small cell lung cancer patients with brain metastases treated with stereotactic radiosurgery

Publication date: Available online 27 October 2017
Source:Radiotherapy and Oncology
Author(s): Wen-Chi Yang, Furen Xiao, Jin-Yuan Shih, Chao-Chi Ho, Ya-Fang Chen, Ham-Min Tseng, Kuan-Yu Chen, Wei-Yu Liao, Chong-Jen Yu, James Chih-Hsin Yang, Sung-Hsin Kuo, Jason Chia-Hsien Cheng, Pan-Chyr Yang, Feng-Ming Hsu
PurposeThe impact of epidermal growth factor receptor (EGFR) mutations on radiotherapy for brain metastases (BM) is undetermined. We evaluated the effects of EGFR mutation status on responses and outcomes in non-small cell lung cancer (NSCLC) patients with BM, treated with upfront or salvage stereotactic radiosurgery (SRS).Methods and materialsFrom 2008 to 2015, 147 eligible NSCLC patients with 300 lesions were retrospectively analyzed. Patterns of tyrosine kinase inhibitor (TKI) therapy were recorded. Radiographic response was assessed. Brain progression-free survival (BPFS) and overall survival were calculated and outcome prognostic factors were evaluated.ResultsMedian follow-up time was 13.5 months. Of the EGFR-genotyped patients, 79 (65%) were EGFR mutants, and 42 (35%) were wild type. Presence of EGFR mutations was associated with higher radiographic complete response rates (CRR). Median time to develop new BM after SRS was significantly longer for mutant-EGFR patients (17 versus 10.5 months, p = 0.02), predominantly for those with adjuvant TKI therapy (26.3 versus 15 months, p = 0.01). EGFR mutations independently predicted better BPFS (HR = 0.55, p = 0.048) in multivariate analysis.ConclusionsIn patients with NSCLC treated with SRS for BM, the presence of EGFR mutations is associated with a higher CRR, longer time for distant brain control, and better BPFS. The combination of SRS and TKI in selective patient group can be an effective treatment choice for BM with favorable brain control and little neurotoxicity.



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Nutritional counseling with or without systematic use of oral nutritional supplements in head and neck cancer patients undergoing radiotherapy

Publication date: Available online 27 October 2017
Source:Radiotherapy and Oncology
Author(s): Emanuele Cereda, Silvia Cappello, Sara Colombo, Catherine Klersy, Ilaria Imarisio, Annalisa Turri, Marilisa Caraccia, Valeria Borioli, Teresa Monaco, Marco Benazzo, Paolo Pedrazzoli, Franco Corbella, Riccardo Caccialanza
BackgroundTo evaluate the benefit of oral nutritional supplements (ONS) in addition to nutritional counseling in head and neck cancer (HNC) patients undergoing radiotherapy (RT).MethodsIn a single-center, randomized, pragmatic, parallel-group controlled trial (ClinicalTrials.gov: NCT02055833; February 2014–August 2016), 159 newly diagnosed HNC patients suitable for to RT regardless of previous surgery and induction chemotherapy were randomly assigned to nutritional counseling in combination with ONS (N = 78) or without ONS (N = 81) from the start of RT and continuing for up to 3 months after its end.Primary endpoint was the change in body weight at the end of RT. Secondary endpoints included changes in protein-calorie intake, muscle strength, phase angle and quality of life and anti-cancer treatment tolerance.ResultsIn patients with the primary endpoint assessed (modified intention-to-treat population), counseling plus ONS (N = 67) resulted in smaller loss of body weight than nutritional counseling alone (N = 69; mean difference, 1.6 kg [95%CI, 0.5–2.7]; P = 0.006). Imputation of missing outcomes provided consistent findings. In the ONS-supplemented group, higher protein-calorie intake and improvement in quality of life over time were also observed (P < 0.001 for all). The use of ONS reduced the need for changes in scheduled anti-cancer treatments (i.e. for RT and/or systemic treatment dose reduction or complete suspension, HR=0.40 [95%CI, 0.18–0.91], P = 0.029).ConclusionIn HNC patients undergoing RT or RT plus systemic treatment, and receiving nutritional counseling, the use of ONS resulted in better weight maintenance, increased protein-calorie intake, improved quality of life and was associated with better anti-cancer treatment tolerance.



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