A randomised controlled feasibility trial of music-assisted language telehealth intervention for minimally verbal autistic children-the MAP study protocol.

BACKGROUND: About 30% of children with autism spectrum disorder (ASD) do not develop functional speech and remain non-verbal or minimally verbal even after years of speech, language and educational interventions. A wide range of interventions have been developed for improving communication in ASD, but none have proved effective in eliciting functional language in ASD children. Research has found that people with ASD are more likely to have perfect pitch and prefer music to language. Further, it seems that language delay tends to co-occur with better musical skills. Brain imaging research has found that music alongside words increases the attention that people with ASD pay to spoken words. METHODS: In this protocol, we describe our music-assisted programmes (MAP) that will use music to attract the attention of people with ASD to speech. MAP may open the brain pathways to language and therefore help improve communication skills for people with ASD more than standard communication protocols. In particular, we aim to develop and test whether individualised, easily used MAP would increase spoken language in 24-60-month-old, nonverbal or minimally verbal children with ASD. We will develop a structured training method, delivered through naturalistic, interactive activities (e.g. songs) to teach language to ASD children. We will test this by comparing two groups: one undertaking music-assisted programmes, and the other receiving speech and language therapy in the way that is recommended in NHS clinics. Participants will be allocated to groups randomly. The feasibility of MAP will be assessed through estimations of recruitment and retention rates, the sensitivity and reliability of the outcome measures, the intensity and frequency of the trial, the usability of the MAP app (beta version), and the burden of the assessments for the children and parents. DISCUSSION: This feasibility randomised controlled trial will establish the acceptability and estimate the power of the MAP intervention to improve early word learning in children with ASD. In the longer term, this research will help us develop an app for parents or carers of children with ASD to design their own songs and implement their own individualised MAP. TRIAL REGISTRATION: ISRCTN, ISRCTN12536062 . Registered on 26 June 2019.

Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.

OBJECTIVE: Clinical, radiologic, and molecular analysis of patients with genomic deletions upstream of the LMNB1 gene. METHODS: Detailed neurologic, MRI examinations, custom array comparative genomic hybridization (aCGH) analysis, and expression analysis were performed in patients at different clinical centers. All procedures were approved by institutional review boards of the respective institutions. RESULTS: Five patients from 3 independent families presented at ages ranging from 32 to 52 years with neurologic symptoms that included progressive hypophonia, upper and lower limb weakness and spasticity, and cerebellar dysfunction and MRIs characterized by widespread white matter alterations. Patients had unique nonrecurrent deletions upstream of the LMNB1, varying in size from 250 kb to 670 kb. Deletion junctions were embedded in repetitive elements. Expression analysis revealed increased LMNB1 expression in patient cells. CONCLUSIONS: Our findings confirmed the association between LMNB1 upstream deletions and leukodystrophy previously reported in a single family, expanding the phenotypic and molecular description of this condition. Although clinical and radiologic features overlapped with those of autosomal dominant leukodystrophy because of LMNB1 duplications, patients with deletions upstream of LMNB1 had an earlier age at symptom onset, lacked early dysautonomia, and appeared to have lesser involvement of the cerebellum and sparing of the spinal cord diameter on MRI. aCGH analysis defined a smaller minimal critical region required for disease causation and revealed that deletions occur at repetitive DNA genomic elements. Search for LMNB1 structural variants (duplications and upstream deletions) should be an integral part of the investigation of patients with autosomal dominant adult-onset leukodystrophy.

Executive Function Coaching: Assisting With Transitioning From Secondary to Postsecondary Education.

OBJECTIVE: ADHD is defined as impairment to self-regulatory behavior and executive functioning (EF). Many students with other learning disabilities (LD) also experience EF impairments. With the rising number of students with ADHD and LD enrolling in higher education, it is important to recognize the challenges these students face and to provide effective support when transitioning from secondary to postsecondary school. This article examines the challenges of the transition from secondary to postsecondary environments, specifically with the student diagnosed with ADHD and/or other LD. METHOD: Scholarly articles relating to the efficacy of EF coaching as well as students with ADHD and/or other LD transitioning from secondary to postsecondary school were examined and then considered for best practices in EF coaching. RESULTS: Although the literature supports that EF coaching can improve EF skills, there is a paucity of empirical studies that examines the efficacy of EF coaching (Franklin & Franklin, 2012). The literature also supports the use of EF coaching for students with ADHD and/or LD when transitioning from highschool to college, however limited research has been published to date. CONCLUSION: With the finite research available in the field of coaching, recommendations for future consideration and research is included to support the need for evidence-based programs. An EF coaching model at Lynn University's Institute for Achievement and Learning (IAL) is discussed and addresses how students are supported during their first year at the University.

Understanding group therapists' use of spiritual and religious interventions in group therapy.

The current study examined therapist characteristics that are related to the use of spiritual and religious interventions in group therapy and to perceived barriers to attending to spirituality in group therapy among a sample of experienced group therapists. Results demonstrated that greater therapist spirituality was associated with more frequent use of both spiritual and religious interventions, as well as lower perceived barriers to attending to spirituality in group therapy. Religious commitment was only uniquely related to perceived barriers, such that therapists with higher religious commitment actually perceived greater barriers. Training in religion and spirituality and comfort with spiritual discussions was also related to therapists' use of religious and spiritual interventions and perceived barriers.

Decreased exhaled nitric oxide levels in patients with mitochondrial disorders.

BACKGROUND: Nitric oxide (NO) deficiency may occur in mitochondrial disorders (MD) and can contribute to the pathogenesis of the disease. It is difficult and invasive to measure systemic nitric oxide. NO is formed in the lungs and can be detected in expired air. Currently, hand-held fractional exhaled nitric oxide (FeNO) measurement devices are available enabling a fast in-office analysis of this non-invasive test. It was postulated that FeNO levels might be reduced in MD. METHODS: Sixteen subjects with definite MD by modified Walker criteria (4 to 30 years of age) and sixteen healthy control subjects of similar age, race and body mass index (BMI) underwent measurement of FeNO in accordance with the American Thoracic Society guidelines. RESULTS: Sixteen patient-control pairs were recruited. The median FeNO level was 6.5 ppm (IQR: 4-9.5) and 10.5 ppm (IQR: 8-20.5) in the MD and control groups, respectively. In 13 pairs (81%), the FeNO levels were lower in the MD cases than in the matched controls (p=0.021). Eleven (69%) cases had very low FeNO levels (≤7ppm) compared to only 1 control (p=0.001). All cases with enzymatic deficiencies in complex I had FeNO ≤7ppm. CONCLUSIONS: Single-breath exhaled nitric oxide recordings were decreased in patients with MD. This pilot study suggests that hand-held FeNO measurements could be an attractive non-invasive indicator of MD. In addition, measurement of FeNO could be used as a parameter to monitor therapeutic response in this population.

Caspase 8 is absent or low in many ex vivo gliomas.

BACKGROUND: Better treatments are required urgently for patients with malignant glioma, which currently is incurable. Death ligands, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), may offer promise for the treatment high-grade glioma if such ligands induce apoptotic signaling in vivo in glioma cells. Caspase 8 is required for death ligand signaling, and its levels may influence the sensitivity of glioma cells to death ligands. It also may act as a tumor suppressor protein. The authors analyzed caspase 8 expression levels in ex vivo glioma specimens and explored potential mechanisms of its regulation. METHODS: Eleven glioblastomas, 5 anaplastic astrocytomas, and 3 low-grade astrocytomas were studied. The levels of caspase 8, caspase 10, cellular FLICE inhibitory protein (c-FLIP), and signal transducer and activator of transcription (STAT)-1 were assayed using quantitative immunoblotting. Caspase 8 mRNA was measured by Northern blot analysis. The methylation status of the caspase 8 gene was determined by bisulfate modification of genomic DNA, cloning, and sequencing. Statistical analyses were performed using nonparametric (Spearman) correlations. RESULTS: Some ex vivo glioma samples lacked detectable caspase 8, with many expressing barely detectable levels. No tumors expressed significant amounts of caspase 10 or c-FLIP. A strong association was found between caspase 8 mRNA and protein levels. Neither expression of the transcription factor STAT-1 nor caspase 8 gene methylation correlated with caspase 8 levels. CONCLUSIONS: The absence of caspase 8 protein in many resected glioma samples implied that many patients with glioma may not benefit from death ligand-based treatments, unless caspase 8 (or caspase 10) protein expression can be elevated. Demethylating agents are unlikely to boost caspase 8 levels in glioma cells, but treatments that increase caspase 8 mRNA levels may up-regulate expression of the protein.

Deletion of Vhlh in chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development.

The von Hippel Lindau tumor suppressor protein (pVHL) is a component of a ubiquitin ligase that promotes proteolysis of the transcription factor hypoxia-inducible-factor 1alpha (HIF1alpha), the key molecule in the hypoxic response. We have used conditional inactivation of murine VHL (Vhlh) in all cartilaginous elements to investigate its role in endochondral bone development. Mice lacking Vhlh in cartilage are viable, but grow slower than control littermates and develop a severe dwarfism. Morphologically, Vhlh null growth plates display a significantly reduced chondrocyte proliferation rate, increased extracellular matrix, and presence of atypical large cells within the resting zone. Furthermore, stabilization of the transcription factor HIF1alpha leads to increased expression levels of HIF1alpha target genes in Vhlh null growth plates. Lastly, newborns lacking both Vhlh and Hif1a genes in growth plate chondrocytes display essentially the same phenotype as Hif1a null single mutant mice suggesting that the Vhlh null phenotype could result, at least in part, from increased activity of accumulated HIF1alpha. This is the first study reporting the novel and intriguing findings that pVHL has a crucial role in endochondral bone development and is necessary for normal chondrocyte proliferation in vivo.

The cyclin-dependent kinase inhibitor p57(Kip2) mediates proliferative actions of PTHrP in chondrocytes.

Parathyroid hormone-related peptide (PTHrP) is a positive regulator of chondrocyte proliferation during bone development. In embryonic mice lacking PTHrP, chondrocytes stop proliferating prematurely, with accelerated differentiation. Because the bone phenotype of mice lacking the cyclin-dependent kinase inhibitor p57(Kip2) is the opposite of the PTHrP-null phenotype, we hypothesized that PTHrP's proliferative actions in chondrocytes might be mediated by opposing p57. We generated p57/PTHrP-null embryos, which showed partial rescue of the PTHrP-null phenotype. There was reversal of the loss of proliferative chondrocytes in most bones, with reversal of the accelerated differentiation that occurs in the PTHrP-null phenotype. p57 mRNA and protein were upregulated in proliferative chondrocytes in the absence of PTHrP. Metatarsal culture studies confirmed the action of PTHrP to decrease p57 mRNA and protein levels in a model in which parathyroid hormone (PTH), used as an analog of PTHrP, increased chondrocyte proliferation rate and the length of the proliferative domain. PTH treatment of p57-null metatarsals had no effect on proliferation rate in round proliferative chondrocytes but still stimulated proliferation in columnar chondrocytes. These studies suggest that the effects of PTHrP on both the rate and extent of chondrocyte proliferation are mediated, at least in part, through suppression of p57 expression.

Caspase-8 levels affect necessity for mitochondrial amplification in death ligand-induced glioma cell apoptosis.

Fifty percent of high-grade glioma patients die within a year of diagnosis and less than two percent survive five years postdiagnosis. Elucidating apoptosis signaling pathways may assist in designing better adjuvant therapies. Preliminary characterizations suggested that glioma cells may either employ mitochondrial-independent or -dependent death receptor-induced apoptotic pathways, characteristic of cells termed type I and type II, respectively. In the present study, we generated panels of clonal transfectants overexpressing various levels of Bcl-2, in two parental glioma cell lines. These cells were used to explore molecular factors determining the necessity for mitochondrial amplification of death receptor signaling. Moderate Bcl-2 expression was sufficient to render one glioma cell line (D270) resistant to apoptosis induced by Fas ligand or TRAIL, consistent with these cells being type II. However, expression of even very high levels of Bcl-2 in a second line (D645) did not affect death ligand sensitivity, indicative of a type I phenotype. D270 cells expressed much less caspase-8 protein than D645 cells. Enforced overexpression of caspase-8 (or cytoplasmic Diablo/Smac) in D270 cells overcame Bcl-2 inhibition of death ligand-induced apoptosis, converting them from type II to type I. This indicates that caspase-8 levels can influence the requirement for mitochondrial involvement in death receptor apoptotic signaling in glioma cells.