A Road Less Travelled: using Experience Based Co-Design to map children's and families' emotional journey following burn injury and identify service improvements.

BACKGROUND: The emotional impact after a child's burn injury is poorly understood. Greater insight into the emotional journey can aid services' ability to meet patients/families' needs. To bridge the gap, this study employed an abbreviated form of Experience Based Co-Design (EBCD) to explore the emotional/experiential aspects of moderate to severe burn injuries in children. METHOD: Following EBCD, parents and health professionals were invited to share their experiences. Interviews were analysed and a short film was produced and shown at a focus group event for health professionals and families. Both positive and negative aspects of the journey were identified along with potential service improvements. RESULTS: Families' journeys could be described by the following five distinct phases: life overturned, dawning reality, riding the emotional roller-coaster, aftershocks and, adapting to a new normal. Key areas for improvements were: communication, isolation, dressing changes and managing expectations. DISCUSSION: EBCD facilitated collaborative discussion between researchers, families and health professionals. Families felt empowered to shape the future of burn care and health professionals felt included. Study challenges were mainly in participant engagement and the scheduling of interviews and the focus event. Overall the study outcome was successful in generating ideas for service improvements, and the production of a training video for healthcare professionals.

Lamotrigine induced lymphadenopathy: Case report and literature review.

Lamotrigine is an anti-epileptic drug often prescribed to children and young females. Side effects include rash, dizziness and diplopia. Over the last twenty years, two cases of lymphadenopathy due to lamotrigine have been reported. We will present the case of a 17-year old female with persistent lymphadenopathy due to lamotrigine. The purpose of this case report is to inform clinicians that lymphadenopathy is a possible side effect of lamotrigine and to highlight the need for further research.

Activation of ß-catenin/TCF targets following loss of the tumor suppressor SNF5.

The SWI/SNF chromatin remodeling complex is a master regulator of developmental cell-fate decisions, although the key target pathways are poorly characterized. Here, we interrogated the contribution of the SWI/SNF subunit and tumor suppressor SNF5 to the regulation of developmental pathways using conditional mouse and cell culture models. We find that loss of SNF5 phenocopies ß-catenin hyperactivation and that SNF5 is essential for regulating Wnt/ß-catenin pathway target expression. These data provide insight into chromatin-based mechanisms that underlie developmental regulation and elucidate the emerging theme that mutation of this tumor suppressor complex can activate developmental pathways by uncoupling them from upstream control.

Moyamoya following cranial irradiation for primary brain tumors in children.

OBJECTIVE: To study the risk factors for the development of moyamoya syndrome after cranial irradiation for primary brain tumors in children. METHODS: We reviewed neuroimaging studies and dosimetry data for 456 children who were treated with radiation for a primary brain tumor and who were prospectively evaluated with serial neuroimaging studies and neurologic evaluations. A total of 345 patients had both adequate neuroimaging and radiation dosimetry data for further analysis. We used survival analysis techniques to examine the relationship of clinically important variables as risk factors for the development of moyamoya over time. RESULTS: Overall, 12 patients (3.5%) developed evidence of moyamoya. The onset of moyamoya was more rapid for patients with neurofibromatosis type 1 (NF1) (median of 38 vs 55 months) and for patients who received >5,000 cGy of radiation (median of 42 vs 67 months). In a multiple Cox proportional hazards regression analysis controlling for age at start of radiation, each 100-cGy increase in radiation dose increased the rate of moyamoya by 7% (hazard ratio [HR] = 1.07, 95% CI: 1.02 to 1.13, p = 0.01) and the presence of NF1 increased the rate of moyamoya threefold (HR = 3.07, 95% CI: 0.90 to 10.46, p = 0.07). CONCLUSIONS: Moyamoya syndrome is a potentially serious complication of cranial irradiation in children, particularly for those patients with tumors in close proximity to the circle of Willis, such as optic pathway glioma. Patients who received higher doses of radiation to the circle of Willis and with neurofibromatosis type 1 have increased risk of the development of moyamoya syndrome.

Children with headache suspected of having a brain tumor: a cost-effectiveness analysis of diagnostic strategies.

OBJECTIVE: To assess the clinical and economic consequences of 3 diagnostic strategies-magnetic resonance imaging (MRI), computed tomography followed by MRI for positive results (CT-MRI), and no neuroimaging with close clinical follow-up-in the evaluation of children with headache suspected of having a brain tumor. Three risk groups based on clinical variables were evaluated. MATERIALS AND METHODS: A decision-analytic Markov model and cost-effectiveness analysis was performed incorporating the risk group prior probability, MRI and CT sensitivity and specificity, tumor survival, progression rates, and cost per strategy. Outcomes were based on quality-adjusted life year (QALY) gained and incremental cost per QALY gained. RESULTS: For low-risk children with chronic nonmigraine headaches of >6 months' duration as the sole symptom (prior probability of brain tumor 0.01%), no neuroimaging with close clinical follow-up was less costly and more effective than the 2 neuroimaging strategies. For the intermediate-risk children with migraine headache and normal neurologic examination (prior probability of brain tumor 0.4%), CT-MRI was the most effective strategy but cost >$1 million per QALY gained compared with no neuroimaging. For high-risk children with headache of <6 months' duration and other clinical predictors of a brain tumor such as an abnormal neurologic examination (prior probability of brain tumor 4%), the most effective strategy was MRI, with cost-effectiveness ratio of $113 800 per QALY gained compared with no imaging. CONCLUSION: Our analysis suggests that MRI maximizes QALY gained at a reasonable cost-effectiveness ratio in children with headache at high risk of having a brain tumor. Conversely, the strategy of no imaging with close clinical follow-up is cost saving in low-risk children. Although the CT-MRI strategy maximizes QALY gained in the intermediate-risk patients, its additional cost per QALY gained is high. In children with headache, appropriate selection of patients and diagnostic strategy may maximize quality-adjusted life expectancy and decrease costs of medical workup.

Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas.

Pheochromocytomas are neural crest-derived tumors that occur mostly sporadically, but may also be part of inherited syndromes. The molecular pathogenesis of sporadic pheochromocytomas remains unknown. Recently, the susceptibility gene for familial paraganglioma syndrome, a disorder embryologically related to pheochromocytomas, was characterized and shown to encode the small subunit of succinate dehydrogenase (SDHD), which is part of the mitochondrial complex II. This complex regulates oxygen-sensing signals. Importantly, hypoxic signals also appear to be related to the pathogenesis of pheochromocytomas associated with von Hippel-Lindau syndrome. We sequenced the entire coding region of the SDHD gene in a series of pheochromocytomas. Although we did not find mutations in the gene, we identified a new intronic single nucleotide polymorphism in 15% of the samples (g.97739A-->G). We also confirmed the existence of a sequence highly homologous to the SDHD complementary DNA in chromosome 1p34--36, a region commonly deleted in pheochromocytomas. Full analysis of this sequence revealed a heterozygous single base substitution in 70% of our samples that was also present in the germline. This sequence does not appear to be transcribed and is probably a processed pseudogene. Therefore, despite its chromosomal location, it is unlikely that this sequence is a target of loss of heterozygosity in pheochromocytomas. In conclusion, mutations of the SDHD gene are not a common event in this series of sporadic pheochromocytomas. The existence of SDHD pseudogenes should be considered when analyzing complementary DNA-based samples.

Post-prandial remnant lipids impair arterial compliance.

OBJECTIVES: We sought to examine the effects of plasma lipids, especially in remnants after a fat meal, on systemic arterial compliance (SAC), a newly recognized cardiovascular risk factor. BACKGROUND: Post-prandial remnants correlate with coronary heart disease events through mechanisms that may include vascular dysfunction, although the effect on SAC has not been studied. METHODS: Systemic arterial compliance was measured non-invasively over 6 h after a fat meal in 16 subjects with varying plasma triglyceride levels. Changes were related to rises in plasma lipids and remnant lipids. Systemic arterial compliance was measured in 20 subjects after a control low-fat meal. RESULTS: The fat meal induced increments in plasma triglyceride and remnant cholesterol and triglyceride (respectively +54%, 50% and 290% at 3 h, analysis of variance <0.001). Systemic arterial compliance fell at 3 h and 6 h by 25% and 27% (analysis of variance <0.001). Baseline SAC correlated significantly with all lipid concentrations at 0, 3 h and 6 h, but only with triglyceride on stepwise regression analysis. The SAC response to the low-fat meal was very small and not significant. CONCLUSIONS: This is the first demonstration of SAC becoming impaired after a fat meal. Remnant lipids and plasma total triglyceride appeared to contribute to the fall in SAC.

Memory deficits among children with craniopharyngiomas.

OBJECTIVE: To describe neuropsychological functioning (with a specific focus on cognition and memory) after surgical treatment of craniopharyngiomas. METHODS: Sixteen patients who were between 6 and 15 years of age at the time of surgery comprised the sample. Each child had been treated for a craniopharyngioma with surgery only, on Dana-Farber Cancer Institute Protocol 92-077. RESULTS: The overall level of cognitive functioning was well within the average range, with both language and visuospatial functioning being generally intact; however, specific memory problems, in both the language and visuospatial domains, were evident. CONCLUSION: Although general cognitive functioning was intact after the surgical treatment of craniopharyngiomas, difficulties in the retrieval of learned information were observed. Neuropsychological assessments, with a focus on memory recall, should be a component of the medical management plan for each child.

Cholesterol-lowering effects of plant sterol esters and non-esterified stanols in margarine, butter and low-fat foods.

OBJECTIVES: To determine the efficacy on plasma cholesterol-lowering of plant sterol esters or non-esterified stanols eaten within low-fat foods as well as margarine. DESIGN: Randomised, controlled, single-blind study with sterol esters and non-esterified plant stanols provided in breakfast cereal, bread and spreads. Study 1 comprised 12 weeks during which sterol esters (2.4 g) and stanol (2.4 g)-containing foods were eaten during 4 week test periods of cross-over design following a 4 week control food period. In Study 2, in a random order cross-over design, a 50% dairy fat spread with or without 2.4 g sterol esters daily was tested. SUBJECTS: Hypercholesterolaemic subjects; 22 in study 1 and 15 in study 2. MAIN OUTCOME MEASURES: Plasma lipids, plasma sterols, plasma carotenoids and tocopherols. RESULTS: Study 1-median LDL cholesterol was reduced by the sterol esters (-13.6%; P<0.001 by ANOVA on ranks; P<0.05 by pairwise comparison) and by stanols (-8.3%; P=0.003, ANOVA and <0.05 pairwise comparison). With sterol esters plasma plant sterol levels rose (35% for sitosterol, 51% for campesterol; P<0.001); plasma lathosterol rose 20% (P=0.03), indicating compensatory increased cholesterol synthesis. With stanols, plasma sitosterol fell 22% (P=0.004), indicating less cholesterol absorption. None of the four carotenoids measured in plasma changed significantly. In study 2, median LDL cholesterol rose 6.5% with dairy spread and fell 12.2% with the sitosterol ester fortified spread (P=0.03 ANOVA and <5% pairwise comparison). CONCLUSION: 1. Plant sterol esters and non-esterified stanols, two-thirds of which were incorporated into low-fat foods, contributed effectively to LDL cholesterol lowering, extending the range of potential foods. 2. The LDL cholesterol-raising effect of butter fat could be countered by including sterol esters. 3. Plasma carotenoids and tocopherols were not reduced in this study. SPONSORSHIP: Meadow Lea Foods, Australia.

Neurological dysfunction associated with postoperative cerebellar mutism.

BACKGROUND AND OBJECTIVES: The postoperative cerebellar mutism syndrome (CMS) is an unique acute postoperative complication characterized by transient decrease in speech output (often mutism), apathy, irritability as well as global cerebellar dysfunction. As much as 25% of patients undergoing a resection of a cerebellar or IV ventricular tumor may develop such a syndrome. In this retrospective study we characterize the clinical features of the CMS and explore potential etiologic mechanisms. METHODS: We conducted a retrospective analysis of medical records and imaging tests of 8 consecutive patients with the CMS identified through the database of the Children's Hospital and Dana-Farber Cancer Institute, Boston, and compared with a control group of 8 unaffected children undergoing a comparable tumor resection. RESULTS: In contrast to the control group, children in the affected group had marked decrease in speech output and comprehension, apathy and lack of initiative, inattention, persistent eye closure, flaccid hemiparesis and a severe global cerebellar dysfunction. Swallowing difficulties and bowel and bladder dysfunction were also observed. The median duration of the syndrome as judged by the persistence of the communication abnormalities was 4 weeks. The recovery was near complete with exception for a persistent global cerebellar dysfunction. A comparison of CT and MRI scans of children in both groups failed to identify distinguishing features. CONCLUSION: A surgical lesion of the midline cerebellum can cause a complex neurological dysfunction such as the CMS. Thus, we postulate that the cerebellum and its connections function as a 'modulatory system' in control of both motor and non-motor functions, including attention and language.

The effects of dietary supplementation with isoflavones from red clover on the lipoprotein profiles of post menopausal women with mild to moderate hypercholesterolaemia.

The effects of dietary isoflavone supplementation using a purified extract of red clover containing approximately biochanin A 26 mg, formononetin 16 mg, daidzein 0.5 mg and genistein 1 mg per tablet at doses of one or two tablets per day were compared to placebo in a three-period, randomised, double blind, ascending dose study in 66 post menopausal women with plasma cholesterol levels between 5.0 and 9.0 mmol/l. Each treatment period lasted 4 weeks and a further nine women received placebo for the full 12-week period. All women consumed a low isoflavone diet for 2 weeks preceding the commencement of the study and for the 12-week study period. Urinary isoflavone excretion was very low in subjects receiving placebo but increased in a dose-dependent manner during therapy with one and two of isoflavone tablets. Dietary supplementation with isoflavones did not significantly alter total plasma cholesterol, LDL cholesterol, HDL cholesterol or plasma triglyceride levels. However, inverse correlations were found between urinary genistein excretion and plasma triglyceride levels and between urinary O-DMA excretion (an isoflavone metabolite) and plasma triglyceride levels in subjects receiving one isoflavone tablet, suggesting a weak relationship between isoflavone intake and plasma triglycerides which may be influenced by individual differences in isoflavone absorption or metabolism. The results suggest that isoflavone phytoestrogens from red clover in the proportions and quantities studied do not significantly alter plasma lipids in post menopausal women with moderately elevated plasma cholesterol levels.

Circulating serpin tumor markers SCCA1 and SCCA2 are not actively secreted but reside in the cytosol of squamous carcinoma cells.

An elevation in the circulating level of the squamous-cell carcinoma antigen (SCCA) can be a poor prognostic indicator in certain types of squamous-cell cancers. Total SCCA in the circulation comprises 2 nearly identical, approximately 45 kDa proteins, SCCA1 and SCCA2. Both proteins are members of the high-molecular weight serine proteinase inhibitor (serpin) family with SCCA1 paradoxically inhibiting lysosomal cysteine proteinases and SCCA2 inhibiting chymotrypsin-like serine proteinases. Although SCCA1 and SCCA2 are detected in the cytoplasm of normal squamous epithelial cells, neither serpin is detected normally in the serum. Thus, their presence in the circulation at relatively high concentrations suggests that malignant epithelial cells are re-directing serpin activity to the fluid phase via an active secretory process. Because serpins typically inhibit their targets by binding at 1:1 stoichiometry, a change in the distribution pattern of SCCA1 and SCCA2 (i.e., intracellular to extracellular) could indicate the need of tumor cells to neutralize harmful extracellular proteinases. The purpose of our study was to determine experimentally the fate of SCCA1 and SCCA2 in squamous carcinoma cells. Using subcellular fractionation, SCCA-green fluorescent fusion protein expression and confocal microscopy, SCCA1 and SCCA2 were found exclusively in the cytosol and were not associated with nuclei, mitochondria, lysosomes, microtubules, actin or the Golgi. In contrast to previous reports, metabolic labeling and pulse-chase experiments showed that neither non-stimulated nor TNFalpha/PMA-stimulated squamous carcinoma cells appreciably secreted these ov-serpins into the medium. Collectively, these data suggest that the major site of SCCA1 and SCCA2 inhibitory activity remains within the cytosol and that their presence in the sera of patients with advanced squamous-cell carcinomas may be due to their passive release into the circulation.

Biology and pathobiology of neuronal development.

Differentiation of neurons within the central nervous system occurs by the combined effects of intrinsic genetic programs and epigenetic stimuli. Disorders causing mental retardation and other abnormalities of higher cortical function arise by disturbances of the normal developmental sequence. MRDD Research Reviews 6:41-46, 2000.

Identification of PATCHED mutations in medulloblastomas by direct sequencing.

Medulloblastoma is the most common malignant embryonic tumors of the central nervous system. The nevoid basal cell carcinoma syndrome (NBCCS), which is caused by mutations of PTCH gene on chromosome 9q22, accounts for about 2% of all medulloblastomas. Previous studies of PTCH in sporadic medulloblastomas using single strand conformational polymorphism (SSCP) detected mutations in about 10% of the tumors. In this study, we directly sequenced the PTCH gene in 20 sporadic medulloblastoma DNA samples. A nonsense mutation (Q694X) and a splice site alteration (2875+1G>A) were identified in two of the samples. The mutations are predicted to result in a truncated PTCH protein and aberrant splicing, respectively. In both cases, only the mutant alleles were identified, indicating that the mutations were associated with loss of the wild-type PTCH allele in the tumor cells. Several novel variants, including 1653T>C, 1672C>T, and 2292C>T, were also found in these tumor samples. One of the two mutations detected in this study had been missed by SSCP, suggesting that the true rate of PTCH mutations in sporadic medulloblastomas may be underestimated by SSCP screening. Nevertheless, the frequency of mutations in this study did not differ from previous reports.

A developmentally regulated switch directs regenerative growth of Schwann cells through cyclin D1.

Sciatic nerve axons in cyclin D1 knockout mice develop normally, become properly ensheathed by Schwann cells, and appear to function normally. However, in the Wallerian degeneration model of nerve injury, the mitotic response of Schwann cells is completely inhibited. The mitotic block is Schwann cell autonomous and developmentally regulated. Rescue analysis (by "knockin" of cyclin E) indicates that D1 protein, rather than regulatory elements of the D1 gene, provides the essential Schwann cell function. Genetic inhibition of the Schwann cell cycle shows that neuronal responses to nerve injury are surprisingly independent of Schwann cell mitotic responses. Even axonal regrowth into the distal zone of a nerve crush injury is not markedly impaired in cyclin D1-/- mice.

Diet high in monounsaturated fat does not have a different effect on arterial elasticity than a low-fat, high-carbohydrate diet.

OBJECTIVE: To compare the effects of a modified-fat diet high in monounsaturated fat, and a low-fat/high-carbohydrate diet on arterial elasticity. DESIGN: Randomized crossover design; each diet period was 1 month and a 2-week wash out period occurred in between. SUBJECTS/SETTING: Thirty healthy, free-living, nonsmoking men and women were recruited from the Melbourne, Australia, metropolitan region of Australia. Men were aged 35 to 55 years and postmenopausal women were aged 50 to 60 years and were not taking hormone replacement therapy. Twenty-eight subjects completed the study. INTERVENTION: Two diets of equal energy value: a modified-fat diet and a low-fat/high-carbohydrate diet; the modified-fat diet had 3 times more energy from monounsaturated fat. MAIN OUTCOME MEASURES: Arterial elasticity and serum lipoprotein concentrations. STATISTICAL ANALYSIS: The general linear model was used to investigate overall effect and any carryover or order effects. Paired t test and the general linear model were used to compare the results from the 2 diet periods. RESULTS: High-density lipoprotein cholesterol concentration was significantly higher on the modified-fat diet than on the low-fat/low-carbohydrate diet. Arterial elasticity and concentrations of total cholesterol, low-density lipoprotein cholesterol, and triglycerides were not significantly different on the 2 diets. APPLICATIONS/CONCLUSIONS: There is no evidence to favor a diet high in monounsaturated fat over a low-fat/high-carbohydrate diet because of an effect on arterial elasticity. Other changes in diet may be needed to cause a beneficial effect on arterial elasticity.

Rapid nuclear responses to target-derived neurotrophins require retrograde transport of ligand-receptor complex.

Target-derived neurotrophins initiate signals that begin at nerve terminals and cross long distances to reach the cell bodies and regulate gene expression. Neurotrophin receptors, Trks, themselves serve as retrograde signal carriers. However, it is not yet known whether the retrograde propagation of Trk activation reflects movement of Trk receptors from neurites to cell bodies or reflects serial activation of stationary Trk molecules. Here, we show that neurotrophins selectively applied to distal neurites of sensory neurons rapidly induce phosphorylation of the transcription factor cAMP response element-binding protein (CREB) and also cause a slower increase in Fos protein expression. Both nuclear responses require activation of neurotrophin receptors (Trks) at distal nerve endings and retrograde propagation of Trk activation to the nerve cell bodies. Using photobleach and recovery techniques to follow biologically active, green fluorescent protein (GFP)-tagged BDNF receptors (TrkB-GFP) in live cells during retrograde signaling, we show that TrkB-GFP moves rapidly from neurites to the cell bodies. This rapid movement requires ligand binding, Trk kinase activity, and intact axonal microtubules. When they reach the cell bodies, the activated TrkB receptors are in a complex with ligand. Thus, the retrograde propagation of activated TrkB from neurites to cell bodies, although rapid, reflects microtubule-dependent transport of phosphorylated Trk-ligand complexes. Moreover, the relocation of activated Trk receptors from nerve endings to cell bodies is required for nuclear signaling responses. Together, these data support a model of retrograde signaling whereby rapid vesicular transport of ligand-receptor complex from the neurites to the cell bodies mediates the nuclear responses.

Basal ganglia germinoma with progressive cerebral hemiatrophy.

The authors describe a 7-year-old Chinese-American female with a germinoma of the basal ganglia who presented with progressive hemiparesis and cerebral hemiatrophy. The additional finding of markedly elevated antiphospholipid antibodies suggests the possibility of an autoimmune pathogenesis for the progressive cerebral atrophy, as well as the later development of cognitive decline, tics, and obsessive-compulsive behaviors.