Publications by authors named "Duncan MacGregor"

64 Publications

One-Stage, Limited-Resection, Epilepsy Surgery for Bottom-of-Sulcus Dysplasia.

Neurology 2021 May 4. Epub 2021 May 4.

Department of Neurology, The Royal Children's Hospital, Parkville, Victoria, Australia,

Objective: To determine if one-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD).

Methods: We reviewed clinical, neuroimaging, electrocorticography (ECoG), operative and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG.

Results: 38 patients with median age at surgery of 10.2 (IQR: 6.0-14.1) years were included. BOSDs involved eloquent cortex in 15 patients. 87% of patients had rhythmic spiking on pre-resection ECoG. Rhythmic spiking was present in 22/24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. 68% of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was FCDIIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17/22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging or histological abnormalities in the gyral crown. At median 6.3 (IQR: 4.8-9.9) years follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication.

Conclusion: BOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping.

Classification Of Evidence: This study provides Class IV evidence that one-stage, limited corticectomy for BOSD is safe and effective for control of seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000012147DOI Listing
May 2021

Resection of tuber centers only for seizure control in tuberous sclerosis complex.

Epilepsy Res 2021 Mar 8;171:106572. Epub 2021 Feb 8.

Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Clinical Sciences, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Neurology, The Royal Children's Hospital, Parkville, Victoria, Australia. Electronic address:

Our previous studies suggest the tuber center is the seizure focus in tuberous sclerosis complex (TSC). We report findings from 5 epilepsy surgeries in 4 children with TSC and focal motor seizures from single tubers in primary sensorimotor cortex in which resection was limited to the cortex in the tuber center. Intraoperative electrocorticography showed epileptiform activity in the tuber center, with or without propagation to the tuber rim and surrounding perituberal cortex. Histopathology showed an abundance of dysmorphic neurons in the tuber center compared to the rim in four paired specimens, dysmorphic neurons being the reported epileptogenic cell line in TSC. Associated focal motor seizures were eliminated in all children (mean follow up 6.3 years) without postoperative deficits. Tuber center resections are a potential alternative to complete tuberectomy in patients with epileptogenic tubers in eloquent cortex and potentially also in children with a high tuber load and multifocal seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eplepsyres.2021.106572DOI Listing
March 2021

Clinical seizure manifestations in the absence of synaptic connections.

Epileptic Disord 2021 Feb;23(1):167-172

Department of Neurology, The Royal Children's Hospital, Parkville, Victoria, Australia, The University of Melbourne, Parkville, Victoria, Australia, Murdoch Children's Research Institute, Parkville, Victoria, Australia.

We report a child with a history of temporal-parietal-occipital disconnection for epilepsy secondary to posterior quadrantic dysplasia who developed recurrent and prolonged bouts of distress and autonomic disturbance associated with EEG and PET evidence of status epilepticus confined to his disconnected cortex. These bouts were refractory to antiseizure medications but resolved following resection of the disconnected cortex. In the absence of synaptic connections, we hypothesise that his seizure-related symptoms were mediated either by neurochemical transmission in preserved vascular and lymphatic channels or by ephaptic transmission to trigeminal nerve fibres in overlying dura, producing symptoms akin to migraine. The case highlights potential means by which seizures may manifest clinically, without synaptic connections, and adds to the differential for symptoms post-disconnection surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2021.1252DOI Listing
February 2021

Dig deeper when it does not make sense: Juvenile xanthomas due to sitosterolemia.

JIMD Rep 2020 Nov 20;56(1):34-39. Epub 2020 Aug 20.

Victorian Clinical Genetics Services Murdoch Children's Research Institute Parkville Victoria Australia.

Sitosterolemia is an extremely rare autosomal recessive disease caused by mutations in either or , which encode for a sterol efflux transporter (sterolin) that pumps sterols out into the intestinal lumen or into bile. This leads to progressive accumulation of plant sterols in blood and tissues. Clinical presentation is variable and may include xanthoma, arthritis, thyroid dysfunction, premature atherosclerotic disease, splenomegaly, and hematologic manifestations. We report a child presented with multiple xanthomas at age 5.5 years, located on the elbow, knee, and toe. Juvenile xanthogranuloma was considered based on histopathologic findings. At 8 years of age, a lipid profile showed markedly elevated total cholesterol (9.4 mmol/L) and low-density lipoprotein cholesterol (LDL-C, 7.4 mmol/L). Simvastatin therapy was initiated, however, the lipid profile was persistently abnormal. At age 8.5 years, genetic testing identified two novel variants: (NM_022437.3[ABCG8]:c.1444del;p.Leu482Trpfs*40) and (NM_022437.3[ABCG8]:c.1640T>C;p.Leu547Pro) in the gene. Plasma sitosterol was subsequently found to be very high, confirming the diagnosis. She was started on a low plant sterol and cholesterol diet for 6 weeks with insignificant response and therefore ezetimibe (10 mg daily) was added. This resulted in significant reduction of cholesterol, LDL, sitosterol levels, and no further increase in the size of the xanthomas. This case emphasizes the diagnostic odyssey, the benefits of genomic testing and importance of a correct diagnosis in order to initiate appropriate therapy. It also illustrates the importance of considering rare conditions, such as sitosterolemia, as a differential diagnosis in patients with hypercholesterolemia and increased LDL-C.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmd2.12161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653237PMC
November 2020

Genetic characterization identifies bottom-of-sulcus dysplasia as an mTORopathy.

Neurology 2020 11 26;95(18):e2542-e2551. Epub 2020 Aug 26.

From the Bruce Lefroy Centre (W.S.L., S.E.M.S., K.P., G.G., P.J.L.), Murdoch Children's Research Institute (W.M., A.S.H., R.J.L.); Department of Paediatrics (W.S.L., S.E.M.S., W.M., E.M.-L., A.S.H., R.J.L., P.J.L.), The University of Melbourne; Departments of Neurosurgery (W.M.), Neurology (E.M.-L., A.S.H., R.J.L.), and Anatomical Pathology (D.M., C.D.), The Royal Children's Hospital, Parkville; and Melbourne Brain Centre (G.J.), The Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia.

Objective: To determine the genetic basis of bottom-of-sulcus dysplasia (BOSD), which is a highly focal and epileptogenic cortical malformation in which the imaging, electrophysiologic, and pathologic abnormalities are maximal at the bottom of sulcus, tapering to a normal gyral crown.

Methods: Targeted panel deep sequencing (>500×) was performed on paired blood and brain-derived genomic DNA from 20 operated patients with drug-resistant focal epilepsy and BOSD. Histopathology was assessed using immunohistochemistry.

Results: Brain-specific pathogenic somatic variants were found in 6 patients and heterozygous pathogenic germline variants were found in 2. Somatic variants were identified in and germline variants were identified in and . Two patients with somatic variants showed a mutation gradient, with higher mutation load at the bottom of sulcus compared to the gyral crown. Immunohistochemistry revealed an abundance of dysmorphic neurons and balloon cells in the bottom of sulcus but not in the gyral crown or adjacent gyri.

Conclusions: BOSD is associated with mTOR pathway dysregulation and shares common genetic etiologies and pathogenic mechanisms with other forms of focal and hemispheric cortical dysplasia, suggesting these disorders are on a genetic continuum.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000010670DOI Listing
November 2020

Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma.

J Immunother Cancer 2020 04;8(1)

Versagenics Inc, Morrisville, North Carolina, USA.

Background: To compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence.

Methods: Participants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity.

Results: The ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4 and CD8 responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)/Human Leukocyte Antigen (HLA) class I double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants.

Conclusions: The vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2019-000410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204806PMC
April 2020

Isolated proteinuria due to CUBN homozygous mutation - challenging the investigative paradigm.

BMC Nephrol 2019 08 22;20(1):330. Epub 2019 Aug 22.

Murdoch Children's Research Institute, Melbourne, Australia.

Background: Proteinuria is a common clinical presentation, the diagnostic workup for which involves many non-invasive and invasive investigations. We report on two siblings that highlight the clinically relevant functional role of cubulin for albumin resorption in the proximal tubule and supports the use of genomic sequencing early in the diagnostic work up of patients who present with proteinuria.

Case Presentation: An 8-year-old boy was referred with an incidental finding of proteinuria. All preliminary investigations were unremarkable. Further assessment revealed consanguineous family history and a brother with isolated proteinuria. Renal biopsy demonstrated normal light microscopy and global glomerular basement membrane thinning on electron microscopy. Chromosomal microarray revealed long continuous stretches of homozygosity (LCSH) representing ~ 4.5% of the genome. Shared regions of LCSH between the brothers were identified and their further research genomic analysis implicated a homozygous stop-gain variant in CUBN (10p12.31).

Conclusions: CUBN mutations have been implicated as a hereditary cause of megaloblastic anaemia and variable proteinuria. This is the second reported family with isolated proteinuria due to biallelic CUBN variants in the absence of megaloblastic anaemia, demonstrating the ability of genomic testing to identify genetic causes of nephropathy within expanding associated phenotypic spectra. Genomic sequencing, undertaken earlier in the diagnostic trajectory, may reduce the need for invasive investigations and the time to definitive diagnosis for patients and families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-019-1474-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704575PMC
August 2019

Second-hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA.

Ann Clin Transl Neurol 2019 07 17;6(7):1338-1344. Epub 2019 Jun 17.

Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Focal cortical dysplasia (FCD) causes drug-resistant epilepsy and is associated with pathogenic variants in mTOR pathway genes. How germline variants cause these focal lesions is unclear, however a germline + somatic "2-hit" model is hypothesized. In a boy with drug-resistant epilepsy, FCD, and a germline DEPDC5 pathogenic variant, we show that a second-hit DEPDC5 variant is limited to dysmorphic neurons, and the somatic mutation load correlates with both dysmorphic neuron density and the epileptogenic zone. These findings provide new insights into the molecular and cellular correlates of FCD determining drug-resistant epilepsy and refine conceptualization of the epileptogenic zone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.50815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649645PMC
July 2019

Emergent decision-making behaviour and rhythm generation in a computational model of the ventromedial nucleus of the hypothalamus.

PLoS Comput Biol 2019 06 3;15(6):e1007092. Epub 2019 Jun 3.

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

The ventromedial nucleus of the hypothalamus (VMN) has an important role in diverse behaviours. The common involvement in these of sex steroids, nutritionally-related signals, and emotional inputs from other brain areas, suggests that, at any given time, its output is in one of a discrete number of possible states corresponding to discrete motivational drives. Here we explored how networks of VMN neurons might generate such a decision-making architecture. We began with minimalist assumptions about the intrinsic properties of VMN neurons inferred from electrophysiological recordings of these neurons in rats in vivo, using an integrate-and-fire based model modified to simulate activity-dependent post-spike changes in neuronal excitability. We used a genetic algorithm based method to fit model parameters to the statistical features of spike patterning in each cell. The spike patterns in both recorded cells and model cells were assessed by analysis of interspike interval distributions and of the index of dispersion of firing rate over different binwidths. Simpler patterned cells could be closely matched by single neuron models incorporating a hyperpolarising afterpotential and either a slow afterhyperpolarisation or a depolarising afterpotential, but many others could not. We then constructed network models with the challenge of explaining the more complex patterns. We assumed that neurons of a given type (with heterogeneity introduced by independently random patterns of external input) were mutually interconnected at random by excitatory synaptic connections (with a variable delay and a random chance of failure). Simple network models of one or two cell types were able to explain the more complex patterns. We then explored the information processing features of such networks that might be relevant for a decision-making network. We concluded that rhythm generation (in the slow theta range) and bistability arise as emergent properties of networks of heterogeneous VMN neurons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pcbi.1007092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6564049PMC
June 2019

The spiking and secretory activity of oxytocin neurones in response to osmotic stimulation: a computational model.

J Physiol 2019 07 9;597(14):3657-3671. Epub 2019 Jun 9.

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.

Key Points: A quantitative model of oxytocin neurones that combines a spiking model, a model of stimulus-secretion coupling and a model of plasma clearance of oxytocin was tested. To test the model, a variety of sources of published data were used that relate either the electrical activity of oxytocin cells or the secretion of oxytocin to experimentally induced changes in plasma osmotic pressure. To use these data to test the model, the experimental challenges involved were computationally simulated. The model predictions closely matched the reported outcomes of the different experiments.

Abstract: Magnocellular vasopressin and oxytocin neurones in the rat hypothalamus project to the posterior pituitary, where they secrete their products into the bloodstream. In rodents, both vasopressin and oxytocin magnocellular neurones are osmoresponsive, and their increased spiking activity is mainly a consequence of an increased synaptic input from osmoresponsive neurons in regions adjacent to the anterior wall of the third ventricle. Osmotically stimulated vasopressin secretion promotes antidiuresis while oxytocin secretion promotes natriuresis. In this work we tested a previously published computational model of the spiking and secretion activity of oxytocin cells against published evidence of changes in spiking activity and plasma oxytocin concentration in response to different osmotic challenges. We show that integrating this oxytocin model with a simple model of the osmoresponsive inputs to oxytocin cells achieves a strikingly close match to diverse sources of data. Comparing model predictions with published data using bicuculline to block inhibitory GABA inputs supports the conclusion that inhibitory inputs and excitatory inputs are co-activated by osmotic stimuli. Finally, we studied how the gain of osmotically stimulated oxytocin release changes in the presence of a hypovolaemic stimulus, showing that this is best explained by an inhibition of an osmotically regulated inhibitory drive to the magnocellular neurones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP278045DOI Listing
July 2019

Models in neuroendocrinology.

Math Biosci 2018 11 1;305:29-41. Epub 2018 Aug 1.

Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK. Electronic address:

The neuroendocrine systems of the hypothalamus are critical for survival and reproduction, and are highly conserved throughout vertebrate evolution. Their roles in controlling body metabolism, growth and body composition, stress, electrolyte balance and reproduction have been intensively studied, and have yielded a rich crop of original and challenging insights into neuronal function, insights that circumscribe a vision of the brain that is quite different from conventional views. Despite the diverse physiological roles of pituitary hormones, most are secreted in a pulsatile pattern, but arising through a variety of mechanisms. An important exception is vasopressin which uses bursting neural activity, but produces a graded secretion response to osmotic pressure, a sustained robust linear response constructed from noisy, nonlinear components. Neuroendocrine systems have many features such as multiple temporal scales and nonlinearity that make their underlying mechanisms hard to understand without mathematical modelling. The models presented here cover the wide range of temporal scales involved in these systems, including models of single cell electrical activity and calcium dynamics, receptor signalling, gene expression, coordinated activity of neuronal networks, whole-organism hormone dynamics and feedback loops, and the menstrual cycle. Many interesting theoretical approaches have been applied to these systems, but important problems remain, at the core the question of what is the true advantage of pulsatility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mbs.2018.07.008DOI Listing
November 2018

More than Grapes and Bleeding: An Updated Look at Pelvic Rhabdomyosarcoma in Young Women.

J Pediatr Adolesc Gynecol 2018 Oct 5;31(5):522-525. Epub 2018 Feb 5.

Department of Gynecology, The Royal Children's Hospital Melbourne, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.

Study Objective: To review our local experience with urogenital rhabdomyosarcoma (RMS) to determine the most common clinical presentation(s).

Design: Retrospective case series of all female patients with urogenital RMS who presented to a tertiary pediatric hospital between 1996 and 2016. All institutional electronic pathology reports were screened for RMS and those that were pelvic in origin and occurred in female patients were included for further analysis. Seventeen cases of urogenital RMS in female patients were identified and reviewed.

Setting: This study was conducted at The Royal Children's Hospital in Melbourne, Australia. This is a tertiary referral center for the state of Victoria and surrounding areas, which services more than 1.5 million pediatric patients.

Participants: Female pediatric patients (ages 0-18 years) who presented to The Royal Children's Hospital with eventual pathologic tissue diagnosis of urogenital RMS.

Main Outcome Measures: The cases were reviewed for clinical presentation, duration of symptoms before initial presentation, time to tissue diagnosis, and outcomes of treatment.

Results: Of the 17 cases reviewed, 5 (29%) presented with perineal mass, 4 (24%) presented with each of abdominal mass and grape-like lesions/hemorrhagic mass at the introitus, 3 (18%) with nonspecific symptoms only, and 1 (6%) with vulvar inflammation.

Conclusion: The clinical presentation of urogenital RMS in women is heterogeneous, and the classically described presentation of grape-like lesions at the introitus and vaginal bleeding represents only a small proportion of clinical presentations. Awareness of other presentations, which appear to be more common than previously recognized, needs to be increased to ensure timely diagnosis and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpag.2018.01.006DOI Listing
October 2018

A Predictive, Quantitative Model of Spiking Activity and Stimulus-Secretion Coupling in Oxytocin Neurons.

Endocrinology 2018 03;159(3):1433-1452

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Oxytocin neurons of the rat hypothalamus project to the posterior pituitary, where they secrete their products into the bloodstream. The pattern and quantity of that release depends on the afferent inputs to the neurons, on their intrinsic membrane properties, and on nonlinear interactions between spiking activity and exocytosis: A given number of spikes will trigger more secretion when they arrive close together. Here we present a quantitative computational model of oxytocin neurons that can replicate the results of a wide variety of published experiments. The spiking model mimics electrophysiological data of oxytocin cells responding to cholecystokinin (CCK), a peptide produced in the gut after food intake. The secretion model matches results from in vitro experiments on stimulus-secretion coupling in the posterior pituitary. We mimic the plasma clearance of oxytocin with a two-compartment model, replicating the dynamics observed experimentally after infusion and injection of oxytocin. Combining these models allows us to infer, from measurements of oxytocin in plasma, the spiking activity of the oxytocin neurons that produced that secretion. We have tested these inferences with experimental data on oxytocin secretion and spiking activity in response to intravenous injections of CCK. We show how intrinsic mechanisms of the oxytocin neurons determine this relationship: In particular, we show that the presence of an afterhyperpolarization (AHP) in oxytocin neurons dramatically reduces the variability of their spiking activity and even more markedly reduces the variability of oxytocin secretion. The AHP thus acts as a filter, protecting the final product of oxytocin cells from noisy fluctuations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/en.2017-03068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934744PMC
March 2018

Spike patterning in oxytocin neurons: Capturing physiological behaviour with Hodgkin-Huxley and integrate-and-fire models.

PLoS One 2017 6;12(7):e0180368. Epub 2017 Jul 6.

Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.

Integrate-and-fire (IF) models can provide close matches to the discharge activity of neurons, but do they oversimplify the biophysical properties of the neurons? A single compartment Hodgkin-Huxley (HH) model of the oxytocin neuron has previously been developed, incorporating biophysical measurements of channel properties obtained in vitro. A simpler modified integrate-and-fire model has also been developed, which can match well the characteristic spike patterning of oxytocin neurons as observed in vivo. Here, we extended the HH model to incorporate synaptic input, to enable us to compare spike activity in the model with experimental data obtained in vivo. We refined the HH model parameters to closely match the data, and then matched the same experimental data with a modified IF model, using an evolutionary algorithm to optimise parameter matching. Finally we compared the properties of the modified HH model with those of the IF model to seek an explanation for differences between spike patterning in vitro and in vivo. We show that, with slight modifications, the original HH model, like the IF model, is able to closely match both the interspike interval (ISI) distributions of oxytocin neurons and the observed variability of spike firing rates in vivo and in vitro. This close match of both models to data depends on the presence of a slow activity-dependent hyperpolarisation (AHP); this is represented in both models and the parameters used in the HH model representation match well with optimal parameters of the IF model found by an evolutionary algorithm. The ability of both models to fit data closely also depends on a shorter hyperpolarising after potential (HAP); this is explicitly represented in the IF model, but in the HH model, it emerges from a combination of several components. The critical elements of this combination are identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180368PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500322PMC
September 2017

Methylation profiling of paediatric pilocytic astrocytoma reveals variants specifically associated with tumour location and predictive of recurrence.

Mol Oncol 2018 08 6;12(8):1219-1232. Epub 2018 Jul 6.

Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Australia.

Childhood pilocytic astrocytomas (PA) are low-grade tumours with an excellent prognosis. However, a minority, particularly those in surgically inaccessible locations, have poorer long-term outcome. At present, it is unclear whether anatomical location in isolation, or in combination with underlying biological variation, determines clinical behaviour. Here, we have tested the utility of DNA methylation profiling to inform tumour biology and to predict behaviour in paediatric PA. Genome-wide DNA methylation profiles were generated for 117 paediatric PAs. Using a combination of analyses, we identified DNA methylation variants specific to tumour location and predictive of behaviour. Receiver-operating characteristic analysis was used to test the predictive utility of clinical and/or DNA methylation features to classify tumour behaviour at diagnosis. Unsupervised analysis distinguished three methylation clusters associated with tumour location (cortical, midline and infratentorial). Differential methylation of 5404 sites identified enrichment of genes involved in 'embryonic nervous system development'. Specific hypermethylation of NEUROG1 and NR2E1 was identified as a feature of cortical tumours. A highly accurate method to classify tumours according to behaviour, which combined three clinical features (age, location and extent of resection) and methylation level at a single site, was identified. Our findings show location-specific epigenetic profiles for PAs, potentially reflecting their cell type of origin. This may account for differences in clinical behaviour according to location independent of histopathology. We also defined an accurate method to predict tumour behaviour at diagnosis. This warrants further testing in similar patient cohorts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/1878-0261.12062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068350PMC
August 2018

A pilot study of peripheral blood BDCA-1 (CD1c) positive dendritic cells pulsed with NY-ESO-1 ISCOMATRIX™ adjuvant.

Immunotherapy 2017 03 10;9(3):249-259. Epub 2017 Feb 10.

Ludwig Institute for Cancer Research, Victoria, Australia.

Aim: Pilot clinical trial of NY-ESO-1 (ESO) protein in ISCOMATRIX™ adjuvant pulsed onto peripheral blood dendritic cells (PBDC), to ascertain feasibility, evaluate toxicity and assess induction of ESO-specific immune responses.

Patients & Methods: Eligible participants had resected cancers expressing ESO or LAGE-1 and were at high risk of relapse. PBDC were produced using CliniMACSplus, with initial depletion of CD1c B cells followed by positive selection of CD1c PBDC. Patients received three intradermal vaccinations of ESO/IMX-pulsed PBDC at 4-week intervals.

Results: The process was feasible and safe. No vaccine-induced immune responses were detected. Assays of immunomodulatory cells did not correlate with outcomes. One patient had a long lasting complete remission.

Conclusion: This method was feasible and safe but was minimally immunogenic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/imt-2016-0132DOI Listing
March 2017

Autoimmune Pancreatitis and IgG4 Related Disease in Three Children.

ACG Case Rep J 2016 Jul 31;3(4):e115. Epub 2016 Aug 31.

Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne, Australia; University of Melbourne, Melbourne, Australia; Murdoch Childrens Research Institute, Parkville, Melbourne, Australia.

We report 3 children who presented with fever and abdominal pain, deranged liver function tests, and on abdominal ultrasound were found to have an enlarged pancreas, substantial abdominal lymphadenopathy, and extrahepatic biliary duct dilatation. After ruling out malignancy, probable immunoglobulin G4-related disease (IgG4RD) associated with autoimmune pancreatitis was considered. This condition was first described in the adults and often mimics pancreatic cancer. It can involve multiple organs, either synchronously or metachronously, and is rarely reported in children. The disorder mostly responds to corticosteroid therapy and other immune suppression. We highlight the difficulty in diagnosing autoimmune pancreatitis/IgG4-related disease in children and illustrate the difference between pediatric and adult presentation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14309/crj.2016.88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018227PMC
July 2016

Evidence of broad-based family support for the use of archival childhood tumour samples in future research.

J Med Ethics 2016 07 10;42(7):460-5. Epub 2016 May 10.

Department of Cancer and Disease Epigenetics, Murdoch Childrens Research Institute, Parkville, Victoria, Australia Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.

Objectives: This study aimed to determine the ability to successfully contact past paediatric patients and their families to request participation in research, to assess familial views on the use of previously collected archival clinical samples for research purposes, and to highlight the ethical and practical issues in obtaining this type of retrospective consent.

Methods: To assess familial views on the use of such samples for research, we contacted a cohort of families with children previously diagnosed with a brain tumour to ask for consent to an epigenetic/genetic study. Examining participants' responses allowed us to gauge their opinions on the use of such tissue for research, and whether they would like to receive genetic information uncovered during research.

Results: We were able to successfully contact 107 out of 178 families and found a significant positive correlation between year of diagnosis and ability to make contact. Of those families contactable that returned a consent form (75/107), 74 agreed to the use of their/their child's archival tissue in future research, and 70 of 74 requested notification should a gene change of potential clinical relevance be found. There were no differences in opinion between parents of living or deceased children or the patients themselves.

Conclusions: This study highlights the importance of time since diagnosis on the ability to make contact with previous patients and their families. When contactable, our data highlight the altruistic views of families towards the use of archival clinical samples for research purposes, irrespective of the outcome of their child's illness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/medethics-2015-103141DOI Listing
July 2016

Pediatric Pleomorphic Xanthoastrocytoma Treated With Surgical Resection Alone: Clinicopathologic Features.

J Pediatr Hematol Oncol 2016 10;38(7):e202-6

*Children's Cancer Centre §Department of Pathology, Royal Children's Hospital †Department of Paediatrics, University of Melbourne ‡Murdoch Children's Research Institute, Melbourne, Vic., Australia.

Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor that usually occurs in children and young adults. It has characteristic histologic features and is regarded as a WHO grade II lesion. Overall survival is reported to be >60%, but published series usually consist of a range of ages and treatment modalities. Gross total resection is associated with superior survival but recurrence rates after gross total resection are not well described, particularly in a pediatric population. We describe 16 cases over 20 years at our institution of pediatric PXA treated with surgical resection alone with a 5-year relapse-free survival of 40% (95% confidence interval, 20%-82%) and overall survival of 76% (95% confidence interval, 55%-100%). Gross total resection was associated with superior relapse-free survival (P<0.05). Some cases have a very long period between symptom onset or radiologic detection and resection, but neither length of symptoms nor radiologic signs of slow growth were associated with survival. PXA is a rare and unusual entity with unpredictable behavior. Complete surgical resection is optimal but does not guarantee relapse-free survival. We propose separation of PXA from other low-grade gliomas in childhood given differing biology and behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000000581DOI Listing
October 2016

Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation.

J Neurooncol 2016 06 19;128(2):293-302. Epub 2016 Mar 19.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, 450 Longwood Ave, Boston, 02115, USA.

Disseminated glioneuronal tumors of childhood are rare. We present a retrospective IRB-approved review of the clinical course and frequency of BRAF mutations in disseminated glioneuronal tumors at two institutions. Defining features of our cohort include diffuse leptomeningeal-spread, often with a discrete spinal cord nodule and oligodendroglioma-like histologic features. Patients were identified through a pathology database search of all cases with disseminated low-grade neoplasms with an oligodendroglioma-like component. De-identified clinical information was collected by chart review and all imaging was reviewed. We retrieved the results of targeted genomic analyses for alterations in BRAF. Ten patients (aged 2-14 years) were identified from the Dana-Farber/Boston Children's Hospital and the Royal Children's Hospital, Melbourne pathology databases. Nine patients received chemotherapy. Eight patients are alive, although three have had episodes of progressive disease. We identified genomic alterations affecting the MAPK pathway in six patients. One patient had a germline RAF1 mutation and a clinical diagnosis of cardio-facio-cutaneous syndrome. BRAF duplications were identified in four and BRAF V600E mutation was identified in one. These data support the presence of targetable genomic alterations in this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-016-2109-xDOI Listing
June 2016

Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors.

Acta Neuropathol 2016 06 26;131(6):847-63. Epub 2016 Feb 26.

Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-016-1549-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039033PMC
June 2016

Nontuberculous Mycobacterial Disease in Children - Epidemiology, Diagnosis & Management at a Tertiary Center.

PLoS One 2016 26;11(1):e0147513. Epub 2016 Jan 26.

Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.

Background: There are limited data on the epidemiology, diagnosis and optimal management of nontuberculous mycobacterial (NTM) disease in children.

Methods: Retrospective cohort study of NTM cases over a 10-year-period at a tertiary referral hospital in Australia.

Results: A total of 140 children with NTM disease, including 107 with lymphadenitis and 25 with skin and soft tissue infections (SSTIs), were identified. The estimated incidence of NTM disease was 0.6-1.6 cases / 100,000 children / year; no increasing trend was observed over the study period. Temporal analyses revealed a seasonal incidence cycle around 12 months, with peaks in late winter/spring and troughs in autumn. Mycobacterium-avium-complex accounted for most cases (77.8%), followed by Mycobacterium ulcerans (14.4%) and Mycobacterium marinum (3.3%). Polymerase chain reaction testing had higher sensitivity than culture and microscopy for acid-fast bacilli (92.0%, 67.2% and 35.7%, respectively). The majority of lymphadenitis cases underwent surgical excision (97.2%); multiple recurrences in this group were less common in cases treated with clarithromycin and rifampicin compared with clarithromycin alone or no anti-mycobacterial drugs (0% versus 7.1%; OR:0.73). SSTI recurrences were also less common in cases treated with two anti-mycobacterial drugs compared with one or none (10.5% versus 33.3%; OR:0.23).

Conclusions: There was seasonal variation in the incidence of NTM disease, analogous to recently published observations in tuberculosis, which have been linked to seasonal variation in vitamin D. Our finding that anti-mycobacterial combination therapy was associated with a reduced risk of recurrences in patients with NTM lymphadenitis or SSTI requires further confirmation in prospective trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147513PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727903PMC
July 2016

Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.

Ann Neurol 2016 Jan 12;79(1):132-7. Epub 2015 Dec 12.

Department of Neurology, Royal Children's Hospital, Melbourne, Australia.

We describe first cousin sibling pairs with focal epilepsy, one of each pair having focal cortical dysplasia (FCD) IIa. Linkage analysis and whole-exome sequencing identified a heterozygous germline frameshift mutation in the gene encoding nitrogen permease regulator-like 3 (NPRL3). NPRL3 is a component of GAP Activity Towards Rags 1, a negative regulator of the mammalian target of rapamycin complex 1 signaling pathway. Immunostaining of resected brain tissue demonstrated mammalian target of rapamycin activation. Screening of 52 unrelated individuals with FCD identified 2 additional patients with FCDIIa and germline NPRL3 mutations. Similar to DEPDC5, NPRL3 mutations may be considered as causal variants in patients with FCD or magnetic resonance imaging-negative focal epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.24502DOI Listing
January 2016

The surgically remediable syndrome of epilepsy associated with bottom-of-sulcus dysplasia.

Neurology 2015 May 17;84(20):2021-8. Epub 2015 Apr 17.

From the Departments of Neurology (A.S.H., R.J.L., G.D.J.), Medical Imaging (S.A.M., M.J.K.), Neurosurgery (W.J.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Parkville; Departments of Neurology (G.D.J.), Radiology (Y.P., G.J.F.), Neurosurgery (G.C.A.F.), and Anatomical Pathology (R.M.K.), Austin Health, Heidelberg; Departments of Paediatrics (A.S.H., S.A.M., R.J.L.), Medicine (G.D.J.), Surgery (G.C.A.F.), Pathology (D.M., R.M.K.), and Radiology (S.A.M., Y.P., G.J.F.), The University of Melbourne; Florey Institute of Neuroscience and Mental Health (A.S.H., S.A.M., M.S., G.D.J.), Heidelberg; Neurosciences (A.S.H., W.J.M., R.J.L.) and Developmental Imaging (S.B., M.J.K.) Groups, Murdoch Children's Research Institute, Parkville, Australia.

Objective: To determine clinical and EEG features that might help identify patients with epilepsy harboring small, intrinsically epileptogenic, surgically treatable, bottom-of-sulcus dysplasias (BOSDs).

Methods: Retrospective review of clinical records, EEG, MRI, and histopathology in 32 patients with drug-resistant epilepsy and MRI-positive (72% 3.0 tesla), pathologically proven (type 2B cortical dysplasia) BOSDs operated at our centers during 2005-2013.

Results: Localization of BOSDs was frontal in 19, insula in 5, parietal in 5, and temporal in 3, on the convexity or interhemispheric surfaces. BOSDs were missed on initial MRI at our centers in 22% of patients. Patients presented with focal seizures during infancy in 9, preschool years in 15, and school years in 8 (median age 5 years). Seizures were stereotyped, predominantly nocturnal, and typically nonconvulsive, with semiology referable to the fronto-central or perisylvian regions. Seizures occurred at high frequency during active periods, but often went into prolonged remission with carbamazepine or phenytoin. Intellect was normal or borderline, except in patients with seizure onset during infancy. Scalp EEG frequently revealed localized interictal epileptiform discharges and ictal rhythms. Patients underwent lesionectomy (median age 14 years) guided by electrocorticography and MRI, with prior intracranial EEG monitoring in only one patient. Twenty-eight patients (88%) became seizure-free, and 20 discontinued antiepileptic medication (median follow-up 4.1 years).

Conclusions: In patients with cryptogenic focal epilepsy, this clinical presentation and course should prompt review of or repeat MRI, looking for a BOSD in the frontal, parietal, or insula cortex. If a BOSD is identified, the patient might be considered for single-stage lesionectomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000001591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442099PMC
May 2015

Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR.

Neurology 2015 May 15;84(20):2029-32. Epub 2015 Apr 15.

From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.

Objective: To define causative somatic mutations in resected brain tissue from an infant with intractable epilepsy secondary to hemispheric cortical dysplasia.

Methods: Whole-exome sequencing was conducted on genomic DNA derived from both resected brain tissue and peripheral blood leukocytes. Comparison of the brain vs blood sequencing results was performed using bioinformatic methods designed to detect low-frequency genetic variation between tissue pairs.

Results: Histopathology of the resected tissue showed dyslamination and dysmorphic neurons, but no balloon cells, consistent with focal cortical dysplasia type IIa. mTOR activation was observed by immunohistochemistry in the dysplasia. A missense mutation (c.4487T>G; p.W1456G) was detected in the FAT domain of MTOR in DNA from the dysplasia but not in lymphocytes. The mutation is predicted damaging (i.e., leading to mTOR activation) and was observed as a low-level mosaic with 8% of cells being heterozygous for the variant.

Conclusions: We report the novel finding of an MTOR mutation associated with nonsyndromic cortical dysplasia. Somatic-specific mutations in MTOR and related genes should be considered in a broader spectrum of patients with hemispheric malformations and more restricted forms of cortical dysplasia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000001594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442098PMC
May 2015

Complicated Henoch-Schönlein purpura.

J Paediatr Child Health 2015 Jun 15;51(6):639-42. Epub 2014 Dec 15.

Department of General Medicine, The Royal Children's Hospital, Melbourne, Victoria, Australia.

We present a case of Henoch Schonlein pupura in a 6-year-old boy demonstrating some of the diagnostic pitfalls, complications and management challenges of this common paediatric condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jpc.12786DOI Listing
June 2015

Infantile sigmoid colon stricture secondary to cytomegalovirus.

ANZ J Surg 2017 Jun 17;87(6):E17-E18. Epub 2014 Nov 17.

Department of Paediatric and Neonatal Surgery, The Royal Children's Hospital, Melbourne, Victoria, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ans.12921DOI Listing
June 2017

Quantitative intratumoural microdistribution and kinetics of (131)I-huA33 antibody in patients with colorectal carcinoma.

EJNMMI Res 2014 30;4:22. Epub 2014 May 30.

Ludwig Institute for Cancer Research, Austin Health, Melbourne 3084, Australia ; Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne 3084, Australia.

Background: The ability of recombinant antibodies to adequately penetrate into tumours is a key factor in achieving therapeutic effect; however, the behaviour of antibodies at a cellular level in tumours is poorly understood. The purpose of this study was to investigate those factors that influence the macroscopic and microscopic intratumoural distribution of an IgG1-humanized antibody, huA33, in colorectal tumours.

Methods: Twelve patients were infused with radiolabelled huA33 at 7 days prior to elective surgery for colorectal carcinoma. Macroscopic huA33 uptake was determined by both gamma well counter and autoradiography measurements of the resected tumour specimens. Microscopic uptake was then quantitated at a cellular level and compared to vascular penetrance. The impact of variation in tumour antigen (GPA33) expression, tumour size, specimen type (primary vs metastatic), presence of macroscopic necrosis, and tumour vasculature on huA33 uptake were examined.

Results: The I-huA33 uptake in whole tumour sections was (mean ± SD) 5.13 ± 2.71 × 10(-3)% injected dose per gram (ID/g). GPA33 was expressed in all viable tumour cells, and huA33 uptake was excellent regardless of tumour size and specimen type. In tumours with macroscopically evident central necrosis (n = 5), huA33 uptake in tumour necrotic centres was lower than in viable peripheries (0.606 ± 0.493 vs 2.98 ± 2.17 × 10(-3)%ID, p = 0.06). However, when corrected for low cell viability in necrotic centres, uptake of huA33 at the cellular level was highly comparable to that in the more viable tumour periphery (7.10 ± 5.10 × 10(-9) vs 3.82 ± 3.67 × 10(-9)%ID/cell, p = 0.4). In the five patients who exhibited macroscopic necrosis in their tumours, huA33 showed excellent tissue penetration, with a maximum penetration distance of 26 μm in peripheral tumour regions and 118 μm in central regions. No correlation was observed between (131)I-huA33 uptake in tumour on a cellular basis and tumour vascularity.

Conclusions: In patients with colorectal carcinoma, monoclonal antibody huA33 effectively targets viable tumour cells in all cellular milieus examined, including effective penetration into necrotic tumour centres, a novel and therapeutically important finding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13550-014-0022-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070025PMC
July 2014

Spike triggered hormone secretion in vasopressin cells; a model investigation of mechanism and heterogeneous population function.

PLoS Comput Biol 2013 15;9(8):e1003187. Epub 2013 Aug 15.

Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.

Vasopressin neurons generate distinctive phasic patterned spike activity in response to elevated extracellular osmotic pressure. These spikes are generated in the cell body and are conducted down the axon to the axonal terminals where they trigger Ca²⁺ entry and subsequent exocytosis of hormone-containing vesicles and secretion of vasopressin. This mechanism is highly non-linear, subject to both frequency facilitation and fatigue, such that the rate of secretion depends on both the rate and patterning of the spike activity. Here we used computational modelling to investigate this relationship and how it shapes the overall response of the neuronal population. We generated a concise single compartment model of the secretion mechanism, fitted to experimentally observed profiles of facilitation and fatigue, and based on representations of the hypothesised underlying mechanisms. These mechanisms include spike broadening, Ca²⁺ channel inactivation, a Ca²⁺ sensitive K⁺ current, and releasable and reserve pools of vesicles. We coupled the secretion model to an existing integrate-and-fire based spiking model in order to study the secretion response to increasing synaptic input, and compared phasic and non-phasic spiking models to assess the functional value of the phasic spiking pattern. The secretory response of individual phasic cells is very non-linear, but the response of a heterogeneous population of phasic cells shows a much more linear response to increasing input, matching the linear response we observe experimentally, though in this respect, phasic cells have no apparent advantage over non-phasic cells. Another challenge for the cells is maintaining this linear response during chronic stimulation, and we show that the activity-dependent fatigue mechanism has a potentially useful function in helping to maintain secretion despite depletion of stores. Without this mechanism, secretion in response to a steady stimulus declines as the stored content declines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pcbi.1003187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744396PMC
February 2014

Changes in the length and diameter of the normal appendix throughout childhood.

J Pediatr Surg 2013 Jul;48(7):1535-9

Douglas Stephens Surgical Research Group, Murdoch Childrens Research Institute, Melbourne 3052, Australia.

Background/aim: It has been proposed that the narrow diameter of the appendix is important in providing a 'safe zone' for commensal intestinal flora, while the length of the appendix can be variable. This study aimed to investigate the relationship between appendiceal length, diameter and age, in children under the age of eighteen years, to determine if the appendix changes in size with age.

Methods: The histological records of all cases of children undergoing appendicectomy at the Royal Children's Hospital (Melbourne) between 2009 and 2011 were retrospectively reviewed. Participants were excluded on the basis of histological evidence of acute inflammation, and data on the diameter and length of the appendix were collected from 210 children, aged zero to seventeen years.

Results: Data were stratified by age for analysis into ≤ 3 years, >3 and ≤ 9, >9 and ≤ 13 and >13 years. Mean diameters per group were 3.7 (± 1.3), 6.3 (± 1.2), 6.7 (± 1.6) and 6.9 (± 1.6) millimetres respectively. Mean lengths per group were 39.7 (± 16.1), 66.3 (± 15.3), 63.7 (± 21.3) and 68.8 (± 18.2) millimetres. Both diameter and length were higher in the older age groups, compared with the ≤ 3 year olds (p < 0.001). A positive correlation was seen between age and appendix diameter (R = 0.5, p < 0.001) and length (R = 0.3, p=0.03) in the ≤ 3 group only. Mean diameter and length values did not differ significantly between groups aged > 3 years old.

Conclusion: This study showed that following an initial growth period during early infancy up to about 3 years, the appendix achieves its adult proportions and does not continue to grow throughout childhood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpedsurg.2013.02.035DOI Listing
July 2013