An Williams

Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations

Objective: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. Methods: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of vision. We quantified mitophagy in dermal fibroblasts, using 2 high throughput imaging systems, by visualizing colocalization of mitochondrial fragments with engulfing autophagosomes. Results: Fibroblasts from 3 biallelic OPA1(−/−) patients with severe DOA had increased mitochondrial fragmentation and mitochondrial DNA (mtDNA)–depleted cells due to decreased levels of OPA1 protein. Similarly, in siRNA-treated control fibroblasts, profound OPA1 knockdown caused mitochondrial fragmentation, loss of mtDNA, impaired mitochondrial function, and mitochondrial mislocalization. Compared to controls, basal mitophagy (abundance of autophagosomes colocalizing with mitochondria) was increased in (1) biallelic patients, (2) monoallelic patients with DOA plus, and (3) OPA1 siRNA–treated control cultures. Mitophagic flux was also increased. Genetic knockdown of the mitophagy protein ATG7 confirmed this by eliminating differences between patient and control fibroblasts. Conclusions: We demonstrated increased mitophagy and excessive mitochondrial fragmentation in primary human cultures associated with DOA plus due to biallelic OPA1 mutations. We previously found that increased mitophagy (mitochondrial recycling) was associated with visual loss in another mitochondrial optic neuropathy, Leber hereditary optic neuropathy (LHON). Combined with our LHON findings, this implicates excessive mitochondrial fragmentation, dysregulated mitophagy, and impaired response to energetic stress in the pathogenesis of mitochondrial optic neuropathies, potentially linked with mitochondrial mislocalization and mtDNA depletion.

Running for the line

In 1823, while playing a game of soccer at school, William Webb-Ellis broke the rules. He picked up the ball and ran the whole length of the pitch with it. This memorial statue is in the town of Rugby, which gave …

Running around in circles following ischemic stroke

I read Shaffer et al ’s paper with great interest, but it gave a strong sense of deja vu.1 The authors and ADC readers may find of interest Sigmund Freud’s comments on this particular topic from …

CHILD PATIENTS, HOSPITALS AND THE HOME IN EIGHTEENTH-CENTURY ENGLAND

Abstract This article seeks to map out some of the principal pathways to medical care used by the parents of poor children. We focus on the most formal provider of healthcare in eighteenth-century towns, the voluntary general hospitals, but we use these institutions as a prism to consider the way that the treatment of child sickness was managed more generally in five local settings. Utilising eighteenth-century hospital admissions and discharge registers we find that not only were children consistently treated as patients; but that these institutions also operated as part of a wider medical network which included domiciliary care, poor law services, and other medical charities. The boundaries surrounding hospital treatment in eighteenth-century towns were thus considerably more porous than is usually thought, and suggests that they operated as part of a wider medical network accessed by poor families for their children.

Timing of gastrostomy insertion in children with a neurodisability: a cross-sectional study of early versus late intervention

Objectives The aim of the study was to assess whether gastrostomy placement before 18 months of age results in a greater increase in z-score for weight and to assess whether admission rates were reduced postgastrostomy in this age group. Design Retrospective cross-sectional study. Setting Single-centre secondary care District General Hospital. Participants All children with a neurodisability with a gastrostomy in situ in September 2011 were included. Those with primary neoplasia and undergoing chemo or radiotherapy or being palliated for an aggressive neurodegenerative disorder were excluded. Those with cystic fibrosis, primary congenital heart disease or Inflammatory bowel disease were also excluded. Forty-one children underwent final analysis. Twenty-four children underwent gastrostomy insertion less than 18 months and 17 children were older than 18 months. Primary and secondary outcome measures Primary outcome was z-scores for weight immediately pregastrostomy and 12 months postgastrostomy. Secondary outcomes were hospital admission rates pregastrostomy and postgastrostomy. Values were compared for those with gastrostomy insertion less than or equal to 18 months against those older than 18 months at insertion. Results Z-score for weight increased significantly in both age groups. There was significantly increased mean difference in the z-score for weight of +1.33 pregastrostomy and postgastrostomy in the less than 18 months age group as compared with an increased mean difference in the z-score for weight of +0.45 in the older age group (p=0.021). There was no significant difference in the admission rates postgastrostomy insertion in either age group. Conclusions Gastrostomy insertion before 18 months of age results in greater z-score for weight gain in children with a neurodisability. This conclusion is limited by the lack of height and skin-fold thickness measurements. Further long-term matched control studies are required to determine the neurodevelopmental and clinical benefit of early gastrostomy placement in such children.

Developmental delay or failure to arrive

limited by puberty. Another similarity is the cerebral immaturity suggested by electroencephalography. As some children with ADHD, without seizures, degenerative conditions, or focal neurologic signs show abnormalities such as Rolandic spikes in a routine EEGs, the inclusion of EEGs in ADHD diagnostics seem essential to the identification of this subgroup. The EEG is the indicator of the need for specific testing, further evaluation and, perhaps, adequate therapy. Not performing routine EEG could result in the oversight of subclinical epileptic discharges in a considerable number of children with ADHD. We suggest that the update of practice parameters for the assessment and treatment of children with ADHD until puberty should include EEG, regardless of the lack of a prior history of overt seizures or other obvious neurological conditions.

Labor improbus omnia vincit; Ambroise Paré and sixteenth century child care.

Ambroise Paré (1510–1590) is regarded as one of the greatest surgeons who ever lived. In the sixteenth century, through his example and his writings, Paré did more than anybody else to raise the previously poor reputation of surgery “to one of dignity and esteem.”1 He significantly influenced the surgical management of wounds, especially those produced by gunshot.2 However, he wrote widely on other areas as well. Although Paré’s writings on obstetrics3 and infant feeding4 have been previously described, there has been little attention given to the other paediatric cases described in his case notes, which this review now addresses.

“To illustrate and increase Chyrurgerie”: Ambroise Paré (1510-1590)

The quincentenary of Ambroise Parés birth celebrates a man who rose from a humble origin to become the leading surgeon of the Renaissance. Now remembered as a celebrated war surgeon, especially for his gentle treatment of gunshot wounds, it is generally forgotten that Paré also treated children and wrote about them. Despite his little schooling, Paré was appointed as the Head of the French College of Surgeons in 1567. Parés contributions to child health include conservative management of childhood deformities, such as clubfoot and scoliosis. He also gave descriptions of conjoined twins and intersex. Paré managed childhood trauma and bladder stones using devices that he invented. This article will briefly demonstrate Parés wide-ranging contribution to pediatric surgery, adding new insights and material to earlier work.

Chapter 22: a history of child neurology and neurodisability.

This chapter reviews the fascinating history of child neurology and neurodisability from amongst its earliest recorded origins, Mesopotamian tablets, through to magnetic resonance imaging. It is the first review of such breadth in this area since Levinson in 1948. As well as covering the traditionally covered areas namely cerebral palsy, epilepsy, and mental retardation, the chapter explores other areas of pediatric neurodisability that have, since Levinson, become mainstream practice and now fall within this area of specialty. These conditions include the autistic spectrum disorders and attention deficit disorder. The dramatic advances in neural imaging and genetics in helping to explain different pediatric neurological conditions are also discussed as well as concepts and understanding concerning recovery from brain damage. The changing epidemiology of neurodisability through effective advances in acute neonatal and pediatric medical care, screening programs and social interventions are also related. Lastly, the fundamental reappraisal of societys attitude toward the disabled following World War II is explored. The lives of the disabled began to be seen to have value, belatedly gaining legal protection against discrimination, gaining dignity, independence, and for the first time being listened to.

G324 ‘The boudiccae’ – 21st century mothers’ voices – a short film

Previous histories presented at this meeting have separately covered individuals, institutions, specialities, subspecialties, and technology in the evolution of paediatrics and child health care. Dr Hannah Newton’s work has demonstrated the importance of mothers’ voices in early modern England (1580–1720).1 With medical advances leading to children surviving with evolving chronic disability, what would historians of the late 20th and early 21st centuries have to say about the voices of mothers of such children with ‘special needs’ ? ‘The Boudiccae’ is a 21st century project created firstly as a 9 voiced play and now as a short film based around 4 such voices. It is a performance piece of interlocking monologues of North-amptonshire (UK) mothers who have children with special needs. It encapsulates what are the principal child health issues today; such managing chronic evolving complex disability, palliative care, child adoption and acceptance of children with complex needs by their non-disabled peers. It highlights the families’ perspective and what they encounter when raising a child with complex health needs. I hope this film will teach compassion in the light of the Francis Report (2013).2 Its target audience is trainee healthcare professionals (medical, nursing, health visiting) whose limited experience of life means they have little to draw on when faced for the first time with children with complex needs and their families. A trailer can be viewed on: https://www.youtube.com/watch?v=32AjK2WIyUU I will gladly offer showings to educational institutions responsible for training healthcare professionals. Please email me to discuss further. Acknowledgements The film was produced by RIG Film Productions. The script was devised by Andrew N. Williams and the screenplay written by Andrew N. Williams and Darren White. The director is Darren White. Northampton General Hospital Charitable Funds, Waitrose Community Fund (2 appeals), the Virtual Academic Unit and an anonymous donor funded the film. Reference Newton, H. (2012) The Sick Child in Early Modern England, 1580–1720. Oxford University Press, Oxford, pp262. ISBN 9780199650491.