Mitochondrial fusion is regulated by Reaper to modulate Drosophila programmed cell death

In most multicellular organisms, the decision to undergo programmed cell death in response to cellular damage or developmental cues is typically transmitted through mitochondria. It has been suggested that an exception is the apoptotic pathway of Drosophila melanogaster, in which the role of mitochondria remains unclear. Although IAP antagonists in Drosophila such as Reaper, Hid and Grim may induce cell death without mitochondrial membrane permeabilization, it is surprising that all three localize to mitochondria. Moreover, induction of Reaper and Hid appears to result in mitochondrial fragmentation during Drosophila cell death. Most importantly, disruption of mitochondrial fission can inhibit Reaper and Hid-induced cell death, suggesting that alterations in mitochondrial dynamics can modulate cell death in fly cells. We report here that Drosophila Reaper can induce mitochondrial fragmentation by binding to and inhibiting the pro-fusion protein MFN2 and its Drosophila counterpart dMFN/Marf. Our in vitro and in vivo analyses reveal that dMFN overexpression can inhibit cell death induced by Reaper or γ-irradiation. In addition, knockdown of dMFN causes a striking loss of adult wing tissue and significant apoptosis in the developing wing discs. Our findings are consistent with a growing body of work describing a role for mitochondrial fission and fusion machinery in the decision of cells to die

The Roles and Acting Mechanism of Caenorhabditis elegans DNase II Genes in Apoptotic DNA Degradation and Development

DNase II enzymes are acidic endonucleases that have been implicated in mediating apoptotic DNA degradation, a critical cell death execution event. C. elegans genome contains three DNase II homologues, NUC-1, CRN-6, and CRN-7, but their expression patterns, acting sites, and roles in apoptotic DNA degradation and development are unclear. We have conducted a comprehensive analysis of three C. elegans DNase II genes and found that nuc-1 plays a major role, crn-6 plays an auxiliary role, and crn-7 plays a negligible role in resolving 3′ OH DNA breaks generated in apoptotic cells. Promoter swapping experiments suggest that crn-6 but not crn-7 can partially substitute for nuc-1 in mediating apoptotic DNA degradation and both fail to replace nuc-1 in degrading bacterial DNA in intestine. Despite of their restricted and largely non-overlapping expression patterns, both CRN-6 and NUC-1 can mediate apoptotic DNA degradation in many cells, suggesting that they are likely secreted nucleases that are retaken up by other cells to exert DNA degradation functions. Removal or disruption of NUC-1 secretion signal eliminates NUC-1's ability to mediate DNA degradation across its expression border. Furthermore, blocking cell corpse engulfment does not affect apoptotic DNA degradation mediated by nuc-1, suggesting that NUC-1 acts in apoptotic cells rather than in phagocytes to resolve 3′ OH DNA breaks. Our study illustrates how multiple DNase II nucleases play differential roles in apoptotic DNA degradation and development and reveals an unexpected mode of DNase II action in mediating DNA degradation

Drosophila cbl Is Essential for Control of Cell Death and Cell Differentiation during Eye Development

Activation of cell surface receptors transduces extracellular signals into cellular responses such as proliferation, differentiation and survival. However, as important as the activation of these receptors is their appropriate spatial and temporal down-regulation for normal development and tissue homeostasis. The Cbl family of E3-ubiquitin ligases plays a major role for the ligand-dependent inactivation of receptor tyrosine kinases (RTKs), most notably the Epidermal Growth Factor Receptor (EGFR) through ubiquitin-mediated endocytosis and lysosomal degradation.Here, we report the mutant phenotypes of Drosophila cbl (D-cbl) during eye development. D-cbl mutants display overgrowth, inhibition of apoptosis, differentiation defects and increased ommatidial spacing. Using genetic interaction and molecular markers, we show that most of these phenotypes are caused by increased activity of the Drosophila EGFR. Our genetic data also indicate a critical role of ubiquitination for D-cbl function, consistent with biochemical models.These data may provide a mechanistic model for the understanding of the oncogenic activity of mammalian cbl genes

Is the APLS formula used to calculate weight-for-age applicable to a Trinidadian population?

In paediatric emergency medicine, estimation of weight in ill children can be performed in a variety of ways. Calculation using the 'APLS' formula (weight = [age + 4] × 2) is one very common method. Studies on its validity in developed countries suggest that it tends to under-estimate the weight of children, potentially leading to errors in drug and fluid administration. The formula is not validated in Trinidad and Tobago, where it is routinely used to calculate weight in paediatric resuscitation

Paediatric procedural sedation within the emergency department

Procedural sedation and analgesia in children requires the use of non-pharmacological and pharmacological approaches to facilitate the management of painful procedures. The development of skills in such techniques has mirrored the development of paediatric emergency medicine as a subspecialty. Governance, education and credentialing must facilitate safe sedation practice, using a structured approach, as sedating children in the busy environment of an emergency department is not without risk. Emergency clinicians, patients and caregivers all have a role to play in developing a safe, effective sedation plan.David Krieser, Amit Kocha

Paediatric procedural sedation within the emergency department

Procedural sedation and analgesia in children requires the use of non-pharmacological and pharmacological approaches to facilitate the management of painful procedures. The development of skills in such techniques has mirrored the development of paediatric emergency medicine as a subspecialty. Governance, education and credentialing must facilitate safe sedation practice, using a structured approach, as sedating children in the busy environment of an emergency department is not without risk. Emergency clinicians, patients and caregivers all have a role to play in developing a safe, effective sedation plan

High prevalence of vitamin D deficiency in 2-17 year olds presenting with acute fractures in southern Australia.

AIM: To determine vitamin D deficiency risk and other lifestyle factors in children aged 2-17 years presenting with an acute fracture to Sunshine Hospital. METHODS: A prospective observational study was undertaken using a convenience sample data collected from children aged 2-17 years of age presenting with an acute fracture. Recruitment was undertaken over a 3-month period from February to May 2014. Risk factors for vitamin D deficiency (skin pigmentation, hours spent outdoors, sunscreen use and obesity) were identified. Patients providing consent, had measurements of serum 25-hydroxyvitamin D (25-OHD). Vitamin D deficiency was defined as < 50 nmol/L. RESULTS: Of the 163 patients recruited into this study, 134 (82%) had one or more risk factor(s) for vitamin D deficiency. Of these, 109 (81%) consented to 25-OHD testing, with a median of 53 nmol/l (range 14-110 nmol/l) obtained. A total of 57 (52% at risk, 35% of total participants) were found to be vitamin D deficient. 45 (80%) had mild deficiency (30-50 nmol/l) and 11 (20%) had moderate deficiency (12.5-29 nmol/l). CONCLUSIONS: One third of all participants, and the majority participants who had one or more risk factor(s) for vitamin D deficiency, were vitamin D deficient. Based on our findings we recommend that vitamin D status be assessed in all children with risk factor of vitamin D deficiency living in urban environments at higher latitudes presenting with fractures. The effect of vitamin D status on fracture risk and fracture healing in children and teenagers is yet to be determined, as do the effects of vitamin D supplementation in vitamin D deficient paediatric patients presenting with acute fracture

Sub‐optimal treatment of paediatric migraine in an emergency department: An observational study

OBJECTIVES: To describe treatment of children presenting to an Australian ED with a final ED diagnosis of migraine. METHODS: Planned substudy of a retrospective cohort study of the epidemiology of headache in children was done. Primary outcome of interest was treatment administered in the ED. RESULTS: Thirty-five children were studied. The most commonly used medications were non-steroidal anti-inflammatory drugs, paracetamol and ondansetron. Specific antimigraine therapy was used uncommonly. Fourteen percent of children received an opiate. CONCLUSION: Treatment of migraine in children was not consistent with the available evidence regarding agents' relative effectiveness. The use of opiates is concerningly high