The neuronal metabolite NAA regulates histone H3 methylation in oligodendrocytes and myelin lipid composition.

The neuronal mitochondrial metabolite N-acetylaspartate (NAA) is decreased in the multiple sclerosis (MS) brain. NAA is synthesized in neurons by the enzyme N-acetyltransferase-8-like (NAT8L) and broken down in oligodendrocytes by aspartoacylase (ASPA) into acetate and aspartate. We have hypothesized that NAA links the metabolism of axons with oligodendrocytes to support myelination. To test this hypothesis, we performed lipidomic analyses using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance thin-layer chromatography (HPTLC) to identify changes in myelin lipid composition in postmortem MS brains and in NAT8L knockout (NAT8L-/-) mice which do not synthesize NAA. We found reduced levels of sphingomyelin in MS normal appearing white matter that mirrored decreased levels of NAA. We also discovered decreases in the amounts of sphingomyelin and sulfatide lipids in the brains of NAT8L-/- mice compared to controls. Metabolomic analysis of primary cultures of oligodendrocytes treated with NAA revealed increased levels of α-ketoglutarate, which has been reported to regulate histone demethylase activity. Consistent with this, NAA treatment resulted in alterations in the levels of histone H3 methylation, including H3K4me3, H3K9me2, and H3K9me3. The H3K4me3 histone mark regulates cellular energetics, metabolism, and growth, while H3K9me3 has been linked to alterations in transcriptional repression in developing oligodendrocytes. We also noted the NAA treatment was associated with increases in the expression of genes involved in sulfatide and sphingomyelin synthesis in cultured oligodendrocytes. This is the first report demonstrating that neuronal-derived NAA can signal to the oligodendrocyte nucleus. These data suggest that neuronal-derived NAA signals through epigenetic mechanisms in oligodendrocytes to support or maintain myelination.

Twenty-four-hour in-house neonatologist coverage and long-term neurodevelopmental outcomes of preterm infants.

OBJECTIVES: To compare short- and long-term neurodevelopmental outcomes at 3 years of corrected age of preterm infants cared for by 24-hour in-house staff neonatologists and those cared for by staff neonatologists during daytime only. METHODS: Retrospective analysis of prospectively collected follow-up data on all nonanomalous preterm infants from 1998 to 2004 excluding year 2001 as a washout period. Infants were divided into two groups based on care provided by staff neonatologists: 24-hour in-house coverage (24-hour coverage 1998-2000) and daytime coverage (day coverage 2002-2004). Short- and long-term outcomes were compared. RESULTS: A total of 387 (78%) of the screened infants were included. Twenty-four-hour coverage (n=179) and day coverage (n=208) groups had a median birth weight (BW) of 875 g (range 470-1250) and 922 g (480-1530; P=0.028), respectively, and both had a median gestational age of 27 weeks. In the day coverage group, a smaller proportion of mothers had chorioamnionitis (20% vs. 30%; P=0.025), received less antibiotics (62% vs. 73%; P=0.023), and infants had fewer cases of confirmed sepsis (14% vs. 23%; P=0.022). In the day coverage group, a larger number of infants had respiratory distress syndrome (87% vs. 77%; P=0.011) and required prolonged mechanical ventilation (median 31 vs. 21 days; P=0.002). The incidence of major neurodevelopmental impairment was not significantly different between the two groups (odds ratio 0.76; 95% confidence interval 0.34-1.65). CONCLUSIONS: Duration of mechanical ventilation was reduced with 24-hour in-house coverage by staff neonatologists. However, 24-hour coverage was not associated with any difference in neurodevelopmental (ND) outcomes at 3-year corrected age.

Colorectal cancer treatment and survival over three decades at four major public hospitals in South Australia: trends by age and in the elderly.

Data from registries at four major public hospitals in South Australia indicate increased 5-year disease-specific survivals for colorectal cancer from 48% to 63% between 1980-1986 and 2005-2010. For 80+ year olds, the increase was smaller, from 47% to 52%. Risk of case fatality halved overall, adjusting for age, gender, stage, differentiation and sub-site. Patients aged 80+ years had a lower risk reduction of about a third (hazards ratio: 0.69; 95% confidence limits, 0.52-0.92). Percentages having surgery and other specified treatments were lower for 80+ year olds than younger cases, although increases in treatment intensity occurred in this age range during 1980-2010, as seen in younger ages, in accordance with guidelines. The study illustrates the important feedback clinical registries can provide to clinicians on care patterns and outcomes in their hospital settings. Feedback can be the subject of local deliberations on how to achieve the best outcomes, including in the elderly by considering the best trade-offs between optimal cancer care and accommodations for co-morbidity and frailty. Clinical registry data can be used in comparative effectiveness research in local settings where there are sufficient case numbers.

Accelerated BEP for metastatic germ cell tumours: a multicenter phase II trial by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP).

BACKGROUND: This Australian single-arm, multicenter, phase II trial evaluated feasibility, tolerability and activity of accelerated bleomycin, etoposide and cisplatin (BEP) as first-line chemotherapy for metastatic germ cell tumours. PATIENTS AND METHODS: Patients were planned to receive cisplatin 20 mg/m(2) and etoposide 100 mg/m(2) days 1-5, and pegfilgrastim 6 mg day 6, all repeated every 2 weeks for four cycles (three cycles for good prognosis). Bleomycin was given at 30 000 IU weekly to a total of 12 doses (9 doses for good prognosis). Primary end point was feasibility, defined as the proportion of patients able to complete the etoposide and cisplatin components of BEP and be eligible to receive a fourth cycle of BEP by day 50. RESULTS: Twelve poor, 16 intermediate and 15 good prognosis (n = 43) eligible patients were enrolled. Two patients aged >40 years were ineligible and excluded from analyses. The regimen was feasible in 86%, not feasible in 7% and not assessable in 7% of patients. Most common grade 3/4 adverse events were non-neutropenic infection (16%) and febrile neutropenia (12%). Complete response (CR) to chemotherapy and surgery was achieved in 33% poor-prognosis, 81% intermediate-prognosis and 100% good-prognosis patients. At median follow-up of 27 months (range 6-42), the 2-year progression-free survival was 50% for poor-prognosis, 94% for intermediate-prognosis and 92% for good-prognosis patients. CONCLUSION: Accelerated BEP is feasible and tolerable. Efficacy data appear to be promising. This trial and a similar UK study provide the rationale for a randomised trial comparing accelerated versus standard BEP. Australian New Zealand Clinical Trials Registry Registration number. ACTRN 12607000294459.

Testosterone deficiency and quality of life in Australasian testicular cancer survivors: a prospective cohort study.

This is the first prospective study in a contemporary Australian/New Zealand population to determine the prevalence of testosterone deficiency in testicular cancer survivors at 12 months from treatment, and any association with poorer quality of life. Hormone assays from 54 evaluable patients in a prospective cohort study revealed biochemical hypogonadism in 18 patients (33%) and low-normal testosterone in 13 patients (24%). We found no association between testosterone levels and quality of life (all P > 0.05). Hypogonadal patients should be considered for testosterone replacement to prevent long-term morbidity.

Educational barriers of nurses caring for sick and at-risk infants in India.

AIM: To gain ideas and information from healthcare providers to optimize the education and clinical practices of nurses caring for sick or at-risk newborns in India. BACKGROUND: Improving infant survival has been identified as a Millennium Development Goals; however, India still faces many challenges with 3.1 million neonatal deaths and 2.6 million stillbirths annually. Skilled nursing care has been associated with decreased morbidity and mortality in newborns. However, core competencies in newborn care education and training are lacking for nurses. METHODS: Qualitative data were collected from 12 focus groups with 101 newborn care providers from three areas of India as well as from a 2-day stakeholders' meeting. Data analysis was undertaken using descriptive and thematic content analysis. RESULTS: Perceived challenges included limited manpower and high nurse turnover, lack of access to evidence-based orientation to newborn care and problems with access to appropriate learner-based, neonatal training. Relevant, ongoing education opportunities, led by nursing leaders were identified to be important solutions. CONCLUSION: Findings provide insight into the current healthcare system in India with specific reference to the nursing care of at-risk newborns. There is a lack of existing resources to provide standardized and specific orientation curricula for nurses. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Policy makers in health and education need to: support and enact learner-based orientation and continuing educational opportunities as well as ongoing competency-based education programmes; encourage nurse leader involvement and support; and provide sustainable system-related supports. Nurses and other health providers need to work together to influence government policy.

International validation of the EORTC QLQ-ELD14 questionnaire for assessment of health-related quality of life elderly patients with cancer.

BACKGROUND: Older people represent the majority of cancer patients but their specific needs are often ignored in the development of health-related quality of life (HRQOL) instruments. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-ELD15 was developed to supplement the EORTC's core questionnaire, the QLQ-C30, for measuring HRQOL in patients aged >70 years in oncology studies. METHODS: Patients (n=518) from 10 countries completed the QLQ-C30, QLQ-ELD15 and a debriefing interview. Eighty two clinically stable patients repeated the questionnaires 1 week later (test-retest analysis) and 107 others, with an expected change in clinical status, repeated the questionnaires 3 months later (response to change analysis, RCA). RESULTS: Information from the debriefing interview, factor analysis and item response theory analysis resulted in the removal of one item (QLQ-ELD15QLQ-ELD14) and revision of the proposed scale structure to five scales (mobility, worries about others, future worries, maintaining purpose and illness burden) and two single items (joint stiffness and family support). Convergent validity was good. In known-group comparisons, the QLQ-ELD14 differentiated between patients with different disease stage, treatment intention, number of comorbidities, performance status and geriatric screening scores. Test-retest and RCA analyses were equivocal. CONCLUSION: The QLQ-ELD14 is a validated HRQOL questionnaire for cancer patients aged 70 years. Changes in elderly patients' self-reported HRQOL may be related to both cancer evolution and non-clinical events.

Results of a 7-day aprepitant schedule for the prevention of nausea and vomiting in 5-day cisplatin-based germ cell tumor chemotherapy.

PURPOSE: The purpose of this study was to determine the efficacy of adding a 7-day aprepitant schedule to a 5HT3 receptor antagonist and dexamethasone for patients with germ cell tumors receiving first-line 5-day cisplatin-based chemotherapy. METHODS: In a single-arm, open-label, multi-center, phase 2 trial, chemo-naive patients received aprepitant 125 mg PO (per oral) on day 1 and 80 mg PO on days 2 to 7, a 5HT3 receptor antagonist on days 1 to 5, and dexamethasone 8 mg on days 1 to 8. The primary endpoint was no emesis (vomiting or dry retching) during days 1 to 7 of cycle 1. RESULTS: Fifty patients were recruited. For cycle 1, proportions reporting no emesis on day 1, no emesis on days 1 to 7, no nausea on day 1, and no nausea on days 1 to 7 were 96, 82, 71, and 27%, respectively. The efficacy was maintained in all cycles with over 80% of patients reporting no emesis on any given day of any given cycle. Emesis was more common on days 4 to 7 (68% episodes) than on days 1 to 3 (32% episodes). Over any 24-h period, 49% of patients with emesis reported no more than two episodes, and 62% of patients with nausea reported intensity as 3 or less on a scale from 0 to 10. There were no unexpected or serious adverse events reported. CONCLUSION: Adding 7 days of aprepitant to a 5HT3 receptor antagonist and dexamethasone effectively controlled acute and delayed emesis with 5-day cisplatin regimens. Days of nausea were more common than days of vomiting.

Treatment of farm dairy effluent with hybrid upflow multilayer bioreactor and activated sludge module.

Biological removal of nitrogen and carbon from farm dairy effluent (FDE) was studied with two laboratory-scale systems following nitrification and denitrification processes. Each system consisted of an upflow multilayer bioreactor (UMBR) as a pre-denitrification unit, an aeration tank (AT) as nitrification unit and a secondary clarifier. The optimization of two operational variables, total hydraulic retention time (HRT) and internal recycle (IR) rate with both real-FDE and a synthetic-wastewater were investigated. First, HRTs of 2, 3, 4 and 5 days were tested with synthetic-wastewater at uniform IR rate. The HRT of 4 days proved optimum with high efficiencies for nitrification (>90%), denitrification (>90%) and total chemical oxygen demand (COD) removal ( approximately 90%). The lowest efficiency was recorded at 2 days HRT with 7% nitrification efficiency. This was followed by experimentation with IR rates of 200%, 300% and 400% on both real-FDE and synthetic-wastewater at optimized HRT. The increase in IR to 300% improved the denitrification potential and overall performance with continuous high nitrification efficiency and COD removal whereas IR of 400% retarded the process. The application of combined UMBR and activated sludge system showed good potential for biological removal of nitrogen from FDE.

Development of Self-Healing Cement Slurry through the Incorporation of Dual-Encapsulated Polyacrylamide for the Prevention of Water Ingress in Oil Well.

In the present work, a novel cross-linked polymer was synthesized though the anionic polymerization of cyanoacrylate with moisture as an initiator, methylene-bis-acrylamide as a cross-linker, and linseed oil as a spacer. Two layers of the synthesized polymer was coated over polyacrylamide for its homogenous impregnation in Class-G cement slurry for the synthesis of cement core. Fourier Transformation Infrared spectroscopy and X-Ray diffraction spectrum of the synthesized polymer and cement core were obtained to investigate the presence of different functional groups and phases. Moreover, the morphologies of the dual-encapsulated polyacrylamide was observed through scanning electron microscopy. Furthermore, the water-absorption capacity of the synthesized dual-encapsulated polyacrylamide in normal and saline conditions were tested. A cement core impregnated with 16% of dosage of dual-encapsulated polyacrylamide possesses an effective self-healing capability during the water-flow test. Moreover, the maximum linear expansion of the cement core was observed to be 26%. Thus, the impregnation of dual-encapsulated polyacrylamide in cement slurry can exhibit a superior self-healing behavior upon water absorption in an oil well.

Cancer in older people: a tale of two disciplines.

Management of cancer in the elderly presents an unprecedented challenge in Australia with the proportion of the population aged over 65 years set to double over the next four decades. Despite the complex healthcare needs of the older patient with cancer, there is currently little communication or cooperation between the fields of oncology and geriatrics. Improved interdisciplinary communication would facilitate care that is framed within current oncology practice while taking account of physiological age, complex comorbidities, risk of adverse events and pharmacological interactions as well as the implications of cognitive impairment on suitability for treatment and consent. An important first step has been taken towards the development of a strategic, focused and collaborative approach to the management of cancer in older people through a national interdisciplinary workshop convened by the Clinical Oncological Society of Australia in April 2008. Engagement and commitment of both oncology and geriatric disciplines is now critical to ensure that momentum is not lost in progressing this important and growing area of healthcare.

Biodegradation of agricultural herbicides in sequencing batch reactors under aerobic or anaerobic conditions.

This study investigated the biodegradability of the herbicides isoproturon and 2,4-dichlorophenoxyacetic acid (2,4-D) in sequencing batch reactors (SBRs). Two laboratory-scale (2L liquid volume) SBRs were employed: one reactor performing under aerobic and the other under anaerobic conditions. The aerobic SBR was operated at an ambient temperature (22+/-2 degrees C), while the anaerobic SBR was run in the lower mesophilic range (30+/-2 degrees C). Each bioreactor was seeded with a 3:1 mixture (by weight) of fresh sludge and biomass that had been previously exposed to both herbicides. The effect of herbicide concentration on either treatment process was explored at a hydraulic retention time (HRT) of 48 h, using glucose as a supplemental carbon substrate. Although no isoproturon degradation was observed in either system during the study, complete 2,4-D removal occurred after an acclimation period of approximately 30 d (aerobic SBR) and 70 d (anaerobic SBR). The aerobic reactor achieved complete 2,4-D utilization at feed concentrations up to 500 mg/L. A further increase to 700 mg/L, however, proved to be inhibitory since 2,4-D biodegradation was negligible. On the other hand, the anaerobic SBR was able to degrade 120 mg/L of 2,4-D, which corresponds to 40% of the maximum feed concentration applied. Moreover, glucose was consumed first throughout the experiment in a sequential utilization pattern relating to 2,4-D, with biodegradation of both substrates following closely first-order kinetics.

Evaluation of clinico-urodynamic outcome of bladder dysfunction after surgery in children with spinal dysraphism - a prospective study.

BACKGROUND: The aim was to asses the clinical profile and urodynamic findings and the outcome of surgery in children with spinal dysraphism. METHOD: Twenty five children with spinal dysraphism who were treated at our institute between January 2005 and June 2006 were studied prospectively. There were 10 with an open spina bifida and 15 closed. The clinical profile of bladder dysfunction was assessed and urodynamic evaluation done pre-operatively in each child. An ultrasound study of the kidneys was also done to assess for hydro-uretero-nephrois. All underwent surgery for their primary and associated malformations. Post-operatively, re-evaluation of bladder dysfunction and urodynamic parameters was performed at 6-8 months. RESULTS: Before operation there was a history indicating that the bladder was involved in 14 of the 25 children. Six of the 10 cases with an open spina bifida showed clinical involvement of the bladder as compared to 8 of 15 with a closed pattern. Urodynamic studies showed evidence of bladder dysfunction in 19 children. Of 10 with a meningomyelocele, there were abnormal urodynamics in 9 as compared to 10 of 15 with closed dysraphism. Follow up urodynamic studies showed improvement in 9 of 20 children 3 of 7 with a meningomyelocele and 6 of 13 with closed dysraphism. CONCLUSION: Children with open spina bifida, as compared to closed dysraphism, tend to have more bladder dysfunction as exemplified on clinical history and urodynamic assessment. A pre-operative urodynamic study helps to identify severity of bladder dysfunction which is clinically overt cases and also identifies subtle bladder dysfunction in clinically silent cases. Evaluation after operation tends to shows better outcome in children with closed dysraphism. The study also identifies deterioration in some patients with seemingly clinical improvement.

Degradation of hexachloroethane by Fenton's reagents.

The effect of hydrogen peroxide (H2O2) concentrations on the degradation of hexachloroethane (HCA) in the absence and the presence of tetrachloroethene (PCE) by Fenton's reagent was investigated at pH 3 with 1 mM iron(II) and H2O2 concentrations ranging from 0.01 M to 2 M. HCA degradation in the absence of PCE increased with increasing H2O2 concentration between 0.2 M and 2 M. In the presence of PCE, HCA degradation was similar to that in the absence of PCE for H2O2 concentration up to 1 M, but significantly higher for 2 M H2O2. We propose that this increase is a result of elevated reductant radicals when PCE is present. This study highlights the need for further investigation into the degradation of contaminant mixtures at higher H2O2 concentrations.

Modeling Cd2+ sorption onto ferrihydrite in the presence of phthalic acid.

Cadmium sorption by ferrihydrite in the presence of phthalic acid was examined over a range of pH (4.0 approximately 8.5) conditions and sorbate/sorbent ratios. The presence of phthalic acid enhanced Cd(2+) sorption by forming ternary complexes on ferrihydrite surface, especially at low pH, but for high pH and high total organic ligand/Fe(mmol/mol) ratios, it decreased Cd(2+) sorption onto ferrihydrite by forming soluble complexes with the phthalate in solution. In binary systems, Cd(2+) and phthalic acid sorption by ferrihydrite was well reproduced using the diffuse layer model with sorption constants derived from the experimental data. Prediction using the optimised binary sorption constants for Cd(2+) sorption onto ferrihydrite in the presence of phthalic was poor and achieving a good fit required the inclusion of two additional ternary complexes.

Serum zinc levels in celiac disease.

This study was done to determine the zinc levels in 30 children with celiac disease. Serum zinc level was estimated at inclusion and zinc supplementation was given for 3 months. Zinc levels were repeated at 3 and 6 months after inclusion. The serum zinc levels of newly diagnosed CD cases (0.64+/-0.34 microg/mL) versus controls (0.94+/-0.14 microg/mL) were significantly lower (95% CI -0.44 to -1.4), whereas in the old cases this difference was non-significant. The serum zinc level among severely malnourished and stunted celiac cases was also significantly lower irrespective of their treatment status. We conclude that serum zinc levels are low in newly diagnosed and severely malnourished children with celiac disease.

Erythropoietin Upregulates Brain Hemoglobin Expression and Supports Neuronal Mitochondrial Activity.

Multiple sclerosis (MS) is a neuro-inflammatory and demyelinating disease. Downregulation of neuronal mitochondrial gene expression and activity have been reported in several studies of MS. We have previously shown that hemoglobin-ß (Hbb) signals to the nucleus of neurons and upregulates H3K4me3, a histone mark involved in regulating cellular metabolism and differentiation. The present study was undertaken to evaluate the effect of erythropoietin (EPO) on the upregulation of hemoglobin and mitochondrial-associated neuroprotection. We found that administering EPO (5000 IU/kg intraperitoneally) to mice upregulated brain Hbb expression, levels of H3K4me3, expression of mitochondrial complex III, complex V, and mitochondrial respiration. We also found that the neuronal mitochondrial metabolite N-acetylaspartate (NAA), a marker of neuronal mitochondrial activity, was increased with EPO treatment. Further, we measured the effects of EPO on preventing mitochondrial deficits in the cuprizone toxic demyelinating mouse model of MS. We found that EPO prevented cuprizone-mediated decreases in Hbb, complex III, and NAA. Our data suggest that EPO mediated regulation of Hbb supports neuronal energetics and may provide neuroprotection in MS and other neurodegenerative diseases where a dysfunction of mitochondria contributes to disease.