Target Impact Location Determination: An Analytic Method

This thesis constructs and implements a model for 2-dimensional impact location determination and applies it to a simple experimental setup. In seeking a versatile solution, only minimal data is used to determine the impact location. In practice, this includes sound waveform data collected by microphones and the location of the microphones themselves. Using this data, the time of arrival (TOA) of the sound can be computed. Then, using TOAs from multiple microphones, time deltas, known as time differences of arrival (TDOAs), can be found. Equipped with TDOAs and the locations of the microphones, hyperbolae can be constructed and intersected to determine the sound’s point of origin. Strikingly, hyperbola construction and intersection proved to be simple to define and implement. Instead, the generation of TOAs and choosing a final point of origin proved to be much more sophisticated problems; the results of which further reinforced the importance of choosing accurate TDOAs. It was found that location determination had varying degrees of success, with the best results found near the center of the experimental apparatus where all microphones are roughly equidistant. Finally, ideas are discussed for further enhancement and areas needing additional iteration

A Novel Tandem Mass Spectrometry Method for Rapid Confirmation of Medium- and Very Long-Chain acyl-CoA Dehydrogenase Deficiency in Newborns

BACKGROUND:Newborn screening for medium- and very long-chain acyl-CoA dehydrogenase (MCAD and VLCAD, respectively) deficiency, using acylcarnitine profiling with tandem mass spectrometry, has increased the number of patients with fatty acid oxidation disorders due to the identification of additional milder, and so far silent, phenotypes. However, especially for VLCADD, the acylcarnitine profile can not constitute the sole parameter in order to reliably confirm disease. Therefore, we developed a new liquid chromatography tandem mass spectrometry (LC-MS/MS) method to rapidly determine both MCAD- and/or VLCAD-activity in human lymphocytes in order to confirm diagnosis. METHODOLOGY:LC-MS/MS was used to measure MCAD- or VLCAD-catalyzed production of enoyl-CoA and hydroxyacyl-CoA, in human lymphocytes. PRINCIPAL FINDINGS:VLCAD activity in controls was 6.95+/-0.42 mU/mg (range 1.95 to 11.91 mU/mg). Residual VLCAD activity of 4 patients with confirmed VLCAD-deficiency was between 0.3 and 1.1%. Heterozygous ACADVL mutation carriers showed residual VLCAD activities of 23.7 to 54.2%. MCAD activity in controls was 2.38+/-0.18 mU/mg. In total, 28 patients with suspected MCAD-deficiency were assayed. Nearly all patients with residual MCAD activities below 2.5% were homozygous 985A>G carriers. MCAD-deficient patients with one other than the 985A>G mutation had higher MCAD residual activities, ranging from 5.7 to 13.9%. All patients with the 199T>C mutation had residual activities above 10%. CONCLUSIONS:Our newly developed LC-MS/MS method is able to provide ample sensitivity to correctly and rapidly determine MCAD and VLCAD residual activity in human lymphocytes. Importantly, based on measured MCAD residual activities in correlation with genotype, new insights were obtained on the expected clinical phenotype

NMDA receptor genotypes associated with the vulnerability to develop dyskinesia

Dyskinesias are involuntary muscle movements that occur spontaneously in Huntington's disease (HD) and after long-term treatments for Parkinson's disease (levodopa-induced dyskinesia; LID) or for schizophrenia (tardive dyskinesia, TD). Previous studies suggested that dyskinesias in these three conditions originate from different neuronal pathways that converge on overstimulation of the motor cortex. We hypothesized that the same variants of the N-methyl--aspartate receptor gene that were previously associated with the age of dyskinesia onset in HD were also associated with the vulnerability for TD and not LID. Genotyping patients with LID and TD revealed, however, that these two variants were dose-dependently associated with susceptibility to LID, but not TD. This suggested that LID, TD and HD might arise from the same neuronal pathways, but TD results from a different mechanism

Functional abdominal complaints in pre-school children: parental reports of health-related quality of life

Purpose The aim of this study is to assess the influence of functional abdominal complaints (FAC) on health-related quality of life in a group of Dutch pre-school children. Methods Parents of children aged up to 6.0 visiting the outpatient pediatric department, Erasmus MC-Sophia, Rotterdam, The Netherlands in the period January 2005-December 2006 for functional abdominal complaints during at least 3 months were asked to complete the Infant/Toddler Quality of life Questionnaire (ITQOL), and questions of the abdominal pain index for use by parents to report pain symptoms in pre-school children. ITQOL scale scores of children with FAC were compared against with Dutch reference values. The abdominal pain index was tested for internal consistency and test-retest reliability. Correlations between ITQOL scale scores and abdominal pain index were assessed by Spearman's rank test. Results Results are based on 81 questionnaires completed by parents of children with FAC (response rate 61%). Children had a median age of 46 months (interquartile range 27-59), 48% girls. A significant impact was observed on most aspects of quality of life, particularly for physical functioning, general development, bodily pain, temperament and moods, general health perceptions and parental emotional impact. Parents of children with functional constipation tended to report lower scores than those of children with other FAC. The abdominal pain index appeared to be valid and was significantly correlated with ITQOL scales bodily pain and general health perceptions. Conclusions A substantial lower health-related quality of life is reported in pre-school children with functional abdominal complaints, with effects on physical, emotional and parental domains. The 5-question severity index of abdominal pain appeared a valid tool and may be helpful to quickly assess the severity of abdominal pain in clinical practice

Resuscitation of Newborn Piglets. Short-Term Influence of FiO2 on Matrix Metalloproteinases, Caspase-3 and BDNF

Perinatal hypoxia-ischemia is a major cause of mortality and cerebral morbidity, and using oxygen during newborn resuscitation may further harm the brain. The aim was to examine how supplementary oxygen used for newborn resuscitation would influence early brain tissue injury, cell death and repair processes and the regulation of genes related to apoptosis, neurodegeneration and neuroprotection.Anesthetized newborn piglets were subjected to global hypoxia and then randomly assigned to resuscitation with 21%, 40% or 100% O(2) for 30 min and followed for 9 h. An additional group received 100% O(2) for 30 min without preceding hypoxia. The left hemisphere was used for histopathology and immunohistochemistry and the right hemisphere was used for in situ zymography in the corpus striatum; gene expression and the activity of various relevant biofactors were measured in the frontal cortex. There was an increase in the net matrix metalloproteinase gelatinolytic activity in the corpus striatum from piglets resuscitated with 100% oxygen vs. 21%. Hematoxylin-eosin (HE) staining revealed no significant changes. Nine hours after oxygen-assisted resuscitation, caspase-3 expression and activity was increased by 30-40% in the 100% O(2) group (n = 9/10) vs. the 21% O(2) group (n = 10; p<0.04), whereas brain-derived neurotrophic factor (BDNF) activity was decreased by 65% p<0.03.The use of 100% oxygen for resuscitation resulted in increased potentially harmful proteolytic activities and attenuated BDNF activity when compared with 21%. Although there were no significant changes in short term cell loss, hyperoxia seems to cause an early imbalance between neuroprotective and neurotoxic mechanisms that might compromise the final pathological outcome

Improving implementation of evidence-based practice in mental health service delivery: protocol for a cluster randomised quasi-experimental investigation of staff-focused values interventions

BACKGROUND: There is growing acceptance that optimal service provision for individuals with severe and recurrent mental illness requires a complementary focus on medical recovery (i.e., symptom management and general functioning) and personal recovery (i.e., having a ‘life worth living’). Despite significant research attention and policy-level support, the translation of this vision of healthcare into changed workplace practice continues to elude. Over the past decade, evidence-based training interventions that seek to enhance the knowledge, attitudes, and skills of staff working in the mental health field have been implemented as a primary redress strategy. However, a large body of multi-disciplinary research indicates disappointing rates of training transfer. There is an absence of empirical research that investigates the importance of worker-motivation in the uptake of desired workplace change initiatives. ‘Autonomy’ is acknowledged as important to human effectiveness and as a correlate of workplace variables like productivity, and wellbeing. To our knowledge, there have been no studies that investigate purposeful and structured use of values-based interventions to facilitate increased autonomy as a means of promoting enhanced implementation of workplace change. METHODS: This study involves 200 mental health workers across 22 worksites within five community-managed organisations in three Australian states. It involves cluster-randomisation of participants within organisation, by work site, to the experimental (values) condition, or the control (implementation). Both conditions receive two days of training focusing on an evidence-based framework of mental health service delivery. The experimental group receives a third day of values-focused intervention and 12 months of values-focused coaching. Well-validated self-report measures are used to explore variables related to values concordance, autonomy, and self-reported implementation success. Audits of work files and staff work samples are reviewed for each condition to determine the impact of implementation. Self-determination theory and theories of organisational change are used to interpret the data. DISCUSSION: The research adds to the current knowledge base related to worker motivation and uptake of workplace practice. It describes a structured protocol that aims to enhance worker autonomy for imposed workplace practices. The research will inform how best to measure and conceptualise transfer. These findings will apply particularly to contexts where individuals are not ‘volunteers’ in requisite change processes. TRIAL REGISTRATION: ACTRN: ACTRN12613000353796

Reliability and validity of the Infant and Toddler Quality of Life Questionnaire (ITQOL) in a general population and respiratory disease sample

Objective: To evaluate feasibility, internal consistency, test-retest reliability, and concurrent and discriminative validity of the Infant and Toddler Quality of Life Questionnaire (ITQOL) for parents of pre-school children with 12 scales (103-items) covering physical and psychosocial domains and impact of child health on parents, in comparison with the TNO-AZL Pre-school Children Quality of Life Questionnaire (TAPQOL). Methods: Parents of children from a random general population sample (2 months-4 years old; n = 500) and of an outpatient clinic sample of children with respiratory disease (5 months-51/2 years old; n = 217) were mailed ITQOL and TAPQOL questionnaires; a retest was sent after two weeks. Results: Feasibility: The response was ≥80% with few missing and non-unique ITQOL-answers (25% at maximum score). Internal consistency: All Cronbach's α >0.70. Test-retest Intraclass Correlation Coefficients (ICCs) were moderate or adequate (≥0.50; p < 0.01) for 10 ITQOL-scales. Validity: ITQOL-scales, with a few exceptions, correlated better with predefined parallel TAPQOL scales than with non-parallel scales. Five to eight ITQOL-scales discriminated clearly between children with few and with many parent-reported chronic conditions, between children with and without doctor-diagnosed respiratory disease and with a low and a high parent-reported medical consumption (p < 0.05). Conclusions: This study supported the evidence that the ITQOL is a feasible instrument with adequate psychometric properties. The study provided reference ITQOL scores for gender/age subgroups. We recommend repeated evaluations of the ITQOL in varied populations, especially among very young children, including repeated assessments of test-retest characteristics and evaluations of responsiveness to change. We recommend developing and evaluating a shortened ITQOL version

Environmental Constraints Guide Migration of Malaria Parasites during Transmission

Migrating cells are guided in complex environments mainly by chemotaxis or structural cues presented by the surrounding tissue. During transmission of malaria, parasite motility in the skin is important for Plasmodium sporozoites to reach the blood circulation. Here we show that sporozoite migration varies in different skin environments the parasite encounters at the arbitrary sites of the mosquito bite. In order to systematically examine how sporozoite migration depends on the structure of the environment, we studied it in micro-fabricated obstacle arrays. The trajectories observed in vivo and in vitro closely resemble each other suggesting that structural constraints can be sufficient to guide Plasmodium sporozoites in complex environments. Sporozoite speed in different environments is optimized for migration and correlates with persistence length and dispersal. However, this correlation breaks down in mutant sporozoites that show adhesion impairment due to the lack of TRAP-like protein (TLP) on their surfaces. This may explain their delay in infecting the host. The flexibility of sporozoite adaption to different environments and a favorable speed for optimal dispersal ensures efficient host switching during malaria transmission

Sustained Na⁺/H⁺ exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation

Hypoxia ischemia (HI)-related brain injury is the major cause of long-term morbidity in neonates. One characteristic hallmark of neonatal HI is the development of reactive astrogliosis in the hippocampus. However, the impact of reactive astrogliosis in hippocampal damage after neonatal HI is not fully understood. In the current study, we investigated the role of Na +/H+ exchanger isoform 1 (NHE1) protein in mouse reactive hippocampal astrocyte function in an in vitro ischemia model (oxygen/glucose deprivation and reoxygenation, OGD/REOX). 2 h OGD significantly increased NHE1 protein expression and NHE1-mediated H+ efflux in hippocampal astrocytes. NHE1 activity remained stimulated during 1-5 h REOX and returned to the basal level at 24 h REOX. NHE1 activation in hippocampal astrocytes resulted in intracellular Na+ and Ca2+ overload. The latter was mediated by reversal of Na+/Ca2+ exchange. Hippocampal astrocytes also exhibited a robust release of gliotransmitters (glutamate and pro-inflammatory cytokines IL-6 and TNFα) during 1-24 h REOX. Interestingly, inhibition of NHE1 activity with its potent inhibitor HOE 642 not only reduced Na+ overload but also gliotransmitter release from hippocampal astrocytes. The noncompetitive excitatory amino acid transporter inhibitor TBOA showed a similar effect on blocking the glutamate release. Taken together, we concluded that NHE1 plays an essential role in maintaining H + homeostasis in hippocampal astrocytes. Over-stimulation of NHE1 activity following in vitro ischemia disrupts Na+ and Ca2+ homeostasis, which reduces Na+-dependent glutamate uptake and promotes release of glutamate and cytokines from reactive astrocytes. Therefore, blocking sustained NHE1 activation in reactive astrocytes may provide neuroprotection following HI. © 2014 Cengiz et al