Ceruloplasmin deletion in myelinating glial cells induces myelin disruption and oxidative stress in the central and peripheral nervous systems.

Ceruloplasmin (Cp) is a ferroxidase enzyme that is essential for cell iron efflux and has been postulated to have a neuroprotective role. During the myelination process, oligodendrocytes (OLs) and Schwann cells (SCs) express high levels of Cp, but the role of this enzyme in glial cell development and function is completely unknown. To define the function of Cp in the myelination of the central and peripheral nervous systems, we have conditionally knocked-out Cp specifically in OLs and SCs during early postnatal development as well as in aged mice. Cp ablation in early OLs (postnatal day 2, P2) significantly affects the differentiation of these cells and the synthesis of myelin through the first four postnatal weeks. The total number of mature myelinating OLs was reduced, and the density of apoptotic OLs was increased. These changes were accompanied with reductions in the percentage of myelinated axons and increases in the g-ratio of myelinated fibers. Cp ablation in young myelinating OLs (P30 or P60) did not affect myelin synthesis and/or OL numbers, however, Cp loss in aged OLs (8 months) induced cell iron overload, apoptotic cell death, brain oxidative stress, neurodegeneration and myelin disruption. Furthermore, Cp deletion in SCs affected postnatal SC development and myelination and produced motor coordination deficits as well as oxidative stress in young and aged peripheral nerves. Together, our data indicate that Cp ferroxidase activity is essential for OLs and SCs maturation during early postnatal development and iron homeostasis in matured myelinating cells. Additionally, our results suggest that Cp expression in myelinating glial cells is crucial to prevent oxidative stress and neurodegeneration in the central and peripheral nervous systems.

Fault-tolerant detection of a quantum error.

A critical component of any quantum error-correcting scheme is detection of errors by using an ancilla system. However, errors occurring in the ancilla can propagate onto the logical qubit, irreversibly corrupting the encoded information. We demonstrate a fault-tolerant error-detection scheme that suppresses spreading of ancilla errors by a factor of 5, while maintaining the assignment fidelity. The same method is used to prevent propagation of ancilla excitations, increasing the logical qubit dephasing time by an order of magnitude. Our approach is hardware-efficient, as it uses a single multilevel transmon ancilla and a cavity-encoded logical qubit, whose interaction is engineered in situ by using an off-resonant sideband drive. The results demonstrate that hardware-efficient approaches that exploit system-specific error models can yield advances toward fault-tolerant quantum computation.

A CNOT gate between multiphoton qubits encoded in two cavities.

Entangling gates between qubits are a crucial component for performing algorithms in quantum computers. However, any quantum algorithm must ultimately operate on error-protected logical qubits encoded in high-dimensional systems. Typically, logical qubits are encoded in multiple two-level systems, but entangling gates operating on such qubits are highly complex and have not yet been demonstrated. Here we realize a controlled NOT (CNOT) gate between two multiphoton qubits in two microwave cavities. In this approach, we encode a qubit in the high-dimensional space of a single cavity mode, rather than in multiple two-level systems. We couple two such encoded qubits together through a transmon, which is driven by an RF pump to apply the gate within 190 ns. This is two orders of magnitude shorter than the decoherence time of the transmon, enabling a high-fidelity gate operation. These results are an important step towards universal algorithms on error-corrected logical qubits.

The use of a simple three-level bronchoscopic assessment of inhalation injury to predict in-hospital mortality and duration of mechanical ventilation in patients with burns.

Major burn centres in Australia use bronchoscopy to assess severity of inhalation injuries despite limited evidence as to how best to classify severity of inhalational injury or its relationship to patient outcomes. All patients with burns who were admitted to the intensive care unit (ICU) at The Alfred Hospital between February 2010 and July 2014 and underwent bronchoscopy to assess inhalational injury, were reviewed. Age, total body surface area burnt, severity of illness indices and mechanisms of injury were extracted from medical histories and local ICU and burns registries. Inhalational injury was classified based on the Abbreviated Injury Score and then grouped into three categories (none/mild, moderate, or severe injury). Univariable and multivariable analyses were undertaken to examine the relationship between inhalational injury and outcomes (in-hospital mortality and duration of mechanical ventilation). One hundred and twenty-eight patients were classified as having none/mild inhalational injury, 81 moderate, and 13 severe inhalation injury. Mortality in each group was 2.3% (3/128), 7.4% (6/81) and 30.7% (4/13) respectively. Median (interquartile range) duration of mechanical ventilation in each group was 26 (11-82) hours, 84 (32-232) hours and 94 (21-146) hours respectively. After adjusting for age, total body surface area burnt and severity of illness, only the severe inhalation injury group was independently associated with increased mortality (odds ratio 20.4 [95% confidence intervals {CI} 1.74 to 239.4], P=0.016). Moderate inhalation injury was independently associated with increased duration of ventilation (odds ratio 2.25 [95% CI 1.53 to 3.31], P <0.001), but not increased mortality. This study suggests that stratification of bronchoscopically-assessed inhalational injury into three categories can provide useful prognostic information about duration of ventilation and mortality. Larger multicentre prospective studies are required to validate these findings.

Participation in leisure activities: differences between children with and without physical disabilities.

The aim of the current study was to compare varied dimensions of participation in leisure activities among school-aged children ages 10-16 with and without disabilities. The Children Leisure Activity Scale (CLASS) was administrated to 294 children, 81 with and 213 without physical disability. Two-way MANCOVA revealed significant differences between the frequency of participation in leisure activities of the study groups: an effect of disability F(4,265=239.57; p<0.001, η(2)=0.78); an effect of gender F(4,265=3.35; p<0.01, η(2)=0.05); and an interaction effect between gender and disability F(4,265=5.23; p<0.001, η(2)=0.64). Children with disabilities, and mostly girls, were found at risk to participate in a narrower variety of activities that involved fewer social interactions. Using linear regressions for each group two different models were identified. Using the CLASS the study contributes evidence-based data regarding children at risk for leisure participation. In addition, the research further established the discriminate validity of the CLASS.

The effect of a computerized visual perception and visual-motor integration training program on improving Chinese handwriting of children with handwriting difficulties.

This study aimed to investigate the effect of a computerized visual perception and visual-motor integration training program to enhance Chinese handwriting performance among children with learning difficulties, particularly those with handwriting problems. Participants were 26 primary-one children who were assessed by educational psychologists and occupational therapists to have handwriting difficulties. They were matched according to their age and then randomly assigned into either the control group or the experimental group. Subjects in the experimental group (n=13) would receive eight sessions of computerized visual perception and visual-motor integration training together with a home training program while those in the control group (n=13) would only receive conventional handwriting training by teachers, which focused mainly on remedial handwriting exercises. Results from repeated measure ANOVA revealed that children in the experimental group showed improvements in their visual perception skills as well as in their handwriting time. Both the "On Paper" time and "In Air" time of this group were improved when compared to the control group. However, no significant differences were found in visual-motor integration skill and handwriting legibility between the two groups after the intervention. This computerized training program focusing on visual perception and visual-motor integration training appeared to be effective in enhancing the handwriting time among children with handwriting difficulties. However, the training program did not seem to improve the legibility of children.

The development and standardization of the Children Activity Scales (ChAS-P/T) for the early identification of children with Developmental Coordination Disorders.

BACKGROUND: Previous studies have emphasized the importance of early identification of children with Developmental Coordination Disorder (DCD) to prevent the development of secondary academic, emotional and social manifestations of the disorder. The aim of this study was to develop a valid parent and teacher questionnaire--the Children Activity Scales for parents (ChAS-P) and for teachers (ChAS-T)--to identify children aged 4-8 years at risk for DCD and to examine the reliability and validity of these questionnaires. METHODS: The questionnaires' content and face validity were established, and then cut-off scores were determined based on responses of 355 teachers and 216 parents. Internal consistencies were also calculated. Factor analyses were performed, and construct validity was determined by examining the questionnaires' ability to discriminate between 30 children aged 5-6.5 years diagnosed with DCD and 30 typically developing children. Concurrent validity was examined by comparing questionnaire scores with those of the Movement Assessment Battery for Children (M-ABC). RESULTS: High values were obtained for internal consistency (0.96-0.94) for the ChAS-T and the ChAS-P respectively. Factor analysis revealed four distinct factors within the ChAS-P and three within the ChAS-T, reinforcing the theoretical validity of the items selected and appropriateness for identifying DCD. Construct validity was indicated by finding significant differences between the groups' scores on the ChAS-T and the ChAS-P. Significant correlations between the children's scores on the questionnaires and those of the M-ABC confirmed their concurrent validity. CONCLUSIONS: Initial results suggest that the ChAS-T and Chas-P are reliable tools to identify children at risk for DCD.

Environmental influences on perceptual and motor skills of children from immigrant Ethiopian families.

The purpose of this study was to examine environmental influences on perceptual and motor skills of children from immigrant Ethiopian families in Israel in comparison with those of Israeli-born children. The subjects were divided into groups based on age (6- to 8-yr.-olds and 10- to 12-yr.-olds) and length of time in Israel. The results of this study show that the perceptual and motor performance of 6- to 8-yr.-old, less recent Ethiopian immigrants is similar to that of the recent Ethiopian immigrants of the same age. A difference exists between those two groups and the Israeli-born children of the same age. In the 10- to 12-yr.-old age group, there is a marked difference between the performance of the two groups of Ethiopian immigrants. The difference between the less recent immigrants and the Israeli-born children is smaller for most tasks; however, the less recent immigrants' performance is still poorer than that of the Israeli children. These results are compatible with those of other studies describing the difficulties encountered by children who had not studied in formal educational settings and those who have had that experience.

Analogues of 1-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta [1,2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase.

The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]-pyridin-11-yl)pi perazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.

Peritoneal dialysis adequacy: a model to assess feasibility with various modalities.

BACKGROUND: The current standard of adequacy for peritoneal dialysis (PD) is to provide a weekly normalized urea clearance (Kt/V) of 2.0 or more and a creatinine clearance (CCr) of 60 liter/1.73 m2 or more. As native renal function is lost, it is important to determine the effectiveness of the available therapeutic modalities in achieving these goals. METHODS: A model to assess our ability to provide a weekly Kt/Vurea of 2.0 or more and a CCr of 60 liter/1.73 m2 or more to anuric patients undergoing continuous ambulatory PD (CAPD) and automated PD (PD Plus) was developed. The body surface area (BSA) distribution was obtained from 38,768 patients undergoing dialysis during January 1997. The distribution of peritoneal transport rates (PTRs) was obtained from 2531 peritoneal equilibration tests performed during 1996. The weekly Kpt/Vurea was calculated for the various PTR groups and the range of BSA with four PD prescriptions: CAPD 8 liters, CAPD 10 liters, PD Plus 12 liters, and PD Plus 15 liters, using a previously validated kinetic program (PackPD). RESULTS: The predicted percentage of patients capable of achieving the adequacy goals for Kt/V and CCr, respectively, were 24.8 and 11. 2 for CAPD 8 liters, 54.2 and 33.0 for CAPD 10 liters, 77.8 and 54.9 for PD Plus 12 liters, and 93.2 and 72.9 for PD Plus 15 liters. CONCLUSIONS: Most patients can attain the current adequacy standards of therapy with automated PD, but few (less than 25%) can do so with standard CAPD in the absence of residual renal function.

Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption.

(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)- (4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.

Inhibitors of farnesyl protein transferase. Synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3-b]pyridine ring system.

Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol.

Frequency and relationships of clinical chemistry and liver and kidney histopathology findings in 13-week toxicity studies in rats.

The relative sensitivities of eight commonly used clinical chemistry end points and histopathology to detect potential toxic effects in liver and kidney were evaluated for a series of 61 13-week rat toxicity studies conducted for the National Toxicology Program. The data consisted of 1-,2- to 3-, and 13 week clinical chemistry measurements and 13-week histopathological assessments of liver and kidney. Except for serum alkaline phosphatase, treatment-related alterations of individual clinical chemistry variables occurred in 20-48% of the studies, depending on the analyte, sampling time, and sex. Liver and kidney lesions were reported for 31% and 41% of the studies respectively. There was an association between treatment-related increases in alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities and histopathological changes in the liver. SDH activity had greater positive and negative predictive values than similar changes in ALT; by week 1 in females and weeks 2-3 in both sexes. SDH predicted morphological hepatic change at study termination with 75% or better accuracy. If increases in activities of both enzymes occurred simultaneously, however, terminal histopathological changes could be predicted, in both sexes, with 75% accuracy by week 1, increasing to 100% by weeks 2-3. There also was an association between treatment-related increases in urea nitrogen (UN) and creatinine (Cre) concentrations and morphological kidney change. Cre concentration had greater positive predictive values than similar changes in UN; by weeks 2-3 in males and week 13 in both sexes. Cre predicted morphological renal change at study termination with 56% or better accuracy. UN concentration was associated and predictive of morphological kidney change only in females at week 13. Depending on time point and sex, serum alkaline phosphatase activity increased in 5-22% of the studies. Increases in total bile acid concentration occurred in 33-48% of the studies. Because both tests are used as markers of cholestasis, this marked discrepancy was unexpected. Treatment-related decreases in alkaline phosphatase activity occurred, however, in 39-56% of the studies; serum alkaline phosphatase may be more useful as an indicator of decreased food intake (decreased activity) than of cholestasis (increased activity). In summary, treatment-related alterations of clinical chemistry and histopathology occurred frequently in this series of toxicity studies in rats. Changes in the chemistry end points also occurred frequently at interim time points, indicating that clinical chemistry evaluations can be useful for detecting potential treatment effects throughout a study. This observation is important, since histopathological evaluations are limited to animal termination and not useful for detecting transient responses or the onset of treatment-related effects.

N-nitrosodiethylamine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced morphological transformation of C3H/10T1/2CL8 cells expressing human cytochrome P450 2A6.

Transfection of specific genes into cells capable of expressing chemically induced morphological cell transformation provides a valuable approach to study the mechanisms of action of carcinogens. A human cytochrome P450 isozyme, CYP2A6, has been successfully expressed from a retroviral vector in transformable C3H/10T1/2 (10T1/2) mouse embryo fibroblasts and these resulting 10T1/2 clones were evaluated for the cytotoxic and transforming activities of two nitrosamines, 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosodiethylamine (DEN). 10T1/2 clone 29 cells, which expressed high levels of CYP2A6 activity, were responsive to the cytotoxic and morphological transforming effects of DEN or NNK on a concentration-related basis. In 10T1/2 clone 29 cells, DEN at 600 micrograms/ml decreased cell survival to 67%, and induced 0.5 type II&III foci/dish. NNK at 400 micrograms/ml administered to 10T1/2 clone 29 cells decreased survival to 57% and induced 0.43 type II&III foci/dish. Wild-type 10T1/2 cells and 10T1/2 clone 4 cells (infected with the vector but not expressing the CYP2A6 activity) were unresponsive. These results indicate that expression of a cDNA coding for cytochrome P450 in 10T1/2 cells can provide information about the role of the enzyme in the activities of chemical carcinogens and also increase the sensitivity of 10T1/2 cells to a larger number of classes of chemical carcinogens.