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1.  Multiplex Networks of Cortical and Hippocampal Neurons Revealed at Different Timescales 
PLoS ONE  2014;9(12):e115764.
Recent studies have emphasized the importance of multiplex networks – interdependent networks with shared nodes and different types of connections – in systems primarily outside of neuroscience. Though the multiplex properties of networks are frequently not considered, most networks are actually multiplex networks and the multiplex specific features of networks can greatly affect network behavior (e.g. fault tolerance). Thus, the study of networks of neurons could potentially be greatly enhanced using a multiplex perspective. Given the wide range of temporally dependent rhythms and phenomena present in neural systems, we chose to examine multiplex networks of individual neurons with time scale dependent connections. To study these networks, we used transfer entropy – an information theoretic quantity that can be used to measure linear and nonlinear interactions – to systematically measure the connectivity between individual neurons at different time scales in cortical and hippocampal slice cultures. We recorded the spiking activity of almost 12,000 neurons across 60 tissue samples using a 512-electrode array with 60 micrometer inter-electrode spacing and 50 microsecond temporal resolution. To the best of our knowledge, this preparation and recording method represents a superior combination of number of recorded neurons and temporal and spatial recording resolutions to any currently available in vivo system. We found that highly connected neurons (“hubs”) were localized to certain time scales, which, we hypothesize, increases the fault tolerance of the network. Conversely, a large proportion of non-hub neurons were not localized to certain time scales. In addition, we found that long and short time scale connectivity was uncorrelated. Finally, we found that long time scale networks were significantly less modular and more disassortative than short time scale networks in both tissue types. As far as we are aware, this analysis represents the first systematic study of temporally dependent multiplex networks among individual neurons.
PMCID: PMC4275261  PMID: 25536059
2.  Large-Scale, High-Resolution Multielectrode-Array Recording Depicts Functional Network Differences of Cortical and Hippocampal Cultures 
PLoS ONE  2014;9(8):e105324.
Understanding the detailed circuitry of functioning neuronal networks is one of the major goals of neuroscience. Recent improvements in neuronal recording techniques have made it possible to record the spiking activity from hundreds of neurons simultaneously with sub-millisecond temporal resolution. Here we used a 512-channel multielectrode array system to record the activity from hundreds of neurons in organotypic cultures of cortico-hippocampal brain slices from mice. To probe the network structure, we employed a wavelet transform of the cross-correlogram to categorize the functional connectivity in different frequency ranges. With this method we directly compare, for the first time, in any preparation, the neuronal network structures of cortex and hippocampus, on the scale of hundreds of neurons, with sub-millisecond time resolution. Among the three frequency ranges that we investigated, the lower two frequency ranges (gamma (30–80 Hz) and beta (12–30 Hz) range) showed similar network structure between cortex and hippocampus, but there were many significant differences between these structures in the high frequency range (100–1000 Hz). The high frequency networks in cortex showed short tailed degree-distributions, shorter decay length of connectivity density, smaller clustering coefficients, and positive assortativity. Our results suggest that our method can characterize frequency dependent differences of network architecture from different brain regions. Crucially, because these differences between brain regions require millisecond temporal scales to be observed and characterized, these results underscore the importance of high temporal resolution recordings for the understanding of functional networks in neuronal systems.
PMCID: PMC4134292  PMID: 25126851
4.  Isoniazid toxicity in a 5-year-old boy 
PMCID: PMC3707995  PMID: 23670154
5.  Long-term Efficacy and Tolerability of Perospirone for Young Help-seeking People at Clinical High Risk: a Preliminary Open Trial 
Interest in the "at-risk mental state" (ARMS) for psychosis has increased because early intervention is expected to delay or prevent the onset of schizophrenia. However, the optimum intervention strategy remains controversial, especially with regard to antipsychotics. Although administration of antipsychotic medications is often associated with adverse effects and raises ethical considerations, recent studies have shown that some novel antipsychotics are safer and more tolerable for young people than conventional antipsychotics. We investigated whether administration of perospirone, a combined serotonin (5-HT)/dopamine antagonist and 5-HT1A receptor agonist, could alleviate prodromal symptoms and be well tolerated by clinical high risk patients.
The participants were outpatients seeking help. The Structured Interview for Prodromal Symptoms was performed in patients identified as being at clinical high risk. The Scale of Prodromal Symptoms (SOPS) was also completed and changes of subjective experience were assessed with the Subjective Well-being under Neuroleptics, short version. The incidence of akathisia was recorded by using the Barnes Akathisia Scale. Subjects were monitored for 26 weeks after starting medication.
SOPS scores improved significantly after 26 weeks of perospirone therapy, while BAS scores did not show deterioration. No serious adverse events occurred during the study.
This trial suggests that perospirone therapy provides a clinical benefit for clinical high risk subjects without causing serious adverse events. Although further placebo-controlled studies are needed for confirmation, perospirone might be one of optimum treatments for individuals at imminent risk of psychosis.
PMCID: PMC3897761  PMID: 24465249
Perospirone; Prodrome; Psychotic disorders; Early intervention; Schizophrenia
6.  The impact of nurse working hours on patient safety culture: a cross-national survey including Japan, the United States and Chinese Taiwan using the Hospital Survey on Patient Safety Culture 
A positive patient safety culture (PSC) is one of the most critical components to improve healthcare quality and safety. The Hospital Survey on Patient Safety Culture (HSOPS), developed by the US Agency for Healthcare Research and Quality, has been used to assess PSC in 31 countries. However, little is known about the impact of nurse working hours on PSC. We hypothesized that long nurse working hours would deteriorate PSC, and that the deterioration patterns would vary between countries. Moreover, the common trends observed in Japan, the US and Chinese Taiwan may be useful to improve PSC in other countries. The purpose of this study was to clarify the impact of long nurse working hours on PSC in Japan, the US, and Chinese Taiwan using HSOPS.
The HSOPS questionnaire measures 12 sub-dimensions of PSC, with higher scores indicating a more positive PSC. Odds ratios (ORs) were calculated using a generalized linear mixed model to evaluate the impact of working hours on PSC outcome measures (patient safety grade and number of events reported). Tukey’s test and Cohen’s d values were used to verify the relationships between nurse working hours and the 12 sub-dimensions of PSC.
Nurses working ≥60 h/week in Japan and the US had a significantly lower OR for patient safety grade than those working <40 h/week. In the three countries, nurses working ≥40 h/week had a significantly higher OR for the number of events reported. The mean score on ‘staffing’ was significantly lower in the ≥60-h group than in the <40-h group in all the three countries. The mean score for ‘teamwork within units’ was significantly lower in the ≥60-h group than in the <40-h group in Japan and Chinese Taiwan.
Patient safety grade deteriorated and the number of events reported increased with long working hours. Among the 12 sub-dimensions of PSC, long working hours had an impact on ‘staffing’ and ‘teamwork within units’ in Japan, the US and Chinese Taiwan.
PMCID: PMC3852210  PMID: 24099314
Patient safety; Patient safety culture; Nurse working hours; Adverse events
7.  The characteristics of patient safety culture in Japan, Taiwan and the United States 
Quality and safety issues are receiving growing attention. Patient safety culture (PSC) plays an important role in patient safety. The characteristics of PSC in various countries, each with a different set of values, have not been determined sufficiently. The aim of this study is to investigate the characteristics of PSC in Japan, Taiwan and the U.S.
A cross-sectional survey was conducted in Japan and Taiwan using the Hospital Survey on PSC (HSOPS) questionnaire developed by the U.S. Agency for Healthcare Research and Quality (AHRQ). Data from Japan and Taiwan were also compared with the U.S. “2010 HSOPS Comparative Database” provided by AHRQ.
Valid response rates in Japan, Taiwan and the U.S. were 66.5% (6,963/10,466), 85.7% (10,019/11,692) and 35.2% (291,341/827,424), respectively. The proportion of respondents with some experience of event reporting during the past 12 months was highest in Japan. In general, U.S. healthcare workers were likely to evaluate their PSC higher than that in Japan or Taiwan. The attitude of continuous improvement in Japan and event reporting of near misses in Taiwan were rated as low. In the U.S., staffing was rated as high.
The results suggest that PSC varies among different countries, and the cultural setting of each country should be given special consideration in the development of effective intervention plans to improve PSC. Additional investigations with improved methodology and a common protocol are required to accurately compare PSCs among countries.
PMCID: PMC3626628  PMID: 23316872
Safety; Organizational culture; Safety management; Attitude of health personnel; Patient safety culture
8.  Quantification of Human Uridine-Diphosphate Glucuronosyl Transferase (UGT) 1A Isoforms in Liver, Intestine and Kidney using nanoLC-MS/MS 
Analytical Chemistry  2011;84(1):98-105.
Uridine-disphosphate glucuronosyl transferase (UGT) enzymes catalyze the formation of glucuronide conjugates of Phase II metabolism. Methods for absolute quantification of UGT1A1 and UGT1A6 were previously established utilizing stable isotope peptide internal standards with LC-MS/MS. The current method expands upon this by quantifying eight UGT1A isoforms by nanobore HPLC coupled with a linear ion trap-time of flight mass spectrometer platform. Recombinant enzyme digests of each of the isoforms were used to determine assay linearity and detection limits. Enzyme expression level in human liver, kidney and intestinal microsomal protein was determined by extrapolation from spiked stable isotope standards. Intraday and Interday variability was <25% for each of the enzyme isoforms. Enzyme expression varied from 3 pmol/mg protein to 96 pmol/mg protein in liver and intestinal microsomal protein digests. Expression levels of UGT1A7, 1A8 and 1A10 were below detection limits (<1 pmol/mg protein) in HLMs. In kidney microsomes the expression of UGT1A3 was below detection limits, but levels of UGT1A4, 1A7, 1A9 and 1A10 protein were higher relative to liver, suggesting that renal glucuronidation could be a significant factor in renal elimination of glucuronide conjugates. This novel method allows quantification of all nine UGT1A isoforms, many previously not amenable to measurement with traditional methods such as immunologically based assays. Quantitative measurement of proteins involved in drug disposition, such as the UGTs, significantly improves the ability to evaluate and interpret in vitro and in vivo studies in drug development.
PMCID: PMC3259189  PMID: 22050083
UGT; nanoLC-MS/MS; quantitative proteomics; human microsomes
9.  Walking the tightrope 
Paediatrics & Child Health  2011;16(9):527.
PMCID: PMC3223882  PMID: 23115486
10.  Pharmacokinetics 101 
Paediatrics & Child Health  2011;16(9):535-536.
PMCID: PMC3223885  PMID: 23115489
11.  Maternal cocaine use during breastfeeding 
Canadian Family Physician  2012;58(11):1218-1219.
Question In my practice several patients have struggled with cocaine abuse during their pregnancies. One woman, now postpartum, wants to breastfeed her infant. Despite being abstinent for the final few months of her pregnancy, I am concerned about the potential adverse effects on her child if she happens to relapse. What is the current evidence about the risks of cocaine exposure during breastfeeding?
Answer Given the substantial benefits of breastfeeding for infant health and development, there is no reason for mothers who previously abused cocaine to avoid breastfeeding. It is important for the health care team to counsel patients both on the serious potential risks of cocaine exposure for babies and on the benefits of breastfeeding, to allow for an informed choice. Additionally, attempts should be made to estimate maternal commitment to breastfeeding and discontinuation of cocaine use, and to offer addiction counseling to mitigate the potential risks of infant cocaine exposure. It is paramount to minimize the risk to the infant, which would certainly include mothers ceasing use of cocaine while breastfeeding. For mothers who elect to breastfeed and use cocaine intermittently, breastfeeding should be delayed sufficiently after cocaine use to allow for drug elimination (approximately 24 hours).
PMCID: PMC3498013  PMID: 23152457
12.  Health Canada advisory on domperidone 
Canadian Family Physician  2012;58(9):952-953.
Question I often prescribe domperidone to women as a galactagogue starting at a dose of 30 mg and increasing the dose as needed. In March of this year, Health Canada released an advisory warning of domperidone use and abnormal heart rhythms and sudden cardiac death. Should I cap doses at 30 mg or stop prescribing domperidone all together to these women?
Answer The Health Canada warning is based on 2 studies. The results of the studies are not directly applicable to breastfeeding and should not change the way you normally manage otherwise healthy breastfeeding women.
PMCID: PMC3440266  PMID: 22972723
13.  Enhancing breast milk production with Domperidone in mothers of preterm neonates (EMPOWER trial) 
The use of mother’s own breast milk during initial hospitalization has a positive impact not only in reducing potential serious neonatal morbidities but also contribute to improvements in neurodevelopmental outcomes. Mothers of very preterm infants struggle to maintain a supply of breast milk during their infants’ prolonged hospitalization. Galactogogues are medications that induce lactation by exerting its effects through oxytocin or prolactin enhancement. Domperidone is a potent dopamine D2 receptor antagonist which stimulates the release of prolactin. Small trials have established its ability in enhancing breast milk production. EMPOWER was designed to determine the safety and efficacy of domperidone in mothers experiencing an inadequate milk supply.
EMPOWER is a multicenter, double masked, randomized controlled phase-II trial to evaluate the safety and effectiveness of domperidone in those mothers identified as having difficulty in breast milk production. Eligible mothers will be randomized to one of two allocated groups: Group A: domperidone 10 mg orally three times daily for 28 days; and Group B: identical placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days. The primary outcome will be determined at the completion of the first 2-week period; the second 2-week period will facilitate answering the secondary questions regarding timing and duration of treatment. To detect an estimated 30% change between the two groups (from 40% to 28%, corresponding to an odds ratio of 0.6), a total sample size of 488 mothers would be required at 80% power and alpha = 0.05. To account for a 15% dropout, this number is increased to 560 (280 per group). The duration of the trial is expected to be 36–40 months.
The use of a galactogogue often becomes the measure of choice for mothers in the presence of insufficient breast milk production, particularly when the other techniques are unsuccessful. EMPOWER is designed to provide valuable information in guiding the practices for this high-risk group of infants and mothers. The results of this trial will also inform both mothers and clinicians about the choices available to increase and maintain sufficient breast milk.
Trial registration
Clinical Identifier: NCT01512225
PMCID: PMC3532128  PMID: 22935052
Domperidone; Galactogogues; Mothers of preterm infants; Breast milk
Critical care medicine  2011;39(4):678-682.
To determine the likelihood that recommended doses of acetaminophen (APAP) are associated with acute liver failure (ALF) in patients with myopathies
retrospective analysis
level III pediatric intensive care unit
two pediatric patients with myopathies and acute liver failure
Clinical Investigations
We determined acetaminophen protein adduct levels, in combination with a literature review and systematic evaluation of the cases, using the Roussel Uclaf Causality Assessment Method (RUCAM) for drug-induced liver injury (DILI) to assess causality between recommended acetaminophen dosing and acute liver failure in two children with myopathies.
Main Results
The serum adduct levels were consistent with the values previously reported in children with acute liver injury following APAP overdose. We found four similar cases of ALF in pediatric and adult patients with myopathies following recommended APAP doses in the literature (n=3) and personal communication (n=1).The RUCAM suggested a probable relationship between APAP use at recommended doses and ALF in our myopathy patients.
Our data suggest that some patients with myopathies receiving recommended doses of APAP may be at increased risk for the development of toxicity resulting in ALF. More studies are needed to corroborate these findings. In the meantime, we would advise physicians to be alert in these patients while taking APAP, especially when critically ill or postoperative.
PMCID: PMC3209512  PMID: 21242792
Acetaminophen; pediatrics; acute liver failure; myopathy; acetaminophen adduct; adverse event
16.  Extending Transfer Entropy Improves Identification of Effective Connectivity in a Spiking Cortical Network Model 
PLoS ONE  2011;6(11):e27431.
Transfer entropy (TE) is an information-theoretic measure which has received recent attention in neuroscience for its potential to identify effective connectivity between neurons. Calculating TE for large ensembles of spiking neurons is computationally intensive, and has caused most investigators to probe neural interactions at only a single time delay and at a message length of only a single time bin. This is problematic, as synaptic delays between cortical neurons, for example, range from one to tens of milliseconds. In addition, neurons produce bursts of spikes spanning multiple time bins. To address these issues, here we introduce a free software package that allows TE to be measured at multiple delays and message lengths. To assess performance, we applied these extensions of TE to a spiking cortical network model (Izhikevich, 2006) with known connectivity and a range of synaptic delays. For comparison, we also investigated single-delay TE, at a message length of one bin (D1TE), and cross-correlation (CC) methods. We found that D1TE could identify 36% of true connections when evaluated at a false positive rate of 1%. For extended versions of TE, this dramatically improved to 73% of true connections. In addition, the connections correctly identified by extended versions of TE accounted for 85% of the total synaptic weight in the network. Cross correlation methods generally performed more poorly than extended TE, but were useful when data length was short. A computational performance analysis demonstrated that the algorithm for extended TE, when used on currently available desktop computers, could extract effective connectivity from 1 hr recordings containing 200 neurons in ∼5 min. We conclude that extending TE to multiple delays and message lengths improves its ability to assess effective connectivity between spiking neurons. These extensions to TE soon could become practical tools for experimentalists who record hundreds of spiking neurons.
PMCID: PMC3216957  PMID: 22102894
17.  Development and applicability of Hospital Survey on Patient Safety Culture (HSOPS) in Japan 
Patient safety culture at healthcare organizations plays an important role in guaranteeing, improving and promoting overall patient safety. Although several conceptual frameworks have been proposed in the past, no standard measurement tool has yet been developed for Japan.
In order to examine possibilities to introduce the Hospital Survey on Patient Safety Culture (HSOPS) in Japan, the authors of this study translated the HSOPS into Japanese, and evaluated its factor structure, internal consistency, and construct validity. Healthcare workers (n = 6,395) from 13 acute care general hospitals in Japan participated in this survey.
Confirmatory factor analysis indicated that the Japanese HSOPS' 12-factor model was selected as the most pertinent, and showed a sufficiently high standard partial regression coefficient. The internal reliability of the subscale scores was 0.46-0.88. The construct validity of each safety culture sub-dimension was confirmed by polychoric correlation, and by an ordered probit analysis.
The results of the present study indicate that the factor structures of the Japanese and the American HSOPS are almost identical, and that the Japanese HSOPS has acceptable levels of internal reliability and construct validity. This shows that the HSOPS can be introduced in Japan.
PMCID: PMC3042910  PMID: 21294920
18.  Perinatal exposure to maternal lamotrigine 
Canadian Family Physician  2010;56(11):1132-1134.
QUESTION The question of neonatal safety during breastfeeding when mothers are taking lamotrigine (LTG) has become more prevalent in my practice. There are some theoretical concerns about breastfeeding while taking LTG, which have been compounded by a published case report of toxicity in the breastfed neonate of a mother taking LTG. How should I advise my patients who wish to breastfeed while taking LTG?
ANSWER Most neonates born to mothers taking LTG have already been exposed to the drug for 9 months in utero, given the chronic indications for which the drug is intended. Lamotrigine exposure via breast milk is considerably less than placental transfer, with serum LTG concentrations in neonates higher at birth than during lactation. While a single case of toxicity has been reported in a neonate exposed to LTG via breast milk, in most circumstances, breastfeeding can be initiated and maintained given the tremendous benefits of mothers’ milk. On the other hand, toxicity during breastfeeding might occur more commonly in the mother, if sufficient and gradual dose readjustments are not undertaken in the weeks following delivery.
PMCID: PMC2980428  PMID: 21075992
19.  Predictive genotype 
PMCID: PMC2871209  PMID: 20479057
20.  Guidelines for maternal codeine use during breastfeeding 
Canadian Family Physician  2009;55(11):1077-1078.
QUESTION In light of the recent evidence of adverse events in infants whose mothers use codeine medication, we have been struggling with the issue of how to manage codeine analgesia in our postpartum patients. What are some guidelines for the safe use of codeine during breastfeeding?
ANSWER Motherisk has summarized recent scientific evidence into suggested guidelines for the safe use of codeine during breastfeeding.
PMCID: PMC2776794  PMID: 19910591
22.  Hyperthyroidism during pregnancy 
Canadian Family Physician  2009;55(7):701-703.
QUESTION I have a 33-year-old patient with hyperthyroidism who is 6 weeks pregnant. Her thyroid function is well controlled with a 5-mg dose of methimazole 3 times daily. She was initially treated with propylthiouracil but was switched to methimazole owing to urticaria. I have heard about birth defects in infants whose mothers used methimazole during pregnancy. How safe is it?
ANSWER In North America, propylthiouracil has been the drug of choice for hyperthyroidism during pregnancy. Methimazole is widely used in Europe, South America, and Asia, and is an alternative for patients who cannot tolerate propylthiouracil. Some case reports raised concern about fetal toxicity from methimazole, which is reportedly characterized by aplasia cutis, esophageal atresia, choanal atresia, facial abnormalities, and mental retardation. However, causality is unclear and the overall risk of congenital abnormalities in infants exposed to methimazole in utero was not higher than in those exposed to nonteratogenic drugs in cohort studies. It is important for a pregnant woman to continue methimazole, if necessary, because uncontrolled hyperthyroidism increases the risk of complications such as preterm labour and low birth weight.
PMCID: PMC2718594  PMID: 19602653
23.  Lead exposure during breastfeeding 
Canadian Family Physician  2008;54(4):515-516.
QUESTION Owing to the recent concerns of lead (Pb) leaking into tap water, one of our female patients is concerned about the effects of Pb exposure to newborns while breastfeeding. How should I advise her and should she switch to formula feeding?
ANSWER Lead exposure through drinking tap water while breastfeeding is not associated with any serious concerns in most available studies. There is currently no safe level of Pb exposure, but environmental exposure within Canada is low. At present, Pb levels in drinking water are carefully monitored by Health Canada and are not likely to be of concern to breastfeeding mothers. Switching to formula feeding is not necessary and not recommended, as improperly prepared formula can have higher Pb levels.
PMCID: PMC2294082  PMID: 18411377
24.  Exposure to attention deficit hyperactivity disorder medications during pregnancy 
Canadian Family Physician  2007;53(7):1153-1155.
QUESTION An 18-year-old patient of mine, currently under treatment for attention deficit hyperactivity disorder (ADHD) with methylphenidate, just found out that she is pregnant. What are the risks for the baby when the mother uses ADHD medications during pregnancy?
ANSWER Available evidence for amphetamines suggests no increased risk of malformations with use of therapeutic doses, and inadvertent exposure during pregnancy is unlikely to be harmful. Human data for methylphenidate and atomoxetine treatment in pregnancy are very limited. Documented cases do not suggest teratogenicity, but we cannot rule out this risk with the information available.
PMCID: PMC1949295  PMID: 17872810
25.  Response 
Canadian Family Physician  2007;53(3):401-402.
PMCID: PMC1949065

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