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Muscle & nerve  2013;48(3):369-374.
The aim of this study was to test the proficiency (accuracy among evaluators) of measured attributes of nerve conduction (NC).
Expert clinical neurophysiologists, without instruction or consensus development, from 4 different medical centers, independently assessed 8 attributes of NC in 24 patients with diabetes mellitus (DM) on consecutive days.
No significant intraobserver differences between days 1 and 2 were found, but significant interobserver differences were seen. Use of standard reference values did not correct for these observed differences.
Interobserver variability was attributed to differences in performance of NC. It was of sufficient magnitude that it is of concern for the conduct of therapeutic trials. To deal with interrater variability in therapeutic trials, the same electromyographers should perform all NC assessments of individual patients or, preferably, NC procedures should be more standardized. A further trial is needed to test whether such standardization would eliminate interobserver variability.
PMCID: PMC3966293  PMID: 23861198
clinical trial; diabetic sensorimotor polyneuropathy; nerve conduction; proficiency; standard reference value
2.  Bacillus anthracis spores and lethal toxin induce IL-1β via functionally distinct signaling pathways 
European journal of immunology  2008;38(6):1574-1584.
Previous reports suggested that lethal toxin (LT)-induced caspase-1 activity and/or IL-1β accounted for Bacillus anthracis (BA) infection lethality. In contrast, we now report that caspase-1-mediated IL-1β expression in response to BA spores is required for anti-BA host defenses. Caspase-1−/− and IL-1β−/− mice are more susceptible than wild-type (WT) mice to lethal BA infection, are less able to kill BA both in vivo and in vitro, and addition of rIL-1β to macrophages from these mice restored killing in vitro. Non-germinating BA spores induced caspase-1 activity, IL-1β and nitric oxide, by which BA are killed in WT but not in caspase-1−/− mice, suggesting that the spore itself stimulated inflammatory responses. While spores induced IL-1β in LT-susceptible and -resistant macrophages, LT induced IL-1β only in LT-susceptible macrophages. Cooperation between MyD88-dependent and -independent signaling pathways was required for spore-induced, but not LT-induced, IL-1β. While both spores and LT induced caspase-1 activity and IL-1β, LT did not induce IL-1β mRNA, and spores did not induce cell death. Thus different components of the same bacterium each induce IL-1β by distinct signaling pathways. Whereas the spore-induced IL-1β limits BA infection, LT-induced IL-1β enables BA to escape host defenses.
PMCID: PMC3681412  PMID: 18493980
Anthrax; Bacillus anthracis; Interleukin-1β; Lethal toxin; Spores
3.  The Secret “Spice”: An Undetectable Toxic Cause of Seizure 
The Neurohospitalist  2011;1(4):182-186.
Neurologists and emergency department physicians are frequently involved in the comprehensive evaluation of a first generalized seizure. An important aspect of this evaluation is a detailed history which can identify a provoked seizure secondary to drug toxicity and hence avoid unnecessary treatment with antiepileptic drugs. “Spice” is an umbrella term for a variety of synthetic cannabinoid products whose inhalation has been associated with an increasing number of toxic side effects resulting in emergency department visits. These side effects (including psychosis, tachyarrhythmia, and seizures) are not typically seen with marijuana (Cannabis sativa) use. We report 2 patients with no prior history of neurological disease that experienced their first generalized tonic–clonic seizure after smoking Spice. The mechanism behind the possible proconvulsant effect of synthetic cannabinoids is not known, but it may be due to their effects at the cannabinoid receptor CB1. Although the US Drug Enforcement Administration placed 5 synthetic cannabinoids into schedule 1 for a 12-month period beginning March 2011, new Spice products containing different synthetic cannabinoids continue to emerge. Because synthetic cannabinoids are not detectable on commercial drug screens it is important that neurologists and emergency department physicians consider Spice inhalation in their differential diagnosis of a first generalized seizure.
PMCID: PMC3726077  PMID: 23983854
Spice; synthetic cannabinoid; cannabis toxicity; marijuana toxicity; first generalized seizure; provoked seizure; toxic seizure
4.  A media advocacy intervention linking health disparities and food insecurity 
Health Education Research  2011;26(6):948-960.
Media advocacy is a well-established strategy for transmitting health messages to the public. This paper discusses a media advocacy intervention that raised issues about how the public interprets messages about the negative effects of poverty on population health. In conjunction with the publication of a manuscript illustrating how income-related food insecurity leads to disparities related to the consumption of a popular food product across Canada (namely, Kraft Dinner®), we launched a media intervention intended to appeal to radio, television, print and Internet journalists. All the media coverage conveyed our intended message that food insecurity is a serious population health problem, confirming that message framing, personal narratives and visual imagery are important in persuading media outlets to carry stories about poverty as a determinant of population health. Among politicians and members of the public (through on-line discussions), the coverage provoked on-message as well as off-message reactions. Population health researchers and health promotion practitioners should anticipate mixed reactions to media advocacy interventions, particularly in light of new Internet technologies. Opposition to media stories regarding the socio-economic determinants of population health can provide new insights into how we might overcome challenges in translating evidence into preventive interventions.
PMCID: PMC3219881  PMID: 21685402
5.  Seasonal Mapping of NICU Temperature Study conducted at the University of Washington Medical Center 
To create a thermal map of ambient air, radiant, and evaporative temperatures and humidity throughout the NICU nursery by season across a calendar year.
Each of the 32 bed cubicles distributed in five rooms in a Level III nursery was measured.
Temperatures were recorded at a consistent time on one day during January, April, July, and October.
Main outcome measures
An electronic monitor (QUESTemp° 34, Quest Technologies, Oconomowoc, WI) was used to measure dry bulb, wet bulb, and globe thermometer temperatures.
ANOVA revealed statistically significant (p < .000) differences in season, room, and season by room interaction. Room ambient air temperatures differed < 2 °F across season. Radiant temperature paralleled air temperature. Humidity, the predominant difference across season, produced evaporative temperatures considerably lower than room air temperature, and the gradient between mean nursery dry bulb and wet bulb temperature was 9.3 °F in summer and 16.8 °F in winter.
The thermal map revealed seasonal thermal differences, particularly in humidity level and evaporative temperature. Room temperature alone does not reflect the total thermal environment. Recommendations include periodic assessment of nurseries including air, evaporative, and radiant temperatures as well as humidity to more fully appreciate the impact of the thermal environment on infants.
PMCID: PMC2919318  PMID: 20386373
nursery; thermal environment; humidity; evaporation
6.  6-Sulfatoxymelatonin Collected From Infant Diapers: Feasibility and Implications for Urinary Biochemical Markers 
Biological research for nursing  2009;11(3):288-292.
The purpose of this study was to assess feasibility and acceptability of using a diaper pad for collection of in-home infant urinary samples and to test the accuracy of diaper pad extraction for 6-sulfatoxymelatonin and creatinine, which was used to correct assay results for urinary volume. To assess feasibility and acceptability, urine samples from 20 infants were collected over a 24-hour day using a cotton pad inserted in the diaper. The accuracy of diaper pad extraction was evaluated in the laboratory setting using urine samples collected from 11 adult volunteers and assayed using enzyme immunosorbent assay (EIA). Urine samples were divided, one aliquot was assayed without extraction and one aliquot was instilled into a diaper pad, extracted, and assayed. Mothers found diaper pad collection acceptable and easy to perform. Of 144 infant urinary samples obtained in the home environment, 59% were usable for assay purposes, the remaining either were contaminated with stool or were of insufficient volume. While creatinine values from diaper pad extracted and non-extracted samples were highly correlated (R2 = 0.947) those of creatinine corrected 6-sulfatoxymelatonin were not (R2 = 0.216). Diaper pad collection procedures altered 6-sulfatoxymelatonin values. Implications for measurement of urinary biochemical substances and statistical analysis are discussed.
PMCID: PMC2871251  PMID: 19502239
infant; urine; methods; biological assay
7.  Circadian Research in Mothers and Infants: How Many Days of Actigraphy Data Are Needed to Fit Cosinor Parameters? 
Journal of nursing measurement  2008;16(3):201-206.
Background and Purpose:
To determine the number of days of actigraphy data required to portray circadian rhythm in mothers and their young infants.
Continuous actigraphy monitoring was performed in 20 mothers-infant pairs over a four-day period. Cycle mesor, amplitude, acrophase, and R2, calculated using from one-to-four days of data, were compared. Parameters, based on four days of data, were correlated with parameters derived from one to three days of data.
There were no differences among mother or infant cosinor parameters except infant acrophase which stabilized after ≥ 2 days of data. Acceptable reliability (r ≥ 0.80) was achieved with ≥ 2 days of data.
A recording period of two days adequately depicted circadian rhythm of actigraphy in mothers and infants.
PMCID: PMC2774919  PMID: 19886472
circadian rhythm; cosinor analysis; method; actigraphy; mother-infant dyad
8.  Preterm Infant State Development 
To further understand state development of preterm infants throughout hospitalization and the effects of selected infant characteristics on state development.
Secondary data analysis of a two-group, experimental design study.
Two nurseries in a Northwest medical center.
Ninety-seven (97) hospitalized, medically stable, preterm infants. Fifty one (51) subjects were females.
Two hundred eighty five (285) real-time video recordings of infants performed during 4-hour interfeeding intervals. Sleep-wake states were coded at 15-second intervals.
Active sleep was the dominant state across postmenstrual ages. Although not statistically significant, preterm infants showed developmental changes in state organization with increased quiet sleep, drowsy, and awake, decreased active sleep, and more defined and less diffuse states over age. A significant gender effect was found, with males having less active sleep (p = .012), more drowsy (p = .03), more awake (p = 0.43), less defined (p = .002), and more diffuse (p = .001) states compared with females.
The predominance of active sleep during the preterm period reflects level of brain maturation. The results emphasize individual variations in state organization influenced by endogenous and environmental factors. Gender differences are potential sources of individual variation.
PMCID: PMC2765199  PMID: 19012716
Gender; Preterm Infant; Sleep; State
9.  Differential Activation of Human TLR4 by E. coli and S. flexneri 2a Lipopolysaccharide: Combined Effects of Lipid A Acylation State and TLR4 Polymorphisms on Signaling1 
The lipid A of LPS activates TLR45 through an interaction with MD-2 and the degree of lipid A acylation affects TLR4 responsiveness. Two TLR4 single nucleotide polymorphisms (SNPs) (Asp299Gly and Thr399Ile) have been associated with LPS-hyporesponsiveness. We hypothesized that the combination of hypoacylation and these SNPs would exhibit a compounded effect on TLR4 signaling. HEK293T transfectants expressing wild-type (WT) or polymorphic TLR4 were stimulated with E. coli (predominantly hexaacylated lipid A) or S. flexneri 2a (a mixture of hexaacylated, pentaacylated, and predominantly tetraacylated lipid A) LPS, or hexaacylated vs. pentaacylated synthetic lipid As. NF-κB-reporter activity was significantly lower in response to S. flexneri 2a than E. coli LPS, and further decreased in polymorphic transfectants. Neither hexaacylated nor pentaacylated synthetic lipid A induced NF-κB activity in WT transfectants under the identical transfection conditions used for LPS; however, increasing human MD-2 expression rescued responsiveness to hexaacylated lipid A only, while murine MD-2 was required to elicit a response to pentaacylated lipid A. Adherent PBMC of healthy volunteers were also compared for LPS-induced TNF-α, IL-6, IL-1β, and IL-10 production. Cytokine levels were significantly lower (~20–90%) in response to S. flexneri than to E. coli LPS/lipid A and PBMC from polymorphic individuals secreted decreased cytokine levels in response to both LPS types and failed to respond to pentaacylated lipid A. Thus, the combination of acylation state and host genetics may significantly impact vaccine immunogenicity and/or efficacy, whether LPS is an integral component of a whole organism vaccine or included as an adjuvant.
PMCID: PMC2739731  PMID: 18178854
TLR4; LPS; lipid A; SNPs; inflammation; human; cytokines; Shigella
10.  Effects of Stimulant Medication Under Varied Motivational Operations 
We evaluated the evocative effects of four conditions (high- and low-preference activities, low and divided attention) and stimulant medication on the behavior of a 16-year-old boy with attention deficit hyperactivity disorder and moderate mental retardation. All behavior (activity engagement, activity changes, inappropriate touching, rude behaviors, and physical aggression) improved with stimulant medication in most conditions, but undesirable behaviors were not reduced to acceptable levels in all conditions. This finding suggests that stimulant medication may be a valuable adjunct to function-based interventions.
PMCID: PMC2649839  PMID: 19721739
motivating operations; stimulant medication; attention deficit hyperactivity disorder
11.  Dopaminergic Modulation of Semantic Priming in Parkinson Disease Running head 
Our purpose is to examine the effect of D2/D3 agonists on semantic priming.
Dopamine appears to restrict the semantic network in semantic priming. However, which dopamine receptor mediates this effect is unknown.
To better understand the receptors involved, 15 nondemented Parkinson disease patients performed a lexical decision task before and one hour after they received their first morning medication dose, eight after D2 and D3 agonists pramipexole or ropinirole, and seven after levodopa. Semantic priming was measured for closely, distantly, and unrelated word pairs across a stimulus onset asynchrony of 700 ms.
Closely related pairs were recognized significantly faster than unrelated and distantly related pairs before the drugs, as well as after D2/D3 agents. After levodopa, closely related pairs remained faster than unrelated, but not faster than distantly related pairs.
This suggests that D1 receptors may mediate the dopaminergic modulation of semantic priming.
PMCID: PMC2729120  PMID: 18797254
dopamine; semantic; priming; language; Parkinson disease
12.  Effect of External Motion on Correspondence Between Infant Actigraphy and Maternal Diary 
Infant behavior & development  2009;32(3):340-343.
Correspondence between infant actigraphy and mother-recorded diary differed significantly when receiver-operator function area under the curve, correlation, and logistic regression were calculated with and without excluding periods of external motion. External motion occurred in 40% of recording time and significantly changed activity count per epoch.
PMCID: PMC2725759  PMID: 19327842
Infant; sleep; actigraphy; instrumentation
13.  Mice Deficient in the CXCR2 Ligand, CXCL1 (KC/GRO-α), Exhibit Increased Susceptibility to Dextran Sodium Sulfate (DSS)-induced Colitis 
Innate immunity  2008;14(2):117-124.
The role of TLRs and MyD88 in the maintenance of gut integrity in response to dextran sodium sulfate (DSS)-induced colitis was demonstrated recently and led to the conclusion that our innate immune response to luminal commensal flora provides necessary signals that facilitate epithelial repair and permit a return to homeostasis after colonic injury. In this report, we demonstrate that a deficit in a single neutrophil chemokine, CXCL1/KC, also results in a greatly exaggerated response to DSS. Mice with a targeted mutation in the gene that encodes this chemokine responded to 2.5% DSS in their drinking water with significant weight loss, bloody stools, and a complete loss of gut integrity in the proximal and distal colon, accompanied by a predominantly mononuclear infiltrate, with few detectable neutrophils. In contrast, CXCL1/KC−/− and wild-type C57BL/6J mice provided water only showed no signs of inflammation and, at this concentration of DSS, wild-type mice administered DSS showed only minimal histopathology, but significantly more infiltrating neutrophils. This finding implies that neutrophil infiltration induced by CXCL1/KC is an essential component of the intestinal response to inflammatory stimuli as well as the ability of the intestine to restore mucosal barrier integrity.
PMCID: PMC2614619  PMID: 18713728
14.  Gliadin Induces an Increase in Intestinal Permeability and Zonulin Release by Binding to the Chemokine Receptor CXCR3 
Gastroenterology  2008;135(1):194-204.e3.
Background & Aims
Celiac disease is an immune-mediated enteropathy triggered by gliadin, a component of the grain protein gluten. Gliadin induces an MyD88-dependent zonulin release that leads to increased intestinal permeability, a postulated early element in the pathogenesis of celiac disease. We aimed to establish the molecular basis of gliadin interaction with intestinal mucosa leading to intestinal barrier impairment.
α-Gliadin affinity column was loaded with intestinal mucosal membrane lysates to identify the putative gliadin-binding moiety. In vitro experiments with chemokine receptor CXCR3 transfectants were performed to confirm binding of gliadin and/or 26 overlapping 20mer α-gliadin synthetic peptides to the receptor. CXCR3 protein and gene expression were studied in intestinal epithelial cell lines and human biopsy specimens. Gliadin-CXCR3 interaction was further analyzed by immunofluorescence microscopy, laser capture microscopy, real-time reverse-transcription polymerase chain reaction, and immunoprecipitation/Western blot analysis. Ex vivo experiments were performed using C57BL/6 wild-type and CXCR3−/− mouse small intestines to measure intestinal permeability and zonulin release.
Affinity column and colocalization experiments showed that gliadin binds to CXCR3 and that at least 2 α-gliadin 20mer synthetic peptides are involved in this binding. CXCR3 is expressed in mouse and human intestinal epithelia and lamina propria. Mucosal CXCR3 expression was elevated in active celiac disease but returned to baseline levels following implementation of a gluten-free diet. Gliadin induced physical association between CXCR3 and MyD88 in enterocytes. Gliadin increased zonulin release and intestinal permeability in wild-type but not CXCR3−/− mouse small intestine.
Gliadin binds to CXCR3 and leads to MyD88-dependent zonulin release and increased intestinal permeability.
PMCID: PMC2653457  PMID: 18485912
15.  Sampling 'hard-to-reach' populations in health research: yield from a study targeting Americans living in Canada 
Some populations targeted in survey research can be hard to reach, either because of lack of contact information, or non-existent databases to inform sampling. Here, we present a methodological "case-report" of the yield of a multi-step survey study assessing views on health care among American emigres to Canada, a hard-to-reach population.
To sample this hard-to-reach population, we held a live media conference, supplemented by a nation-wide media release announcing the study. We prepared an 'op-ed' piece describing the study and how to participate. We paid for advertisements in 6 newspapers. We sent the survey information to targeted organizations. And lastly, we asked those who completed the web survey to send the information to others. We use descriptive statistics to document the method's yield.
The combined media strategies led to 4 television news interviews, 10 newspaper stories, 1 editorial and 2 radio interviews. 458 unique individuals accessed the on-line survey, among whom 310 eligible subjects provided responses to the key study questions. Fifty-six percent reported that they became aware of the survey via media outlets, 26% by word of mouth, and 9% through both the media and word of mouth.
Our multi-step communication method yielded a sufficient sample of Americans living in Canada. This combination of paid and unpaid media exposure can be considered by others as a unique methodological approach to identifying and sampling hard-to-reach populations.
PMCID: PMC2525653  PMID: 18710574
16.  Transient Receptor Potential Vanilloid 1 Agonists Cause Endoplasmic Reticulum Stress and Cell Death in Human Lung CellsS 
Transient receptor potential vanilloid 1 (TRPV1) is a calcium-selective ion channel expressed in human lung cells. We show that activation of the intracellular subpopulation of TRPV1 causes endoplasmic reticulum (ER) stress and cell death in human bronchial epithelial and alveolar cells. TRPV1 agonist (nonivamide) treatment caused calcium release from the ER and altered the transcription of growth arrest- and DNA damage-inducible transcript 3 (GADD153), GADD45α, GRP78/BiP, ATF3, CCND1, and CCNG2) in a manner comparable with prototypical ER stress-inducing agents. The TRPV1 antagonist N-(4-tert-butylbenzyl)-N′-(1-[3-fluoro-4-(methylsulfonylamino)-phenyl]ethyl)thiourea (LJO-328) inhibited mRNA responses and cytotoxicity. EGTA and ruthenium red inhibited cell surface TRPV1 activity, but they did not prevent ER stress gene responses or cytotoxicity. Cytotoxicity paralleled eukaryotic translation initiation factor 2, subunit 1 (EIF2α) phosphorylation and the induction of GADD153 mRNA and protein. Transient overexpression of GADD153 caused cell death independent of agonist treatment, and cells selected for stable overexpression of a GADD153 dominant-negative mutant exhibited reduced sensitivity. Salubrinal, an inhibitor of ER stress-induced cytotoxicity via the EIF2αK3/EIF2α pathway, or stable overexpression of the EIF2α-S52A dominant-negative mutant also inhibited cell death. Treatment of the TRPV1-null human embryonic kidney 293 cell line with TRPV1 agonists did not initiate ER stress responses. Likewise, n-benzylnonanamide, an inactive analog of nonivamide, failed to cause ER calcium release, an increase in GADD153 expression, and cytotoxicity. We conclude that activation of ER-bound TRPV1 and stimulation of GADD153 expression via the EIF2αK3/EIF2α pathway represents a common mechanism for cytotoxicity by cell-permeable TRPV1 agonists. These findings are significant within the context of lung inflammatory diseases where elevated concentrations of endogenous TRPV1 agonists are probably produced in sufficient quantities to cause TRPV1 activation and lung cell death.
PMCID: PMC2291394  PMID: 17332266

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