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1.  Human Movement Detection and Idengification Using Pyroelectric Infrared Sensors 
Sensors (Basel, Switzerland)  2014;14(5):8057-8081.
Pyroelectric infrared (PIR) sensors are widely used as a presence trigger, but the analog output of PIR sensors depends on several other aspects, including the distance of the body from the PIR sensor, the direction and speed of movement, the body shape and gait. In this paper, we present an empirical study of human movement detection and idengification using a set of PIR sensors. We have developed a data collection module having two pairs of PIR sensors orthogonally aligned and modified Fresnel lenses. We have placed three PIR-based modules in a hallway for monitoring people; one module on the ceiling; two modules on opposite walls facing each other. We have collected a data set from eight subjects when walking in three different conditions: two directions (back and forth), three distance intervals (close to one wall sensor, in the middle, close to the other wall sensor) and three speed levels (slow, moderate, fast). We have used two types of feature sets: a raw data set and a reduced feature set composed of amplitude and time to peaks; and passage duration extracted from each PIR sensor. We have performed classification analysis with well-known machine learning algorithms, including instance-based learning and support vector machine. Our findings show that with the raw data set captured from a single PIR sensor of each of the three modules, we could achieve more than 92% accuracy in classifying the direction and speed of movement, the distance interval and idengifying subjects. We could also achieve more than 94% accuracy in classifying the direction, speed and distance and idengifying subjects using the reduced feature set extracted from two pairs of PIR sensors of each of the three modules.
PMCID: PMC4063065  PMID: 24803195
pyroelectric infrared sensor; human movement detection; human idengification; machine learning; occupancy sensing; occupant localization
2.  A Comparison of Momentary Time Sampling and Partial-Interval Recording for Evaluating Functional Relations 
In the current study, momentary time sampling (MTS) and partial-interval recording (PIR) were compared to continuous-duration recording of stereotypy and to the frequency of self-injury during a treatment analysis to determine whether the recording method affected data interpretation. Five previously conducted treatment analysis data sets were analyzed by creating separate graphic displays for each measurement method (duration or frequency, MTS, and PIR). An expert panel interview and structured criterion visual inspection were used to evaluate treatment effects across measurement methods. Results showed that treatment analysis interpretations based on both discontinuous recording methods often matched those based on frequency or duration recording; however, interpretations based on MTS were slightly more likely to match those based on duration and those based on PIR were slightly more likely to match those based on frequency.
PMCID: PMC1986695  PMID: 17970263
measurement; momentary time sampling; partial-interval recording
3.  Oxygen Radical Scavenger Activity, EPR, NMR, Molecular Mechanics and Extended-Hückel Molecular Orbital Investigation of the Bis(Piroxicam)Copper(II) Complex 
Metal-Based Drugs  1995;2(1):43-56.
The oxygen radical scavenger activity (ORSA) of [CuII(Pir)2] (HPir = Piroxicam = 4-hydroxy -2- methyl -N-2- pyridyl -2H- 1,2-benzothiazine -3- carboxamide 1,1-dioxide) was determined by chemiluminescence of samples obtained by mixing human neutrophils (from healthy subjects) and [CuII(Pir)2(DMF)2] (DMF = N,N -dimethylformammide) in DMSO/GLY/PBS (2:1:2, v/v) solution (DMSO = dimethylsulfoxide, GLY = 1,2,3-propantriol, PBS = Dulbecco’s buffer salt solution). The ratio of the residual radicals, for the HPir (1.02·10−4M) and [CuII(Pir)2(DMF)2] (1.08·10−5M)/HPir (8.01·10−−5M) systems was higher than 12 (not stimulated) [excess of piroxicam was added (Cu/Pir molar ratio ≈1:10) in order to have most of the metal complexed as bischelate]. In contrast, the ratio of residual radicals for the CuCl2 (1.00·10−5M) and [CuII(Pir)2(DMF)2] (1.08·10−5M)/Hpir (8.01·10−5M)system was 5. The [CuII(Pir)2] compound is therefore a stronger radical scavenger than either HPir or CuCl2. A molecular mechanics (MM) analysis of the gas phase structures of neutral HPir, its zwitterionic (HPir+-) and anionic (Pir-) forms, and some CuII-piroxicam complexes based on X-ray structures allowed calculation of force constants. The most stable structure for HPir has a ZZZ conformation similar to that found in the CuII (and CdII complexes) in the solid state as well as in the gas phase. The structure is stabilized by a strong H bond which involves the N(amide)-H and O(enolic) groups. The MM simulation for the [CuII(Pir)2(DMF)2] complex showed that two high repulsive intramolecular contacts exist between a pyridyl hydrogen atom of one Pir- molecule with the O donor of the other ligand. These interactions activate a transition toward a pseudo-tetrahedral geometry, in the case the apical ligands are removed. On refluxing a suspension of [CuII(Pir)2(DMF)2] in acetone a brown microcystalline solid with the Cu(Pir)2·0.5DMF stoichiometry was in fact prepared. 13C spin-lattice relaxation rates of neutral, zwitterionic and anionic piroxicam, in DMSO solution are explained by the thermal equilibrium between the three most stable structures of the three forms, thus confirming the high quality of the force field. The EPR spectrum of [CuII(Pir)2(DMF)2] (DMSO/GLY, 2:1, v/v, 298 and 110 K) agrees with a N2O2+O2 pseudo-octahedral coordination geometry. The EPR spectrum of [CuII(Pir)2·0.5DMF agrees with a pseudo-tetrahedral coordination geometry. The parameters extracted from the room temperature spectra of the solution phases are in agreement with the data reported for powder and frozen solutions. The extended-Hückel calculations on minimum energy structures of [CuII(Pir)2(DMF)2] and [CuII(Pir)2] (square planar) revealed that the HOMOs have a relevant character of dx2−y2. On the other hand the HOMO of a computer generated structure for [CuII(Pir)2] (pseudo-tetrahedral) has a relevant character of dxy atomic orbital. A dxy orbital is better suited to allow a dπ-pπ interaction to the O2- anion. Therefore this work shows that the anti-inflammatory activity of piroxicam could be due in part to the formation of [CuII(Pir)2] chelates, which can exert a SOD-like activity.
PMCID: PMC2364950  PMID: 18472745
4.  Central Nervous System Effects of the Second-Generation Antihistamines Marketed in Japan -Review of Inter-Drug Differences Using the Proportional Impairment Ratio (PIR)- 
PLoS ONE  2014;9(12):e114336.
Second-generation antihistamines (AHs) have, in general, fewer sedative effects than the first-generation. However, important inter-drug differences remain in the degree of cognitive and/or psychomotor impairment. The extent to which a particular compound causes disruption can be conveniently compared, to all other AHs, using the Proportional Impairment Ratio (PIR). Although the PIR can differentiate the relative impairment caused by individual drugs, there is no indication of the reliability of the ratios obtained.
To calculate the PIRs –together with 95% confidence intervals (CIs), as an index of reliability– and compare AHs currently, or soon to be, available in Japan, with respect to their intrinsic capacity to cause impairment.
Results from studies of cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mequitazine, and olopatadine were included in the PIR calculations. All data utilised came from crossover studies in healthy volunteers which were randomised and placebo and positive-internal controlled. Existing databases from studies reporting the sedative effects of AHs on objective (speed, accuracy, memory) and subjective (feeling) psychometrics were augmented, via results from suitable studies published after the previous reviews. The null value for a PIR was one.
A total of 45 studies were finally included for this review. Of the AHs assessed, fexofenadine, ebastine, and levocetirizine showed a PIR for objective tests of 0. However, only fexofenadine (PIR = 0.49) had an upper limit of the 95% CI of less than 1. Fexofenadine, levocetirizine, desloratadine, olopatadine, loratadine, and mequitazine all had a PIR for subjective ratings of 0, but the upper limits of the 95% CIs were all in excess of 1, although fexofenadine (PIR = 2.57) was the lowest.
The results show that there are differences between second-generation AHs in the extent of sedation produced. However, subjective ratings indicate that patients may not necessarily be aware of this.
PMCID: PMC4264760  PMID: 25501360
5.  PIR-B Deficient Mice Are Susceptible to Salmonella Infection1 
Paired immunoglobulin-like receptors of activating (PIR-A) and inhibitory (PIR-B) isoforms are expressed by many hematopoietic cells including B lymphocytes and myeloid cells. To determine the functional roles of PIR-A and PIR-B in primary bacterial infection, PIR-B-deficient (PIR-B-/-) and wild-type (WT) control mice were injected intravenously with an attenuated strain of Salmonella enterica Typhimurium (WB335). PIR-B-/- mice were found to be more susceptible to Salmonella infection than WT mice as evidenced by high mortality rate, high bacterial loads in the liver and spleen, and a failure to clear bacteria from the circulation. While blood levels of major cytokines and Salmonella-specific antibodies were mostly comparable in the two groups of mice, distinct patterns of inflammatory lesions were found in their livers at 7- to 14-d post-infection: diffuse spreading along the sinusoids in PIR-B-/- mice versus nodular restricted localization in WT mice. PIR-B-/- mice have more inflammatory cells in the liver but fewer B cells and CD8+ T cells in the spleen than WT mice at 14-d post-infection. PIR-B-/- bone marrow-derived macrophages (BMMφ) failed to control intracellular replication of Salmonella in vitro, in part due to inefficient phagosomal oxidant production, when compared with WT BMMφ. PIR-B-/- BMMφ also produced more nitrite and TNFα upon exposure to Salmonella than WT BMMφ. These findings suggest that the disruption of PIR-A and PIR-B balance affects their regulatory roles in host defense to bacterial infection.
PMCID: PMC2613810  PMID: 18768880
6.  Informatics Strategies for Large-Scale Novel Cross-Linking Analysis 
Journal of proteome research  2007;6(9):3412-3421.
The detection of protein interactions in biological systems represents a significant challenge for today’s technology. Chemical cross-linking provides the potential to impart new chemical bonds in a complex system that result in mass changes in a set of tryptic peptides detected by mass spectrometry. However, system complexity and cross-linking product heterogeneity have precluded widespread chemical cross-linking use for large-scale identification of protein–protein interactions. The development of mass spectrometry identifiable cross-linkers called protein interaction reporters (PIRs) has enabled on-cell chemical cross-linking experiments with product type differentiation. However, the complex datasets resultant from PIR experiments demand new informatics capabilities to allow interpretation. This manuscript details our efforts to develop such capabilities and describes the program X-links, which allows PIR product type differentiation. Furthermore, we also present the results from Monte Carlo simulation of PIR-type experiments to provide false discovery rate estimates for the PIR product type identification through observed precursor and released peptide masses. Our simulations also provide peptide identification calculations based on accurate masses and database complexity that can provide an estimation of false discovery rates for peptide identification. Overall, the calculations show a low rate of false discovery of PIR product types due to random mass matching of approximately 12% with 10 ppm mass measurement accuracy and spectral complexity resulting from 100 peptides. In addition, consideration of a reduced database resulting from stage 1 analysis of Shewanella oneidensis MR-1 containing 367 proteins resulted in a significant reduction of expected identification false discovery rate estimation compared to that from the entire Shewanella oneidensis MR-1 proteome.
PMCID: PMC2475505  PMID: 17676784
7.  Impact of Poverty on Serum Phosphate Concentrations in the Third National Health and Nutrition Examination Survey 
Increased serum phosphate is associated with adverse health outcomes. High intake of inexpensive processed and fast foods is common in impoverished communities and is linked with excessive dietary phosphorus intake and elevated serum phosphate concentrations in chronic kidney disease patients. We examined the impact of socioeconomic status on dietary phosphorus intake and serum phosphate concentrations in the general population.
Cross-sectional study.
14,261 adult participants in the Third National Health and Nutrition Examination Survey.
Predictors and Outcomes
Poverty to income ratio (PIR; family income indexed to the federal poverty level) was the primary index of socioeconomic status. Serum phosphate was the primary outcome variable.
Although estimated phosphorus intake decreased with decreasing quartiles of PIR (P < 0.001), serum phosphate was inversely associated with PIR (P = 0.003). The relationship between lower PIR and higher serum phosphate remained significant after adjustment for demographic, laboratory, and dietary intake characteristics (P = 0.02). Compared to participants in the highest PIR quartile (income >300% of the federal poverty level), participants in the lowest quartile (income < the federal poverty level) had more than twice the odds of hyperphosphatemia (≥4.4 mg/dl) in unadjusted and multivariable-adjusted logistic regression analyses (OR 2.2, 95%CI 1.5, 3.2).
Although lower income was associated with decreased estimated phosphorus intake, increasing poverty was independently linked with increased serum phosphate and higher likelihood of hyperphosphatemia. These findings may indicate that conventional dietary instruments underestimate phosphorus intake, especially among impoverished individuals. Further studies are needed to explore these possibilities.
PMCID: PMC2937203  PMID: 20537917
Phosphate; Poverty; Nutrition
8.  Assessment of Predictive Markers for Placental Inflammatory Response in Preterm Births 
PLoS ONE  2014;9(10):e107880.
Placental inflammatory response (PIR) is associated with adverse neonatal outcomes such as sepsis, cerebral palsy, low birth weight, preterm birth, and neonatal mortality. However, there is an urgent need for noninvasive and sensitive biomarkers for prediction of PIR. In this study, we evaluated the clinical usefulness of maternal serum inflammatory markers for prediction of PIR in women with impending preterm birth. We conducted a retrospective cohort study of 483 patients who delivered preterm neonates. Serum levels of leukocyte differential counts, C-reactive protein (CRP), and neutrophil to lymphocyte ratio (NLR) were compared between women with no placental inflammation and women with PIR. The mean neutrophil counts, CRP levels, and NLR in both the patients with histologic chorioamnionitis (HCA) alone and those with HCA with funisitis were significantly higher than those in women with no placental inflammation. Compared to leukocyte subset or CRP, NLR in women with funisitis was significantly higher than in women with HCA alone and showed higher predictive accuracy, along with 71.4% sensitivity, 77.9% specificity, 80.7% positive predictive value, and 67.8% negative predictive value for prediction of PIR. On Kaplan-Meier survival analysis, women with both an elevated level of CRP and a high NLR had a shorter admission-to-delivery interval compared to women with either an elevated level of CRP or a high NLR alone. NLR may be a predictive marker of PIR and could be used as a cost-effective parameter for identifying women at risk of PIR.
PMCID: PMC4188518  PMID: 25291377
9.  Role of Self-Efficacy in the Relationship Between Patient-Provider Relationships and Psychological Insulin Resistance Among Patients with Type 2 Diabetes 
Psychological insulin resistance (PIR) affects patients’ self-care behaviors and quality of life due to the delay of insulin treatment for optimal glycemic control. Although effective patient-provider communication and relationships have been shown to improve patients’ overall treatment adherence and attitude toward treatment, little is known about the potential mechanisms by which effective patient-provider communication and relationships decrease PIR and whether these relationships are mediated by diabetes self-efficacy. The purpose of this study is to examine whether diabetes self-efficacy among patients with type 2 diabetes (T2D) mediates the relationships between PIR and perceived patient-provider relationships. A total of 178 patients with T2D participated in a cross-sectional study. Data were obtained by patient interview using validated measures of diabetes attitude, diabetes knowledge, self-efficacy, and patient-provider communication. PIR was measured by using a validated measure, Barriers to Insulin Treatment. A structural equation model was developed to estimate direct and indirect effects of patient-provider relationship on PIR when self-efficacy was controlled as a mediator. Diabetes knowledge and attitude were not significantly associated with PIR. Better patient-provider relationship was directly associated with lower PIR (β = −.40, p = 0.008). When diabetes self-efficacy was included as a mediator, the direct effect between patient-provider relationship and PIR changed (β = −.27, p = 0.034), indicating that better patient-provider relationship that reduces PIR is due to greater diabetes self-efficacy. The findings suggest that development of intervention programs aimed at improving diabetes self-efficacy—which may be positively correlated with better patient-provider relationship—is needed to reduce PIR.
PMCID: PMC4288822  PMID: 25584361
psychological insulin resistance; self-efficacy; patient-provider relationship; mediator
10.  Biochemical Nature and Cellular Distribution of the Paired Immunoglobulin-like Receptors, PIR-A and PIR-B  
PIR-A and PIR-B, paired immunoglobulin-like receptors encoded, respectively, by multiple Pira genes and a single Pirb gene in mice, are relatives of the human natural killer (NK) and Fc receptors. Monoclonal and polyclonal antibodies produced against a recombinant PIR protein identified cell surface glycoproteins of ∼85 and ∼120 kD on B cells, granulocytes, and macrophages. A disulfide-linked homodimer associated with the cell surface PIR molecules was identified as the Fc receptor common γ (FcRγc) chain. Whereas PIR-B fibroblast transfectants expressed cell surface molecules of ∼120 kD, PIR-A transfectants expressed the ∼85-kD molecules exclusively intracellularly; PIR-A and FcRγc cotransfectants expressed the PIR-A/ FcRγc complex on their cell surface. Correspondingly, PIR-B was normally expressed on the cell surface of splenocytes from FcRγc−/− mice whereas PIR-A was not. Cell surface levels of PIR molecules on myeloid and B lineage cells increased with cellular differentiation and activation. Dendritic cells, monocytes/macrophages, and mast cells expressed the PIR molecules in varying levels, but T cells and NK cells did not. These experiments define the coordinate cellular expression of PIR-B, an inhibitory receptor, and PIR-A, an activating receptor; demonstrate the requirement of FcRγc chain association for cell surface PIR-A expression; and suggest that the level of FcRγc chain expression could differentially affect the PIR-A/PIR-B equilibrium in different cell lineages.
PMCID: PMC2192985  PMID: 9892613
Fc receptor γ chain; activating receptor; inhibitory receptor; dendritic cells; innate immunity
11.  Relationship between tort claims and patient incident reports in the Veterans Health Administration 
Quality & safety in health care  2005;14(2):117-122.
Objective: The Veterans Health Administration's patient incident reporting system was established to obtain comprehensive data on adverse events that affect patients and to act as a harbinger for risk management. It maintains a dataset of tort claims that are made against Veterans Administration's employees acting within the scope of employment. In an effort to understand the thoroughness of reporting, we examined the relationship between tort claims and patient incident reports (PIRs).
Methods: Using social security and record numbers, we matched 8260 tort claims and 32 207 PIRs from fiscal years 1993–2000. Tort claims and PIRs were considered to be related if the recorded dates of incident were within 1 month of each other. Descriptive statistics, odds ratios, and two sample t tests with unequal variances were used to determine the relationship between PIRs and tort claims.
Results: 4.15% of claims had a related PIR. Claim payment (either settlement or judgment for plaintiff) was more likely when associated with a PIR (OR 3.62; 95% CI 2.87 to 4.60). Payment was most likely for medication errors (OR 8.37; 95% CI 2.05 to 73.25) and least likely for suicides (OR 0.25; 95% CI 0.11 to 0.55).
Conclusions: Although few tort claims had a related PIR, if a PIR was present the tort claim was more likely to result in a payment; moreover, the payment was likely to be higher. Underreporting of patient incidents that developed into tort claims was evident. Our findings suggest that, in the Veterans Health Administration, there is a higher propensity to both report and settle PIRs with bad outcomes.
PMCID: PMC1743988  PMID: 15805457
12.  iTRAQ Quantitative Proteomics in the Analysis of Tears in Dry Eye Patients 
We analyzed the change in protein expression of tear film proteins in dry eye (DE) and non-DE (NDE) patients using isobaric tag for relative and absolute quantitation (iTRAQ) technology.
We categorized 24 participants into NDE, and mild (MDE), moderate-to-severe (MSDE), and mixed (MXDE) DE on the basis of clinical DE tests. Tear samples (n = 6 subjects/group) were collected using Schirmer's strips. Proteins were extracted from strips and were quantified using the Bradford assay. Protein from each sample was pooled as internal standard (IS), and 20 μg protein from each sample and the IS were digested and labeled with different tandem mass tag (TMT) isobaric mass tag labeling reagent. The reaction was quenched and the labeled peptides were mixed. Samples were injected for liquid chromatography-mass spectrometry (LC/MS/MS) analysis on the Orbitrap mass spectrometer. Bioinformatic analyses were performed using protein information resource (PIR).
Combined results showed a total of 386 proteins in tears as determined by the iTRAQ experiments. An average of 163 proteins was detected in each of 6 biologic replicates. Of those, 55% were detected 6 times and 90% were detected multiple times (>2). In addition to the down-regulation of commonly reported proteins, such as lipocalin-1, lysozyme, and prolactin-inducible protein across all sub groups of DE, a number of proteins were significantly differentially regulated in MSDE and other subgroups of DE. A greater number of proteins were down-regulated in MSDE versus MDE, and the specific functions involved include response to stimulus (8 vs. 6 proteins), immune system process (6 vs. 4), regulation of biologic processes (3 vs. 3), and ion transport (2 vs. 2).
iTRAQ is one of the newest tools for quantitative mass spectrometry in tear proteome research. Differences in the protein ratios can be detected between normal and DE patients. PIR is a useful resource to interpret pathways and functions of proteins.
This study reports the proteins identified in tears of different sub groups of dry eye patients by using a novel iTRAQ method of quantitative proteomics. This study showed greater number of proteins down-regulated in moderate to severe dry eye group than other sub groups of dry eye. Unique proteins were associated with each sub group of dry eye. iTRAQ technology is a relatively new protein quantification method, especially in tear film which allows the analysis of multiple samples to be obtained simultaneously.
PMCID: PMC3410666  PMID: 22736608
13.  The Protein Information Resource 
Nucleic Acids Research  2003;31(1):345-347.
The Protein Information Resource (PIR) is an integrated public resource of protein informatics that supports genomic and proteomic research and scientific discovery. PIR maintains the Protein Sequence Database (PSD), an annotated protein database containing over 283 000 sequences covering the entire taxonomic range. Family classification is used for sensitive identification, consistent annotation, and detection of annotation errors. The superfamily curation defines signature domain architecture and categorizes memberships to improve automated classification. To increase the amount of experimental annotation, the PIR has developed a bibliography system for literature searching, mapping, and user submission, and has conducted retrospective attribution of citations for experimental features. PIR also maintains NREF, a non-redundant reference database, and iProClass, an integrated database of protein family, function, and structure information. PIR-NREF provides a timely and comprehensive collection of protein sequences, currently consisting of more than 1 000 000 entries from PIR-PSD, SWISS-PROT, TrEMBL, RefSeq, GenPept, and PDB. The PIR web site ( connects data analysis tools to underlying databases for information retrieval and knowledge discovery, with functionalities for interactive queries, combinations of sequence and text searches, and sorting and visual exploration of search results. The FTP site provides free download for PSD and NREF biweekly releases and auxiliary databases and files.
PMCID: PMC165487  PMID: 12520019
14.  Preparation of solid dispersions of nonsteroidal anti-inflammatory drugs with acrylic polymers and studies on mechanisms of drug-polymer interactions 
AAPS PharmSciTech  2002;3(2):35-45.
This work studied the mechanisms of interaction between Eudragit RS100 (RS) and RL100 (RL) polymers with 3 nonsteroidal anti-inflammatory drugs: diflunisal (DIF), flurbiprofen (FLU), and piroxicam (PIR). Solid dispersions of polymers and drugs at different weight ratios were prepared by coevaporation of their ethanol solutions. The resulting coevaporates were characterized in the solid state (Fourier-transformed infrared spectroscopy (FT-IR) IR, differential scanning calorimetry, powder-x-ray diffractometry) as well as by studying the in vitro drug release in a gastroenteric environment. Absorption tests from drug solutions to the solid polymers were also performed to better explain the mechanism of interactions between them. The preparative conditions did not induce changes in the crystalline state of the drugs (amorphization or polymorphic change). Drugs strongly interacted with the ammonium groups present in polymers, giving an electrostatic interaction that reinforced the mere physical dispersion of drug molecules within polymer networks. Such interactions are related to the chemical structure of the drugs and to their dissociated or undissociated state. The dispersion of drugs in the polymer matrices strongly influenced their dissolution rate, which appeared slower and more gradual than those of the pure drugs, when polymer ratios were increased. RL coevaporates usually displayed higher dissolution rates. The kinetic evaluation of the dissolution profile, however, suggested that both the drug solubility in the external medium and its diffusion capacity within the polymer network are involved. In the sorption experiments, RL showed a greater adsorptive capacity than RS, in relation to the greater number of quaternary ammonium functions, which behave as activity sites for the electrostatic interactions. In the presence of Tris-HCl buffer (pH 7.4), drug adsorption was reduced, as a consequence of the competition of the chloride ions with drug anions for the polymer binding sites. In general, DIF and FLU displayed a similar interaction with RS and RL active sites; PIR's was different. The different molecular structures of these agents can justify such findings. The presence of a carboxyl group (instead of another dissociable acidic moiety, like the hydroxy-enolic one in the PIR molecule) could help explain the strong interaction with RS and RL polymers' quaternary ammonium centers. Preliminary studies like ours are important in helping develop better forecasting and increasing the understanding of the incorporation/release behavior of drugs from particulate delivery systems that can be made from these polymers.
PMCID: PMC2750312  PMID: 12916947
Eudragit RS100; Eudragit RL100; diflunisal; flurbiprofen; piroxicam; solid dispersions; coevaporates
15.  Socioeconomic Status, Self-Rated Health, and Mortality in a Multiethnic Sample of US Adults 
Journal of Epidemiology  2011;21(5):337-345.
To examine the association between socioeconomic status (SES), self-rated health (SRH), and mortality separately by race-ethnicity in a nationally representative sample of US adults.
We analyzed data from 16 716 adult women and men who were followed up for mortality for up to 12 years as part of the third National Health and Nutrition Examination survey (NHANES III). Poverty-income ratio (PIR) and education were assessed as measures of SES. All-cause mortality (n = 2850) was recorded from the NHANES III linked mortality file.
Lower PIR was associated with mortality after adjustment for lifestyle, clinical risk factors, and SRH in all racial-ethnic groups (P-trend <0.005). In contrast, after adjusting for lifestyle and clinical risk factors, lower education was not associated with all-cause mortality in non-Hispanic whites (P-trend = 0.16), whereas the association remained significant after adjustment for SRH and lifestyle and clinical risk factors in other race-ethnicities (P-trend = 0.005; P-interaction between education categories and race-ethnicity was 0.02).
Our results suggest that lower PIR was associated with mortality in all racial-ethnic groups. In contrast, lower education was significantly associated with mortality only in racial-ethnic groups other than non-Hispanic whites. Our results indicate that, beyond lifestyle and clinical risk factors, adjusting for SRH resulted in only a modest change in the association of SES and mortality.
PMCID: PMC3899432  PMID: 21747210
education; income; self-rating of health; ethnicity; mortality; United States
16.  Unobtrusive assessment of walking speed in the home using inexpensive PIR sensors 
Walking speed and activity are important measures of functional ability in the elderly. Our earlier studies have suggested that continuous monitoring may allow us to detect changes in walking speed that are also predictive of cognitive changes. We evaluated the use of passive infrared (PIR) sensors for measuring walking speed in the home on an ongoing basis. In comparisons with gait mat estimates (ground truth) and the results of a timed walk test (the clinical gold standard) in 18 subjects, we found that the clinical measure overestimated typical walking speed, and the PIR sensor estimations of walking speed were highly correlated to actual gait speed. Examination of in-home walking patterns from more than 100,000 walking speed samples for these subjects suggested that we can accurately assess walking speed in the home. We discuss the potential of this approach for continuous assessment.
PMCID: PMC2846826  PMID: 19965096
17.  Pir1p Mediates Translocation of the Yeast Apn1p Endonuclease into the Mitochondria To Maintain Genomic Stability 
Molecular and Cellular Biology  2001;21(5):1647-1655.
The mitochondrial genome is continuously subject to attack by reactive oxygen species generated through aerobic metabolism. This leads to the formation of a variety of highly genotoxic DNA lesions, including abasic sites. Yeast Apn1p is localized to the nucleus, where it functions to cleave abasic sites, and apn1 Δ mutants are hypersensitive to agents such as methyl methanesulfonate (MMS) that induce abasic sites. Here we demonstrate for the first time that yeast Apn1p is also localized to the mitochondria. We found that Pir1p, initially isolated as a cell wall constituent of unknown function, interacts with the C-terminal end of Apn1p, which bears a bipartite nuclear localization signal. Further analysis revealed that Pir1p is required to cause Apn1p mitochondrial localization, presumably by competing with the nuclear transport machinery. pir1Δ mutants displayed a striking (∼3-fold) increase of Apn1p in the nucleus, which coincided with drastically reduced levels in the mitochondria. To explore the functional consequences of the Apn1p-Pir1p interaction, we measured the rate of mitochondrial mutations in the wild type and pir1Δ and apn1Δ mutants. pir1Δ and apn1Δ mutants exposed to MMS exhibited 3.6- and 5.8-fold increases, respectively, in the rate of mitochondrial mutations, underscoring the importance of Apn1p in repair of the mitochondrial genome. We conclude that Pir1p interacts with Apn1p, at the level of either the cytoplasm or nucleus, and facilitates Apn1p transport into the mitochondria to repair damaged DNA.
PMCID: PMC86710  PMID: 11238901
18.  Momentary time sampling as an estimate of percentage time: A field validation 
This study examined the percentage time estimates of momentary time sampling against the real time obtained with handheld computers in a natural setting. Twenty-two concurrent observations were conducted in elementary schools by one observer who used 15-s momentary time sampling and a second who used a handheld computer. Results for the six behaviors showed a close correspondence between the momentary time sampling percentage observation intervals and the real time percentage observation time, although 15-s momentary time sampling tended not to sample low-frequency short-duration behaviors. The results confirmed laboratory findings that short-interval momentary time sampling estimates percentage time accurately for a wide range of behavior frequencies and durations, and suggested that observers using momentary time sampling in a natural setting are able to obtain accurate data.
PMCID: PMC1286269  PMID: 16795737
time sample; methodology; naturalistic observations
19.  Performance of the auxotrophic Saccharomyces cerevisiae BY4741 as host for the production of IL-1β in aerated fed-batch reactor: role of ACA supplementation, strain viability, and maintenance energy 
Saccharomyces cerevisiae BY4741 is an auxotrophic commonly used strain. In this work it has been used as host for the expression and secretion of human interleukin-1β (IL1β), using the cell wall protein Pir4 as fusion partner. To achieve high cell density and, consequently, high product yield, BY4741 [PIR4-IL1β] was cultured in an aerated fed-batch reactor, using a defined mineral medium supplemented with casamino acids as ACA (auxotrophy-complementing amino acid) source. Also the S. cerevisiae mutant BY4741 Δyca1 [PIR4-IL1β], carrying the deletion of the YCA1 gene coding for a caspase-like protein involved in the apoptotic response, was cultured in aerated fed-batch reactor and compared to the parental strain, to test the effect of this mutation on strain robustness. Viability of the producer strains was examined during the runs and a mathematical model, which took into consideration the viable biomass present in the reactor and the glucose consumption for both growth and maintenance, was developed to describe and explain the time-course evolution of the process for both, the BY4741 parental and the BY4741 Δyca1 mutant strain.
Our results show that the concentrations of ACA in the feeding solution, corresponding to those routinely used in the literature, are limiting for the growth of S. cerevisiae BY4741 [PIR4-IL1β] in fed-batch reactor. Even in the presence of a proper ACA supplementation, S. cerevisiae BY4741 [PIR4-IL1β] did not achieve a high cell density. The Δyca1 deletion did not have a beneficial effect on the overall performance of the strain, but it had a clear effect on its viability, which was not impaired during fed-batch operations, as shown by the kd value (0.0045 h-1), negligible if compared to that of the parental strain (0.028 h-1). However, independently of their robustness, both the parental and the Δyca1 mutant ceased to grow early during fed-batch runs, both strains using most of the available carbon source for maintenance, rather than for further proliferation. The mathematical model used evidenced that the energy demand for maintenance was even higher in the case of the Δyca1 mutant, accounting for the growth arrest observed despite the fact that cell viability remained comparatively high.
The paper points out the relevance of a proper ACA formulation for the outcome of a fed-batch reactor growth carried out with S. cerevisiae BY4741 [PIR4-IL1β] strain and shows the sensitivity of this commonly used auxotrophic strain to aerated fed-batch operations. A Δyca1 disruption was able to reduce the loss of viability, but not to improve the overall performance of the process. A mathematical model has been developed that is able to describe the behaviour of both the parental and mutant producer strain during fed-batch runs, and evidence the role played by the energy demand for maintenance in the outcome of the process.
PMCID: PMC2806294  PMID: 20042083
20.  Preoperative Oral Carbohydrate Improved Postoperative Insulin Resistance in Rats through the PI3K/AKT/mTOR Pathway 
Preoperative oral carbohydrate (OCH) improves postoperative insulin resistance (PIR) and insulin sensitivity. However, the exact mechanisms involved in the improvement of PIR with respect to preoperative OCH are still not clear. The aim of this study was to investigate the involvement of preoperative OCH and PI3K/AKT/mTOR pathway in reducing PIR in rats.
Forty male Sprague-Dawley rats were randomly assigned to PreOp, glucose, saline, and fasting groups. Rats in the PreOp, glucose, and saline groups received OCH, 5% glucose solution, and saline, respectively. Rats in the fasting group did not receive anything but were fasted 3 h before surgery. Blood glucose, insulin and leucine levels, and insulin resistance, secretion, and sensitivity indexes were measured before and after surgery. mRNA and protein (total and phosphorylated) levels of mTOR, IRS-1, PI3K, PKB/AKT, and GlUT4 were measured using real-time polymerase chain reaction and Western blot in skeletal muscles.
In the PIR experiment, blood glucose, serum insulin, insulin resistance, and serum leucine levels were all significantly lower in the PreOp group than in the other 3 groups (P<0.05) after surgery. HOMA-ISI were higher in the PreOp group vs the other 3 groups after surgery (P<0.05), and HOMA-β in the PreOp group was higher than that in the other 3 groups at 30 and 120 min after surgery. Additionally, post-operative phosphorylated IRS-1, PI3K, and AKT protein levels were significantly higher in the PreOp group than in the other 3 groups (P<0.05), but no significant differences were observed in their respective protein levels (P>0.05).
OCH decreases postoperative insulin resistance and improves postoperative insulin sensitivity in skeletal muscles through the PI3K/AKT/mTOR pathway.
PMCID: PMC4288420  PMID: 25553410
Leucine; Insulin Resistance; Perioperative Care; Phosphoinositide Phospholipase C; TOR Serine-Threonine Kinases
21.  Prevalence and Trends of Severe Obesity among US Children and Adolescents 
Academic pediatrics  2009;9(5):322-329.
To determine the extent to which the 2007 definitions for severe (body mass index ≥99th percentile for age and gender) and morbid (BMI ≥ 40 kg/m2) obesity affects different groups of American children and adolescents and has increased over time.
Analysis of nationally representative data from the National Health and Nutrition Examination Surveys (NHANES) II, III, and 1999–2004;12,384 US children and adolescents ages 2–19 years were included in the analysis. Outcome measures were the proportion of subjects with severe (BMI ≥99th percentile) and morbid (BMI ≥40 kg/m2) obesity, with age, gender, race, and poverty-income ratio (PIR) as key variables.
In 1999–2004, 3.8% of children 2–19 yr had a BMI ≥99th percentile, with higher prevalence among boys than girls (4.6% vs. 2.9%; p<0.001). Prevalence was highest among Blacks, 5.7% and Mexican Americans, 5.2%, compared with Whites 3.1% (p< 0.001). The prevalence differed by PIR category as well (4.3% for those with PIR ≤3 vs. 2.5% for those with PIR > 3; p = 0.002). A BMI ≥40 was found in 1.3% of adolescents 12–19 yr, with similar associations with race and poverty. The overall prevalence of BMI ≥99th percentile has increased by more than 300% since NHANES II (1976), and over 70% since NHANES III (1994) in children 2–19 years of age.
Rates of severe childhood obesity have tripled in the last 25 years, with significant differences by race, gender and poverty. This places demands on healthcare and community services, especially because the highest rates are among children who are frequently underserved by the health care system.
PMCID: PMC2746875  PMID: 19560993
morbid obesity; nutrition surveys; trends; children; adolescents
22.  A simple method for construction of pir+ Enterobacterial hosts for maintenance of R6K replicon plasmids 
BMC Research Notes  2012;5:157.
The R6K replicon is one of the best studied bacterial plasmid replicons. Replication of the R6K plasmid and derivatives harboring its γ origin of replication (oriR6Kγ) is dependent on the pir gene-encoded π protein. Originally encoded by R6K, this protein is usually provided in trans in hosts engineered to support replication of plasmids harboring oriR6Kγ. In Escherichia coli this is commonly achieved by chromosomal integration of pir either via lysogenization with a λpir phage or homologous recombination at a pre-determined locus.
Current methods for construction of host strains for oriR6Kγ-containing plasmids involve procedures that do not allow selection for presence of the pir gene and require cumbersome and time-consuming screening steps. In this study, we established a mini-Tn7-based method for rapid and reliable construction of pir+ host strains. Using a curable mini-Tn7 delivery plasmid, pir expressing derivatives of several commonly used E. coli cloning and mobilizer strains were isolated using both the wild-type pir+ gene as well as the copy-up pir-116 allele. In addition, we isolated pir+ and pir-116 expressing derivatives of a clinical isolate of Salmonella enterica serovar Typhimurium. In both E. coli and S. enterica serovar Typhimurium, the presence of the pir+ wild-type or pir-116 alleles allowed the replication of oriR6Kγ-containing plasmids.
A mini-Tn7 system was employed for rapid and reliable engineering of E. coli and S. enterica serovar Typhimurium host strains for plasmids containing oriR6Kγ. Since mini-Tn7 elements transpose in most, if not all, Gram negative bacteria, we anticipate that with relatively minor modifications this newly established method will for the first time allow engineering of other bacterial species to enable replication of plasmids with oriR6Kγ.
PMCID: PMC3338088  PMID: 22433797
23.  Construction of a Library of Human Glycosyltransferases Immobilized in the Cell Wall of Saccharomyces cerevisiae▿  
Applied and Environmental Microbiology  2006;72(11):7003-7012.
Fifty-one human glycosyltransferases were expressed in Saccharomyces cerevisiae as immobilized enzymes and were assayed for enzymatic activities. The stem and catalytic regions of sialyl-, fucosyl-, galactosyl-, N-acetylgalactosaminyl-, and N-acetylglucosaminyltransferases were fused with yeast cell wall Pir proteins, which anchor glycosyltransferases at the yeast cell wall glucan. More than 75% of expressed recombinant glycosyltransferases retained their enzymatic activities in the yeast cell wall fraction and will be used as a human glycosyltransferase library. In increasing the enzymatic activities of immobilized glycosyltransferases, several approaches were found to be effective. Additional expression of yeast protein disulfide isomerase increased the expression levels and activities of polypeptide N-acetylgalactosaminyltransferases and other glycosyltransferases. PIR3 and/or PIR4 was more effective than PIR1 as a cell wall anchor when the Pir-glycosyltransferase fusions were expressed under the control of the constitutive glyceraldehyde-3-phosphate dehydrogenase promoter. Oligosaccharides such as Lewis x, Lewis y, and H antigen were successfully synthesized using this immobilized glycosyltransferase library, indicating that the Pir-fused glycosyltransferases are useful for the production of various human oligosaccharides.
PMCID: PMC1636194  PMID: 16936046
24.  Transcriptional response of rat frontal cortex following acute In Vivo exposure to the pyrethroid insecticides permethrin and deltamethrin 
BMC Genomics  2008;9:546.
Pyrethroids are neurotoxic pesticides that interact with membrane bound ion channels in neurons and disrupt nerve function. The purpose of this study was to characterize and explore changes in gene expression that occur in the rat frontal cortex, an area of CNS affected by pyrethroids, following an acute low-dose exposure.
Rats were acutely exposed to either deltamethrin (0.3 – 3 mg/kg) or permethrin (1 – 100 mg/kg) followed by collection of cortical tissue at 6 hours. The doses used range from those that cause minimal signs of intoxication at the behavioral level to doses well below apparent no effect levels in the whole animal. A statistical framework based on parallel linear (SAM) and isotonic regression (PIR) methods identified 95 and 53 probe sets as dose-responsive. The PIR analysis was most sensitive for detecting transcripts with changes in expression at the NOAEL dose. A sub-set of genes (Camk1g, Ddc, Gpd3, c-fos and Egr1) was then confirmed by qRT-PCR and examined in a time course study. Changes in mRNA levels were typically less than 3-fold in magnitude across all components of the study. The responses observed are consistent with pyrethroids producing increased neuronal excitation in the cortex following a low-dose in vivo exposure. In addition, Significance Analysis of Function and Expression (SAFE) identified significantly enriched gene categories common for both pyrethroids, including some relating to branching morphogenesis. Exposure of primary cortical cell cultures to both compounds resulted in an increase (~25%) in the number of neurite branch points, supporting the results of the SAFE analysis.
In the present study, pyrethroids induced changes in gene expression in the frontal cortex near the threshold for decreases in ambulatory motor activity in vivo. The penalized regression methods performed similarly in detecting dose-dependent changes in gene transcription. Finally, SAFE analysis of gene expression data identified branching morphogenesis as a biological process sensitive to pyrethroids and subsequent in vitro experiments confirmed this predicted effect. The novel findings regarding pyrethroid effects on branching morphogenesis indicate these compounds may act as developmental neurotoxicants that affect normal neuronal morphology.
PMCID: PMC2626604  PMID: 19017407
25.  Taking a closer look: time sampling and measurement error1 
A person manufactured his in-seat behavior for 15, 30-min sessions so that there were three blocks of five sessions where the behavior occurred 20%, 50%, and 80% of the time. Whole interval, partial interval, and momentary time-sample measures of the behavior were taken and compared to the continuous measure of the behavior i.e., per cent of time the behavior occurred. For interval time sampling, the difference between the continuous and sample measures i.e., measurement error, was: (1) extensive, (2) unidirectional, (3) a function of the time per response, and (4) inconsistent across changes in the continuous measure. A procedural analysis demonstrated that the frequency and duration of behavior are confounded in interval time sampling. Momentary time sampling was found to be superior to interval time sampling in estimating the duration a behavior occurs.
PMCID: PMC1311189  PMID: 16795556
time sampling; partial interval; whole interval; momentary; measurement error

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