Distribution by Scientific Domains
Distribution within Chemistry

Terms modified by Ka

  • ka bp
  • ka value

  • Selected Abstracts

    The relationships between half-life (t1/2) and mean residence time (MRT) in the two-compartment open body model

    Eyal Sobol
    Abstract Rationale. In the one-compartment model following i.v. administration the mean residence time (MRT) of a drug is always greater than its half-life (t1/2). However, following i.v. administration, drug plasma concentration (C) versus time (t) is best described by a two-compartment model or a two exponential equation: C=Ae,,t+Be,,t, where A and B are concentration unit-coefficients and , and , are exponential coefficients. The relationships between t1/2 and MRT in the two-compartment model have not been explored and it is not clear whether in this model too MRT is always greater than t1/2. Methods. In the current paper new equations have been developed that describe the relationships between the terminal t1/2 (or t1/2,) and MRT in the two-compartment model following administration of i.v. bolus, i.v. infusion (zero order input) and oral administration (first order input). Results. A critical value (CV) equals to the quotient of (1,ln2) and (1,,/,) (CV=(1,ln2)/(1,,/,)=0.307/(1,,/,)) has been derived and was compared with the fraction (f1) of drug elimination or AUC (AUC-area under C vs t curve) associated with the first exponential term of the two-compartment equation (f1=A/,/AUC). Following i.v. bolus, CV ranges between a minimal value of 0.307 (1,ln2) and infinity. As long as f1t1/2 and vice versa, and when f1=CV, then MRT=t1/2. Following i.v. infusion and oral administration the denominator of the CV equation does not change but its numerator increases to (0.307+,T/2) (T-infusion duration) and (0.307+,/ka) (ka-absorption rate constant), respectively. Examples of various drugs are provided. Conclusions. For every drug that after i.v. bolus shows two-compartment disposition kinetics the following conclusions can be drawn (a) When f1<0.307, then f1t1/2. (b) When ,/,>ln2, then CV>1>f1 and thus, MRT>t1/2. (c) When ln2>,/,>(ln4,1), then 1>CV>0.5 and thus, in order for t1/2>MRT, f1 has to be greater than its complementary fraction f2 (f1>f2). (d) When ,/,<(ln4,1), it is possible that t1/2>MRT even when f2>f1, as long as f1>CV. (e) As , gets closer to ,, CV approaches its maximal value (infinity) and therefore, the chances of MRT>t1/2 are growing. (f) As , becomes smaller compared with ,, ,/, approaches zero, the denominator approaches unity and consequently, CV gets its minimal value and thus, the chances of t1/2>MRT are growing. (g) Following zero and first order input MRT increases compared with i.v. bolus and so does CV and thus, the chances of MRT>t1/2 are growing. Copyright © 2004 John Wiley & Sons, Ltd. [source]

    Molecular recognition of sugars by lanthanide (III) complexes of a conjugate of N, N -bis[2-[bis[2-(1, 1-dimethylethoxy)-2-oxoethyl]amino]ethyl]glycine and phenylboronic acid

    Elisa Battistini
    Abstract A novel conjugate of phenylboronic acid and an Ln(DTPA) derivative, in which the central acetate pendant arm was replaced by the methylamide of L -lysine, was synthesized and characterized. The results of a fit of variable 17O NMR data and a 1H NMRD profile show that the water residence lifetime of the Gd(III) complex (150,ns) is shorter than that of the parent compound Gd(DTPA)2, (303,ns). Furthermore, the data suggest that several water molecules in the second coordination sphere of Gd(III) contribute to the relaxivity of the conjugate. The Ln(III) complexes of this conjugate are highly suitable for molecular recognition of sugars. The interaction with various sugars was investigated by 11B NMR spectroscopy. Thanks to the thiourea function that links the phenylboronic acid targeting vector with the DTPA derivative, the interactions are stronger than that of phenylboronic acid itself. In particular, the interaction with N -propylfructosamine, a model for the glucose residue in glycated human serum albumin (HSA), is very strong. Unfortunately, the complex also shows a rather strong interaction with hexose-free HSA (KA,=,705,±,300). Copyright © 2007 John Wiley & Sons, Ltd. [source]

    Keratoacanthoma: A Clinico-Pathologic Enigma

    Robert A. Schwartz MD
    Background. Keratoacanthoma (KA) is an extraordinary entity. Once considered a benign neoplasm that resembled a highly malignant one (pseudomalignancy), it is now viewed in an opposite light as a cancer that resembles a benign neoplasm (pseudobenignity). Objective. The goal was to delineate the malignant potential of this neoplasm based on the author's experience and a review of recent data and research and to emphasize the KA as a possible part of an autosomal dominant familial cancer syndrome, the Muir,Torre syndrome. Methods. This is a review of the literature. Results. In this work, the KA is reviewed with recent advances emphasized. Conclusion. KA is an abortive malignancy that rarely progresses into an invasive SCC. The KA may serve as a marker for the important autosomal dominant familial cancer syndrome, the Muir,Torre syndrome, as a result of a defective DNA mismatch repair gene. [source]

    Calmodulin and profilin coregulate axon outgrowth in Drosophila

    You-Seung Kim
    Abstract Coordinated regulation of actin cytoskeletal dynamics is critical to growth cone movement. The intracellular molecules calmodulin and profilin actively regulate actin-based motility and participate in the signaling pathways used to steer growth cones. Here we show that in the developing Drosophila embryo, calmodulin and profilin convey complimentary information that is necessary for appropriate growth cone advance. Reducing calmodulin activity by expression of a dominant inhibitor (KA) stalls axon extension of pioneer neurons within the CNS, while a partial loss of profilin function decreases extension of motor axons in the periphery. Yet, surprisingly, when calmodulin and profilin are simultaneously reduced, the ability of both CNS pioneer axons and motor axons to extend beyond the choice points is restored. In the CNS, at the time when growth cones must decide whether to cross or not to cross the midline, a reduction in calmodulin and/or roundabout signaling causes axons to cross the midline inappropriately. These inappropriate crossings are suppressed when profilin activity is simultaneously reduced. Interestingly, the mutual suppression of calmodulin and profilin activity requires a minimal level of profilin. In KA combinations with profilin null alleles, defects in axon extension and midline guidance are synergistically enhanced rather than suppressed. Together, our data indicate that the growth cone must coordinate the activity of both calmodulin and profilin in order to advance past selected choice points, including those dictating midline crossovers. © 2001 John Wiley & Sons, Inc. J Neurobiol 47: 26,38, 2001 [source]

    Protective effects of naloxone in two-hit seizure model

    EPILEPSIA, Issue 3 2010
    Lu Yang
    Summary Purpose:, Early life status epilepticus (SE) could enhance the vulnerability of the immature brain to a second SE in adulthood (two-hit seizure model). Naloxone has been proved to possess inflammation inhibitory effects in nervous system. This study was designed to evaluate the dose-dependent protective effects of naloxone in kainic acid (KA),induced two-hit seizure model. Methods:, After KA-induced SE at postnatal day 15 (P15), Sprague-Dawley rats were infused with either saline or different doses (1.92, 3.84, 5.76, and 7.68 mg/kg) of naloxone continuously for 12 h. De novo synthesis of cytokines (interleukin-1, [IL-1,], S100B) was assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) at 12 h after P15 SE. Glial activation states were analyzed by western blotting of glial markers (glial fibrillary acidic protein [GFAP], S100B, Iba1) both at 12 h after P15 SE and at P45. After a second SE at P45, cognitive deteriorations were evaluated by Morris water tests and neuron injuries were evaluated by TdT-mediated dUTP nick end labeling (TUNEL) assays. Results:, Naloxone reduced IL-1, synthesis and microglial activation most potently at a dose of 3.84 mg/kg. Attenuation of S100B synthesis and astrocyte activation were achieved most dramatically by naloxone at a dose of 5.76 mg/kg, which is equal to the most powerful dose in ameliorating cognitive injuries and neuron apoptosis after second SE. Conclusions:, Naloxone treatment immediately after early life SE could dose-dependently reduce cytokine production, glial activation, and further lower the vulnerability of immature brains to a second hit in adulthood. [source]

    Seizures in the Developing Brain Cause Adverse Long-term Effects on Spatial Learning and Anxiety

    EPILEPSIA, Issue 12 2004
    Umit Sayin
    Summary:,Purpose: Seizures in the developing brain cause less macroscopic structural damage than do seizures in adulthood, but accumulating evidence shows that seizures early in life can be associated with persistent behavioral and cognitive impairments. We previously showed that long-term spatial memory in the eight-arm radial-arm maze was impaired in rats that experienced a single episode of kainic acid (KA)-induced status epilepticus during early development (postnatal days (P) 1,14). Here we extend those findings by using a set of behavioral paradigms that are sensitive to additional aspects of learning and behavior. Methods: On P1, P7, P14, or P24, rats underwent status epilepticus induced by intraperitoneal injections of age-specific doses of KA. In adulthood (P90,P100), the behavioral performance of these rats was compared with that of control rats that did not receive KA. A modified version of the radial-arm maze was used to assess short-term spatial memory; the Morris water maze was used to evaluate long-term spatial memory and retrieval; and the elevated plus maze was used to determine anxiety. Results: Compared with controls, rats with KA seizures at each tested age had impaired short-term spatial memory in the radial-arm maze (longer latency to criterion and more reference errors), deficient long-term spatial learning and retrieval in the water maze (longer escape latencies and memory for platform location), and a greater degree of anxiety in the elevated plus maze (greater time spent in open arms). Conclusions: These findings provide additional support for the concept that seizures early in life may be followed by life-long impairment of certain cognitive and behavioral functions. These results may have clinical implications, favoring early and aggressive control of seizures during development. [source]

    High-frequency Oscillations after Status Epilepticus: Epileptogenesis and Seizure Genesis

    EPILEPSIA, Issue 9 2004
    Anatol Bragin
    Summary:,Purpose: To investigate the temporal relation between high-frequency oscillations (HFOs) in the dentate gyrus and recurrent spontaneous seizures after intrahippocampal kainite-induced status epilepticus. Methods: Recording microelectrodes were implanted bilaterally in different regions of hippocampus and entorhinal cortex. A guide cannula for microinjection of kainic acid (KA) was implanted above the right posterior CA3 area of hippocampus. After recording baseline electrical activity, KA (0.4 ,g/0.2 ,l) was injected. Beginning on the next day, electrographic activity was recorded with video monitoring for seizures every day for 8 h/day for ,30 days. Results: Of the 26 rats studied, 19 revealed the appearance of sharp-wave activity and HFOs in the frequency range of 80 to 500 Hz in the dentate gyrus ipsilateral to the KA injection. In the remaining seven rats, no appreciable activity was noted in this frequency range. In some rats with recurrent seizures, HFOs were in the ripple frequency range (100,200 Hz); in others, HFOs were in the fast ripple frequency range (200,500 Hz), or a mixture of both oscillation frequencies was found. The time of detection of the first HFOs after status epilepticus varied between 1 and 30 days, with a mean of 6.3 ± 2.0 (SEM). Of the 19 rats in which HFO activity appeared, all later developed recurrent spontaneous seizures, whereas none of the rats without HFOs developed seizures. The sooner HFO activity was detected after status epilepticus, the sooner the first spontaneous seizure occurred. A significant inverse relation was found between the time to the first HFO detection and the subsequent rate of spontaneous seizures. Conclusions: A strong correlation was found between a decreased time to detection of HFOs and an increased rate of spontaneous seizures, as well as with a decrease in the duration of the latent period between KA injection and the detection of spontaneous seizures. Two types of HFOs were found after KA injection, one in the frequency range of 100 to 200 Hz, and the other, in the frequency range of 200 to 500 Hz, and both should be considered pathological, suggesting that both are epileptogenic. [source]

    NBQX or Topiramate Treatment after Perinatal Hypoxia-induced Seizures Prevents Later Increases in Seizure-induced Neuronal Injury

    EPILEPSIA, Issue 6 2004
    Sookyong Koh
    Summary: Purpose: To evaluate the efficacy of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f) quinoxaline-2,3-dione) and topiramate (TPM) given after hypoxia-induced seizures in preventing the delayed effect of hypoxia on subsequent susceptibility to seizures and neuronal injury. Methods: We used "two-hit" rodent seizure model to study the long-term effect of perinatal hypoxia on later kainate (KA) seizure-induced neuronal damage and investigated the therapeutic efficacy of a postseizure treatment protocol in reversing the conditioning effect of early-life seizures. Results: Hypoxia at P10 induces seizures without cell death but causes an increase in susceptibility to second seizures induced by KA as early as 96 h after hypoxia, and this lowered seizure threshold persists to adulthood. Furthermore, perinatal hypoxia increases KA-induced neuronal injury at postnatal day (P)21 and 28/30. Repeated doses of NBQX (20 mg/kg) or TPM (30 mg/kg) given for 48 h after hypoxia-induced seizures prevent the increase in susceptibility to KA seizure-induced hippocampal neuronal injury at P28/30. Conclusions: Our results suggest that ,-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor blockade after hypoxia prevents the priming effect of perinatal hypoxia-induced seizures and that this protection occurs independent of its anticonvulsant action. [source]

    Seizure Suppression by Adenosine A1 Receptor Activation in a Mouse Model of Pharmacoresistant Epilepsy

    EPILEPSIA, Issue 7 2003
    Nicolette Gouder
    Summary: Purpose: Because of the high incidence of pharmacoresistance in the treatment of epilepsy (20,30%), alternative treatment strategies are needed. Recently a proof-of-principle for a new therapeutic approach was established by the intraventricular delivery of adenosine released from implants of engineered cells. Adenosine-releasing implants were found to be effective in seizure suppression in a rat model of temporal lobe epilepsy. In the present study, activation of the adenosine system was applied as a possible treatment for pharmacoresistant epilepsy. Methods: A mouse model for drug-resistant mesial temporal lobe epilepsy was used, in which recurrent spontaneous seizure activity was induced by a single intrahippocampal injection of kainic acid (KA; 200 ng in 50 nl). Results: After injection of the selective adenosine A1 -receptor agonist, 2-chloro- N6 -cyclopentyladenosine (CCPA; either 1.5 or 3 mg/kg, i.p.), epileptic discharges determined in EEG recordings were completely suppressed for a period of ,3.5 h after the injections. Seizure suppression was maintained when 8-sulfophenyltheophylline (8-SPT), a non,brain-permeable adenosine-receptor antagonist, was coinjected systemically with CCPA. In contrast, systemic injection of carbamazepine or vehicle alone did not alter the seizure pattern. Conclusions: This study demonstrates that activation of central adenosine A1 receptors leads to the suppression of seizure activity in a mouse model of drug-resistant epilepsy. We conclude that the local delivery of adenosine into the brain is likely to be effective in the control of intractable seizures. [source]

    Magnetic Resonance Imaging Follow-up of Progressive Hippocampal Changes in a Mouse Model of Mesial Temporal Lobe Epilepsy

    EPILEPSIA, Issue 6 2000
    Viviane Bouilleret
    Summary: Purpose: Hippocampal sclerosis (HS) is the most frequent lesion found in mesial temporal lobe epilepsy (mTLE). MR imaging is considered to be the most sensitive and specific method to detect HS. Despite extensive studies performed on humans and except in a recent study, the morphologic pattern of HS is usually analyzed when the disease has already fully developed, thus not allowing any insight into the mapping of the progressive morphologic changes inducing the development of mTLE. We have recently characterized a model of mTLE that reproduces the unilateral pattern of HS, induced by intrahippocampal injection of low doses of kainate (KA) in mice. Methods: In this study, we monitored the temporal evolution of the development of HS in this model of mTLE by using T2 -weighted sequence, T2 -relaxation time measurements, and T1 -weighted spin-echo technique after injection of gadolinium, from 1 h to 120 days after KA injection. Results: HS induced by intrahippocampal KA injection occurred in two phases. First, we observed a transient hyperintense T2 -weighted signal in the cortex above the injected hippocampus, most likely indicative of vasogenic edema partly due to the neurotoxic effect of KA. The concomitant increase in the T2 signal in the injected hippocampus and ipsilateral amygdala likely reflects the phase of cytotoxic edema occurring probably in relation to the excitotoxic consequences of both KA and seizure activity. Second, from 15 days on, a persistent unilateral increased T2 signal was detected in the hippocampus, which most probably reflects gliosis. Conclusions: Our findings indicate that longitudinal follow-up would permit a better understanding of the mechanisms underlying the constitution of HS in humans and eventually development of prevention strategies. [source]

    High epitope density in a single protein molecule significantly enhances antigenicity as well as immunogenicity: a novel strategy for modern vaccine development and a preliminary investigation about B,cell discrimination of monomeric proteins

    Wanli Liu
    Abstract Although early studies have shown a close correlation between epitope density and epitope-specific humoral immune responses, few attempts have been made to quantitatively compare the antigenic and immunogenic differences between protein molecules bearing low or high degrees of epitope density, nor have studies quantitatively investigated the mechanism of B,cell discrimination of monomeric antigens. In this study, we prepared glutathione S-transferase (GST) fusion proteins bearing various copies of the M2e epitope from the influenza virus M2,protein [GST-(M2e)8, GST-(M2e)4 and GST-(M2e)1], which were used to detect and compare the real-time kinetic binding with M2e-specific mAb by surface plasma resonance. Our data show clearly that fusion proteins bearing higher M2e epitope density resulted in higher average avidity for M2e-specific mAb. Furthermore, it was observed that fusion proteins bearing high M2e epitope density could induce polyclonal antibodies (pAb) with enhanced an average affinity constant (KA) for M2e epitope peptide compared to fusion proteins bearing low epitope density. The average KA of pAb induced by GST-(M2e)8 (3.08 × 108,M,1 or 9.96 × 108,M,1) was up to two orders of magnitude greater than the average KA of pAb induced by GST-(M2e)1 (2.00 × 106,M,1 or 3.43 × 106,M,1). Thus, the data presented here demonstrate that high epitope density in a single protein molecule significantly enhances antigenicity and immunogenicity. These findings enrich our knowledge of how epitope density might relate to the recognition, activation and antibody production processes of epitope-specific immature B,cells. [source]

    Prokineticin 2 depolarizes paraventricular nucleus magnocellular and parvocellular neurons

    Erik A. Yuill
    Abstract Blind whole-cell patch-clamp techniques were used to examine the effects of prokineticin 2 (PK2) on the excitability of magnocellular (MNC), parvocellular preautonomic (PA), and parvocellular neuroendocrine (NE) neurons within the hypothalamic paraventricular nucleus (PVN) of the rat. The majority of MNC neurons (76%) depolarized in response to 10 nm PK2, effects that were eliminated in the presence of tetrodotoxin (TTX). PK2 also caused an increase in excitatory postsynaptic potential (EPSP) frequency, a finding that was confirmed by voltage clamp recordings demonstrating increases in excitatory postsynaptic current (EPSC) frequency. The depolarizing effects of PK2 on MNC neurons were also abolished by kynurenic acid (KA), supporting the conclusion that the effects of PK2 are mediated by the activation of glutamate interneurons within the hypothalamic slice. PA (68%) and NE (67%) parvocellular neurons also depolarized in response to 10 nm PK2. However, in contrast to MNC neurons, these effects were maintained in TTX, indicating that PK2 directly affects PA and NE neurons. PK2-induced depolarizations observed in PA and NE neurons were found to be concentration-related and receptor mediated, as experiments performed in the presence of A1MPK1 (a PK2 receptor antagonist) abolished the effects of PK2 on these subpopulations of neurons. The depolarizing effects of PK2 on PA and NE neurons were also shown to be abolished by PD 98059 (a mitogen activated protein kinase (MAPK) inhibitor) suggesting that PK2 depolarizes PVN parvocellular neurons through a MAPK signalling mechanism. In combination, these studies have identified separate cellular mechanisms through which PK2 influences the excitability of different subpopulations of PVN neurons. [source]

    Rapid and long-term alterations of hippocampal GABAB receptors in a mouse model of temporal lobe epilepsy

    Andrea Straessle
    Abstract Alterations of ,-aminobutyric acid (GABA)B receptor expression have been reported in human temporal lobe epilepsy (TLE). Here, changes in regional and cellular expression of the GABAB receptor subunits R1 (GBR1) and R2 (GBR2) were investigated in a mouse model that replicates major functional and histopathological features of TLE. Adult mice received a single, unilateral injection of kainic acid (KA) into the dorsal hippocampus, and GABAB receptor immunoreactivity was analysed between 1 day and 3 months thereafter. In control mice, GBR1 and GBR2 were distributed uniformly across the dendritic layers of CA1,CA3 and dentate gyrus. In addition, some interneurons were labelled selectively for GBR1. At 1 day post-KA, staining for both GBR1 and GBR2 was profoundly reduced in CA1, CA3c and the hilus, and no interneurons were visible anymore. At later stages, the loss of GABAB receptors persisted in CA1 and CA3, whereas staining increased gradually in dentate gyrus granule cells, which become dispersed in this model. Most strikingly, a subpopulation of strongly labelled interneurons reappeared, mainly in the hilus and CA3 starting at 1 week post-KA. In double-staining experiments, these cells were selectively labelled for neuropeptide Y. The number of GBR1-positive interneurons also increased contralaterally in the hilus. The rapid KA-induced loss of GABAB receptors might contribute to epileptogenesis because of a reduction in both presynaptic control of transmitter release and postsynaptic inhibition. In turn, the long-term increase in GABAB receptors in granule cells and specific subtypes of interneurons may represent a compensatory response to recurrent seizures. [source]

    Functional role of fumarate site Glu59 involved in allosteric regulation and subunit,subunit interaction of human mitochondrial NAD(P)+ -dependent malic enzyme

    FEBS JOURNAL, Issue 4 2009
    Ju-Yi Hsieh
    Here we report on the role of Glu59 in the fumarate-mediated allosteric regulation of the human mitochondrial NAD(P)+ -dependent malic enzyme (m-NAD-ME). In the present study, Glu59 was substituted by Asp, Gln or Leu. Our kinetic data strongly indicated that the charge properties of this residue significantly affect the allosteric activation of the enzyme. The E59L enzyme shows nonallosteric kinetics and the E59Q enzyme displays a much higher threshold in enzyme activation with elevated activation constants, KA,Fum and ,KA,Fum. The E59D enzyme, although retaining the allosteric property, is quite different from the wild-type in enzyme activation. The KA,Fum and ,KA,Fum of E59D are also much greater than those of the wild-type, indicating that not only the negative charge of this residue but also the group specificity and side chain interactions are important for fumarate binding. Analytical ultracentrifugation analysis shows that both the wild-type and E59Q enzymes exist as a dimer,tetramer equilibrium. In contrast to the E59Q mutant, the E59D mutant displays predominantly a dimer form, indicating that the quaternary stability in the dimer interface is changed by shortening one carbon side chain of Glu59 to Asp59. The E59L enzyme also shows a dimer,tetramer model similar to that of the wild-type, but it displays more dimers as well as monomers and polymers. Malate cooperativity is not significantly notable in the E59 mutant enzymes, suggesting that the cooperativity might be related to the molecular geometry of the fumarate-binding site. Glu59 can precisely maintain the geometric specificity for the substrate cooperativity. According to the sequence alignment analysis and our experimental data, we suggest that charge effect and geometric specificity are both critical factors in enzyme regulation. Glu59 discriminates human m-NAD-ME from mitochondrial NADP+ -dependent malic enzyme and cytosolic NADP+ -dependent malic enzyme in fumarate activation and malate cooperativity. [source]

    Kinetic mechanism for p38 MAP kinase ,

    FEBS JOURNAL, Issue 18 2005
    A partial rapid-equilibrium random-order ternary-complex mechanism for the phosphorylation of a protein substrate
    p38 Mitogen-activated protein kinase alpha (p38 MAPK,) is a member of the MAPK family. It is activated by cellular stresses and has a number of cellular substrates whose coordinated regulation mediates inflammatory responses. In addition, it is a useful anti-inflammatory drug target that has a high specificity for Ser-Pro or Thr-Pro motifs in proteins and contains a number of transcription factors as well as protein kinases in its catalog of known substrates. Fundamental to signal transduction research is the understanding of the kinetic mechanisms of protein kinases and other protein modifying enzymes. To achieve this end, because peptides often make only a subset of the full range of interactions made by proteins, protein substrates must be utilized to fully elucidate kinetic mechanisms. We show using an untagged highly active form of p38 MAPK,, expressed and purified from Escherichia coli[Szafranska AE, Luo X & Dalby KN (2005) Anal Biochem336, 1,10) that at pH 7.5, 10 mm Mg2+ and 27 °C p38 MAPK, phosphorylates ATF2,115 through a partial rapid-equilibrium random-order ternary-complex mechanism. This mechanism is supported by a combination of steady-state substrate and inhibition kinetics, as well as microcalorimetry and published structural studies. The steady-state kinetic experiments suggest that magnesium adenosine triphosphate (MgATP), adenylyl (,,,-methylene) diphosphonic acid (MgAMP-PCP) and magnesium adenosine diphosphate (MgADP) bind p38 MAPK, with dissociation constants of KA = 360 µm, KI = 240 µm, and KI > 2000 µm, respectively. Calorimetry experiments suggest that MgAMP-PCP and MgADP bind the p38 MAPK,,ATF2,115 binary complex slightly more tightly than they do the free enzyme, with a dissociation constant of Kd , 70 µm. Interestingly, MgAMP-PCP exhibits a mixed inhibition pattern with respect to ATF2,115, whereas MgADP exhibits an uncompetitive-like pattern. This discrepancy occurs because MgADP, unlike MgAMP-PCP, binds the free enzyme weakly. Intriguingly, no inhibition by 2 mm adenine or 2 mm MgAMP was detected, suggesting that the presence of a ,-phosphate is essential for significant binding of an ATP analog to the enzyme. Surprisingly, we found that inhibition by the well-known p38 MAPK, inhibitor SB 203580 does not follow classical linear inhibition kinetics at concentrations >,100 nm, as previously suggested, demonstrating that caution must be used when interpreting kinetic experiments using this inhibitor. [source]

    Immunoexpression of Bcl-x in squamous cell carcinoma and keratoacanthoma: differences in pattern and correlation with pathobiology

    HISTOPATHOLOGY, Issue 3 2009
    Kong-Bing Tan
    Aims:, Bcl-x is an important anti-apoptotic member of the Bcl-2 family. The aim was to determine its immunoexpression in cutaneous squamous cell carcinoma (SCC) and keratoacanthoma (KA). Methods and results:, Sixteen SCCs and 39 KAs were investigated by Bcl-x immunohistochemistry. Bcl-x immunoreactivity was mostly diffuse in SCC (75% of cases), whereas that in KA was typically confined to the mid-to-upper spinous keratinocytes (95%) (P < 0.0001). There was a trend for SCC to have a higher likelihood of immunopositivity (weighted staining score ,6 of 12) compared with KA (88% versus 59%, P = 0.058). Twenty-nine per cent of regressing KA had immunopositivity, whereas 47% and 82% of its stable and proliferating counterparts, respectively, had equivalent positivity (P = 0.024). Conclusions:, These results provide some insight into the pathobiology of SCC and KA. The generally diffuse and stronger Bcl-x immunoreactivity in SCC suggests that the protein contributes to the survival advantage and aggressiveness of the tumour. In KA, the preferential reactivity of the mid-to-upper neoplastic keratinocytes can plausibly be explained by such differentiated cells attempting to prolong their existence under rapidly evolving circumstances, whereas the reduced reactivity in regressing KA is consistent with the end stage of the tumour. [source]

    Maternal distancing and event memory at 20 months

    Nathalie Prudhomme
    Abstract Maternal distancing strategies (Sigel, 1993 in The Development and Meaning of Psychological Distance, Cocking R, Renninger KA (eds). Erlbaum: Hillsdale, NJ; 141,158) with 20-month-olds were analysed during a mother,child interaction in a free play situation. Then, they were related to memory performance of the children as assessed by the elicited imitation paradigm with 4 three-step sequences of actions (Bauer, Hertsgaard, Child Dev. 1993; 64:1204). The aim of this work was to (1) confirm that the Sigel's model of distancing could be used with very young children under two; (2) study relationships between maternal distancing that stimulate representational competence of the child and memory performance of the children. Results showed two different patterns of correlations depending on the sequence type: for enabling sequences, significant positive correlations were obtained for the first two distancing levels whereas for arbitrary sequences no correlation was found whatever the distancing level. As discussed, the first pattern brings new arguments in support of declarative memory before the age of 2 years and reframes the memory development in a Vygotskyian interactionist perspective. The second pattern of correlations calls for replication and more investigation about the processes implied in memory of very young children for different sequence types. Copyright © 2003 John Wiley & Sons, Ltd. [source]

    Spectral, kinetic, and redox properties of basic fuchsin in homogeneous aqueous and sodium dodecyl sulfate micellar media

    N. Ramanathan
    Effect of anionic surfactant on the optical absorption spectra and redox reaction of basic fuchsin, a cationic dye, has been studied. Increase in the absorbance of the dye band at 546 nm with sodium dodecyl sulfate (SDS) is assigned to the incorporation of the dye in the surfactant micelles with critical micellar concentration (CMC) of 7.3 × 10,3 mol dm,3. At low surfactant concentration (<5 × 10,3 mol dm,3) decrease in the absorbance of the dye band at 546 nm is attributed to the formation of a dye,surfactant complex (1:1). The environment, in terms of dielectric constant, experienced by basic fuchsin inside the surfactant micelles has been estimated. The association constant (KA) for the formation of dye,SDS complex and the binding constant (KB) for the micellization of dye are determined. Stopped-flow studies, in the premicellar region, indicated simultaneous depletion of dye absorption and formation of new band at 490 nm with a distinct isosbestic point at 520 nm and the rate constant for this region increased with increasing SDS concentration. The reaction of hydrated electron with the dye and the decay of the semireduced dye are observed to be slowed down in the presence of SDS. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 629,636, 2003 [source]

    Oral health status and treatment needs among school children in Sana'a City, Yemen

    KA Al-Haddad
    To cite this article: Int J Dent Hygiene DOI: 10.1111/j.1601-5037.2009.00398.x Al-Haddad KA, Al-Hebshi NN, Al-Ak'hali MS. Oral health status and treatment needs among school children in Sana'a City, Yemen. Abstract:, Data on the oral health status and treatment needs among Yemeni children are lacking. Objectives:, To assess caries prevalence, treatment needs and gingival health status among school children in Sana'a City and to examine how these are affected by age, gender and khat chewing. Methods:, 1489 children (6- to 14-year old) were randomly selected from 27 schools representing all nine districts of Sana'a City. Dental caries and treatment needs were evaluated using standard WHO oral survey methods. The plaque index (PI), calculus index (CI) and the gingival index (GI), recorded at the six Ramfjord's teeth, were used to assess gingival health status. Results:, 4.1% of the study subjects were caries-free. Prevalence of these was significantly higher among the males. Overall, mean dmfs, dmft, DMFS and DMFT scores were 8.45, 4.16, 3.59 and 2.25 respectively. The decayed component accounted for >85% of the scores. The highest dmfs/dmft means were found among the 6,8 years age group, while the highest DMFS/DMFT means were scored by the 12,14 years age group. The need for restorative treatment and extractions was high; the former was significantly higher among the females. All subjects had gingivitis; the mean PI, CI and GI were 1.25, 0.3 and 1.36 respectively. Khat chewing did not affect caries experience; however, it was significantly associated with higher PI, CI and GI scores. Conclusions:, The prevalence of caries, gingivitis and treatment needs among children in Sana'a city is high. More surveys in other Yemeni cities to generate comprehensive data are required. [source]

    The totally miscible in ternary hydrogen-bonded polymer blend of poly(vinyl phenol)/phenoxy/phenolic

    Shiao-Wei KuoArticle first published online: 28 MAY 200
    Abstract The individual binary polymer blends of phenolic/phenoxy, phenolic/poly(vinyl phenol) (PVPh), and phenoxy/PVPh have specific interaction through intermolecular hydrogen bonding of hydroxyl,hydroxyl group to form homogeneous miscible phase. In addition, the miscibility and hydrogen bonding behaviors of ternary hydrogen bond blends of phenolic/phenoxy/PVPh were investigated by using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy, and optical microscopy. According to the DSC analysis, every composition of the ternary blend shows single glass transition temperature (Tg), indicating that this ternary hydrogen-bonded blend is totally miscible. The interassociation equilibrium constant between each binary blend was calculated from the appropriate model compounds. The interassociation equilibrium constant (KA) of each individually binary blend is higher than any self-association equilibrium constant (KB), resulting in the hydroxyl group tending to form interassociation hydrogen bond. Photographs of optical microscopy show this ternary blend possess lower critical solution temperature (LCST) phase diagram. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009 [source]

    A kinetic evaluation of the anaerobic digestion of two-phase olive mill effluent in batch reactors

    Francisco Raposo
    Abstract A comparative kinetic study was carried out on the anaerobic digestion of two-phase olive mill effluent (TPOME) using three 1-dm3 volume stirred tank reactors, one with freely suspended biomass (control), and the other two with biomass supported on polyvinyl chloride (PVC) and bentonite (aluminium silicate), respectively. The reactors were batch fed at mesophilic temperature (35 °C) using volumes of TPOME of between 50 and 600 cm3, corresponding to chemical oxygen demand (COD) loadings in the range of 1.02,14.22 g, respectively. The process followed first-order kinetics and the specific rate constants, K0, were calculated. The K0 values decreased considerably from 2.59 to 0.14 d,1, from 1.93 to 0.23 d,1 and from 1.52 to 0.17 d,1 for the reactors with suspended biomass (control) and biomass immobilized on PVC and bentonite, respectively, when the COD loadings increased from 1.02 to 14.22 g; this showed an inhibition phenomenon in the three reactors studied. The values of the critical inhibitory substrate concentration (S*), theoretical kinetic constant without inhibition (KA) and the inhibition coefficient or inhibitory parameter for each reactor (n) were determined using the Levenspiel model. Copyright © 2004 Society of Chemical Industry [source]

    The Spiral of Silence and Fear of Isolation

    Kurt Neuwirth
    This research explores the relationship between fear of isolation and allied concepts derived from the communication apprehension (CA) literature,CA-trait and CA-state,on opinion expression. The study took place during the final run-up to the Fall 2002 U.S. Congressional elections, and the research topic focused on the debate surrounding the possibility of the United States invading Iraq. The results suggest that (a) CA-trait, CA-state, and fear of isolation are empirically distinct; (b) these constructs differentially predict opinion expression; and (c) customary ways of assessing opinion expression in past research likely have underestimated conformity effects. Résumé Une solution structurelle aux dilemmes de communication dans une communauté virtuelle Dans un contexte de communication multivoque comme celui d'une communauté virtuelle, les individus peuvent être fortement tentés de profiter des contributions des autres tout en s,abstenant eux-mêmes de contribuer, ce qui en définitive mènerait à l'effondrement de la communauté. Afin de trouver une solution structurelle au « dilemme de communication », cette étude a comparé le rendement de deux structures de communication : l,une fondée sur les réseaux interpersonnels (NEX)(p. ex. les blogues) et l'autre s,appuyant sur un babillard électronique public (GEX). Dans le cadre d'une expérience longitudinale inter-sujets de 2 x 2 x 2, il est apparu que de changer GEX pour NEX pourrait augmenter le nombre de contributions faites par des individus. De plus, il fut observé que NEXétait une structure efficace pour la communication N personnes, particulièrement lorsqu,un grand nombre d'individus étaient impliqués. Les conclusions laissent entendre que la motivation incitant à coopérer d,un individu est fonction de la structure incitative d'une forme particulière d'échange d,information, ce qui signifie que de modifier la forme de l'échange peut être une solution possible aux dilemmes de communication dans les communautés virtuelles. Abstract Schweigespirale und Isolationsfurcht Vorliegender Beitrag untersucht die Beziehung zwischen Isolationsfurcht und aus der Literatur zur Kommunikationsangst (KA) hergeleiteten verwandten Konzepten (KA-Persönlichkeitsmerkmal und KA-Zustand) in Bezug auf die Meinungsäußerung einer Person. Die Studie wurde während der Hauptphase der U.S.-amerikanischen Kongresswahlen im Herbst 2002 durchgeführt und fokussierte die Debatte um die Möglichkeit des Einmarsches amerikanischer Truppen in den Irak. Die Ergebnisse zeigen, dass 1) KA-Persönlichkeitsmerkmal, KA-Zustand und Isolationsangst empirisch abgrenzbar sind, 2) diese Konstrukte Meinungsäußerung auf verschiedene Weise vorhersagen und 3) die klassische Art und Weise der Erfassung von Meinungsäußerungen in der Forschung bislang Konformitätseffekte unterschätzt hat. Resumen El Espiral del Silencio y el Miedo al Aislamiento Esta investigación explora la relación entre el Miedo al Aislamiento y conceptos aliados derivados de la literatura sobre Aprehensión Comunicacional (CA) --CA-como Rasgo y CA-como Estado,en la expresión de la opinión. El estudio se llevó a cabo durante la última ronda en las elecciones para el Congreso en el Otoño del 2002 y el tema de investigación se enfocó en el debate alrededor de la posibilidad de que los Estados Unidos invadieran Irak. Los resultados sugieren que 1) CA-como Rasgo, CA-como Estado, y el Miedo al Aislamiento son empíricamente distintos; 2) estos constructores predicen la expresión de opiniones en forma diferencial; y 3) las formas habituales de evaluar la expresión de opinión en investigaciones anteriores han probablemente subestimado los efectos de conformidad. ZhaiYao Yo yak [source]

    Eruptive squamous cell carcinomas, keratoacanthoma type, arising in a multicolor tattoo

    Gary Goldenberg
    Permanent tattoos are formed through the injection of ink solids through the epidermis into the dermis and can cause multiple adverse reactions. We report a 38-year-old man who presented to our Dermatologic Surgery Unit with a diagnosis of a superficially invasive squamous cell carcinoma (SCC), keratoacanthoma (KA) type, of the left forearm in a 1-month-old tattoo. Since his initial biopsy, he developed four more similar lesions on his left forearm within his tattoo. On physical examination, the patient had a large, multicolor tattoo on his left forearm, a well-healed surgical biopsy site and four erythematous hyperkeratotic papules within differently pigmented areas of the patient's tattoo. Histopathological examination showed KA and tattoo pigment. Based on the eruptive nature of these lesions, their clinical presentation and the histopathological changes, we report this as the first case of eruptive KA arising in a multicolor tattoo. [source]

    Is there a special relationship between CD30-positive lymphoproliferative disorders and epidermal proliferation?

    Yvana P. Cespedes
    The relationship between CD30+ lymphoma and epithelial proliferations is not well defined. CD30+ lymphoma and lymphomatoid papulos (LyP) share immunohistochemical epitopes and some other features. A single case of LyP associated with multiple keratoacanthomas (KAs) was recently reported. We report two cases of atypical lymphocytic proliferation with features of CD30+ lymphoma and LyP intimately associated to KA and squamous cell carcinoma (SCC), KA type. This similar combination of an epidermal tumor and apparent involvement with atypical lymphocytic infiltrates raises the possibility of an association between the two entities. We speculate that the association may be more than expected to occur by chance and suggest several mechanisms by which the association may evolve. [source]

    Synthetic peptide vaccine development: measurement of polyclonal antibody affinity and cross-reactivity using a new peptide capture and release system for surface plasmon resonance spectroscopy

    Paul J. Cachia
    Abstract A method has been developed for measurement of antibody affinity and cross-reactivity by surface plasmon resonance spectroscopy using the EK-coil heterodimeric coiled-coil peptide capture system. This system allows for reversible capture of synthetic peptide ligands on a biosensor chip surface, with the advantage that multiple antibody-antigen interactions can be analyzed using a single biosensor chip. This method has proven useful in the development of a synthetic peptide anti- Pseudomonas aeruginosa (PA) vaccine. Synthetic peptide ligands corresponding to the receptor binding domains of pilin from four strains of PA were conjugated to the E-coil strand of the heterodimeric coiled-coil domain and individually captured on the biosensor chip through dimerization with the immobilized K-coil strand. Polyclonal rabbit IgG raised against pilin epitopes was injected over the sensor chip surface for kinetic analysis of the antigen-antibody interaction. The kinetic rate constants, k(on) and k(off), and equilibrium association and dissociation constants, KA and KD, were calculated. Antibody affinities ranged from 1.14,×,10,9 to 1.60,×,10,5,M. The results suggest that the carrier protein and adjuvant used during immunization make a dramatic difference in antibody affinity and cross-reactivity. Antibodies raised against the PA strain K pilin epitope conjugated to keyhole limpet haemocyanin using Freund's adjuvant system were more broadly cross-reactive than antibodies raised against the same epitope conjugated to tetanus toxoid using Adjuvax adjuvant. The method described here is useful for detailed characterization of the interaction of polyclonal antibodies with a panel of synthetic peptide ligands with the objective of obtaining high affinity and cross-reactive antibodies in vaccine development. Copyright © 2004 John Wiley & Sons, Ltd. [source]

    Protection against kainate neurotoxicity by ginsenosides: Attenuation of convulsive behavior, mitochondrial dysfunction, and oxidative stress

    Eun-Joo Shin
    Abstract We previously demonstrated that kainic acid (KA)-mediated mitochondrial oxidative stress contributed to hippocampal degeneration and that ginsenosides attenuated KA-induced neurotoxicity and neuronal degeneration. Here, we examined whether ginsenosides affected KA-induced mitochondrial dysfunction and oxidative stress in the rat hippocampus. Treatment with ginsenosides attenuated KA-induced convulsive behavior dose-dependently. KA treatment increased lipid peroxidation and protein oxidation and decreased the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio to a greater degree in the mitochondrial fraction than in the hippocampal homogenate. KA treatment resulted in decreased Mn-superoxide dismutase expression anddiminished the mitochondrial membrane potential. Furthermore, KA treatment increased intramitochondrial Ca2+ and promoted ultrastructural degeneration in hippocampal mitochondria. Treatment with ginsenosides dose-dependently attenuated convulsive behavior and the KA-induced mitochondrial effects. Protection appeared to be more evident in mitochondria than in tissue homogenates. Collectively, the results suggest that ginsenosides prevent KA-induced neurotoxicity by attenuating mitochondrial oxidative stress and mitochondrial dysfunction. © 2008 Wiley-Liss, Inc. [source]

    Role of kainate receptor activation and desensitization on the [Ca2+]i changes in cultured rat hippocampal neurons

    Ana P. Silva
    Abstract We investigated the role of kainate (KA) receptor activation and desensitization in inducing the increase in the intracellular free Ca2+ concentration ([Ca2+]i) in individual cultured rat hippocampal neurons. The rat hippocampal neurons in the cultures were shown to express kainate receptor subunits, KA2 and GluR6/7, either by immunocytochemistry or by immunoblot analysis. The effect of LY303070, an ,-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor antagonist, on the alterations in the [Ca2+]i caused by kainate showed cell-to-cell variability. The [Ca2+]i increase caused by kainate was mostly mediated by the activation of AMPA receptors because LY303070 inhibited the response to kainate in a high percentage of neurons. The response to kainate was potentiated by concanavalin A (Con A), which inhibits kainate receptor desensitization, in 82.1% of the neurons, and this potentiation was not reversed by LY303070 in about 38% of the neurons. Also, upon stimulation of the cells with 4-methylglutamate (MGA), a selective kainate receptor agonist, in the presence of Con A, it was possible to observe [Ca2+]i changes induced by kainate receptor activation, because LY303070 did not inhibit the response in all neurons analyzed. In toxicity studies, cultured rat hippocampal neurons were exposed to the drugs for 30 min, and the cell viability was evaluated at 24 hr using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The selective activation of kainate receptors with MGA, in the presence of Con A, induced a toxic effect, which was not prevented by LY303070, revealing a contribution of a small subpopulation of neurons expressing kainate receptors that independently mediate cytotoxicity. Taken together, these results indicate that cultured hippocampal neurons express not only AMPA receptors, but also kainate receptors, which can modulate the [Ca2+]i and toxicity. J. Neurosci. Res. 65:378,386, 2001. © 2001 Wiley-Liss, Inc. [source]

    A multiplex immunoassay demonstrates reductions in gingival crevicular fluid cytokines following initial periodontal therapy

    D. H. Thunell
    Thunell DH, Tymkiw KD, Johnson GK, Joly S, Burnell KK, Cavanaugh JE, Brogden KA, Guthmiller JM. A multiplex immunoassay demonstrates reductions in gingival crevicular fluid cytokines following initial periodontal therapy. J Periodont Res 2009; doi: 10.1111/j.1600-0765.2009.01204.x. © 2009 John Wiley & Sons A/S Background and Objective:, Cytokines and chemokines play an important role in the pathogenesis of periodontal diseases. The objective of this study was to quantitatively assess the effect of initial periodontal therapy on gingival crevicular fluid levels of a comprehensive panel of cytokines and chemokines, including several less extensively studied mediators. Material and Methods:, Clinical examinations were performed and gingival crevicular fluid samples obtained from six subjects with generalized severe chronic periodontitis prior to initial periodontal therapy and at re-evaluation (6,8 weeks). Four diseased and two healthy sites were sampled in each subject. Twenty-two gingival crevicular fluid mediators were examined using a multiplex antibody capture and detection platform. Statistical analyses were performed by fitting mixed effects linear models to log-transformed gingival crevicular fluid values. Results:, Gingival crevicular fluid interleukin (IL)-1, and IL-1, were the only cytokines to differ in initially diseased vs. initially healthy sites. Following initial therapy, 13 of the 16 detectable cytokines and chemokines decreased significantly in diseased sites, including IL-1,, IL-1,, IL-2, IL-3, IL-6, IL-7, IL-8, IL-12 (p40), CCL5/regulated on activation, normally T cell expressed and secreted (RANTES), eotaxin, macrophage chemotactic protein-1, macrophage inflammatory protein-1, and interferon-,. At healthy sites, only three of the 16 mediators were significantly altered following therapy. Conclusion:, This is the first study, to our knowledge, to evaluate such an extensive panel of gingival crevicular fluid mediators within the same sample prior to and following initial therapy. The results confirm that periodontal therapy effectively reduces pro-inflammatory cytokines and chemokines, including less well-described mediators that may be important in initiation and progression of periodontitis. The multiplex assay will prove useful for future gingival crevicular fluid studies. [source]

    Binding of cationic porphyrin to human serum albumin studied using comprehensive spectroscopic methods

    Bo Zhou
    Abstract The interaction between cationic porphyrin, a potential valuable anti-tumor and antibiotic drug, and human serum albumin (HSA) was investigated using spectroscopy methods. The binding constants were obtained using fluorescence quenching method (KSV,=,(3.24,±,0.29),×,104 M,1) and surface plasmon resonance (SPR) spectroscopy (KA,=,(6.287,±,0.407),×,104 M,1). The association rate constant (ka,=,1622,±,72.9 M,1,s,1) and dissociation rate constant (Kd,=,0.02589,±,0.0024 s,1) of the binding process were also calculated. Compared with the two results, it was known that one of the binding sites was near the tryptophan residue and also there existed other binding sites. The Fourier transform infrared (FT-IR) spectroscopy and circular dichroism (CD) spectroscopy indicated that the confirmation of HSA was nearly not affected with the addition of porphyrin. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:105,113, 2009 [source]

    The Anxiolytic Effect of Two Oriental Herbal Drugs in Japan Attributed to Honokiol from Magnolia Bark

    An improved elevated plus-maze test in mice revealed that seven daily treatments with two differnt traditional Chinese medicines, known as Kampo medicines in Japan, Hange-koboku-to (composed of extracts of 5 plants) and Saiboku-to (composed of extracts of 10 plants), produced an anxiolytic effect, and the effect was mainly due to the presence of honokiol derived from magnolia. This study was carried out to evaluate the anxiolytic potential of honokiol, Hange-koboku-to and Saiboku-to, which were prescribed with two different magnolia samples: Kara-koboku (Magnoliae officinalis) (KA) or Wa-koboku (Magnoliae obovata) (WA). The doses of test samples were adjusted to ensure a constant dose of honokiol at 0.2 mg kg,1. Although the doses of magnolol (an isomer of honokiol), as well as those of undetermined chemicals, varied among samples, the seven daily treatments with 9 out of 10 test samples produced an anxiolytic effect almost equivalent to that produced by 0.2 mg kg,1 honokiol. The only exception was the sample containing the lowest amount of honokiol. Magnolia-free preparations of Hange-koboku-to or Saiboku-to did not have any anxiolytic effect. These results confirm that honokiol derived from magnolia is the causal chemical of the anxiolytic effect of Hange-koboku-to and Saiboku-to. [source]