Flash pulmonary oedema: think of coronary artery disease first.
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Aged↗
Biomedical subjects
J Kelly
Publications and source records attributed to J Kelly.
Purification and characterization of the human PDE4A catalytic domain (PDE4A330-723) expressed in Sf9 cells.
The human PDE4A catalytic domain (PDE4A330-723) expressed in Sf9 cells was found to be heavily phosphorylated on both serines of the conserved SPS motif by mass spectrometric analysis. The purified protein exists as a tetramer at a concentration approximately 1 mg/ml from light scattering measurement and has a Km of 2 microM in hydrolyzing cAMP. In comparison, a partially purified PDE4A330-723 expressed in Escherichia coli has an apparent Km of 10 microM. The EC50 values for the Mg2+- or Co2+-mediated cAMP hydrolysis between the two enzymes differed by less than twofold. In addition, both enzymes exhibit similar sensitivities toward inhibition by a diverse set of inhibitors. Together with the fact that its adjacent peptide was covalently labeled by an electrophilic cAMP analogue, these results support that the SPS motif is not part of but is positioned near the active site. An efficient purification protocol that provides a highly purified PDE4A catalytic domain suitable for crystallization study is described.
3',5'-Cyclic-AMP Phosphodiesterases↗
Is immunohistochemical analysis an appropriate diagnostic technique for bone marrow micrometastases?
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Bone Marrow Neoplasms↗
The immune response to a DNA vaccine can be modulated by co-delivery of cytokine genes using a DNA prime-protein boost strategy.
A large-scale DNA vaccination trial was performed in sheep to investigate whether co-delivery of the cytokine genes IL-4, IL-5, IL-15, GM-CSF or IFN-gamma could modulate the immune response generated to an antigen, in a DNA prime-recombinant protein boost regime. Vaccination with the recombinant EG95 protein has been shown to induce protection in sheep from Echinococcus granulosus infection, the causative agent of hydatid disease. Here we demonstrate that vaccination with DNA encoding EG95 effectively primed the humoral response, as judged by high IgG anti-EG95 titres detected one-week after a boost with the recombinant protein. However, by two weeks after protein-boost the titres in the control group had reached levels similar to the groups primed with EG95 DNA. Priming with two doses of DNA vaccine followed by boosting with recombinant protein induced a predominantly IgG1 response. In contrast, priming and boosting with the protein vaccine generated a strong IgG2 response. Co-delivery of the EG95 DNA vaccine with DNA encoding GM-CSF enhanced the antibody titre to EG95 while co-delivery of IFN-gamma or IL-4 encoding DNA appeared to reduce the ability of the DNA vaccine to prime an IgG antibody response. This study has demonstrated the efficacy of the co-delivery of cytokines to modulate immune responses generated in a DNA prime-protein boost strategy.
Animals↗
Anti-ischemic and cognition-enhancing properties of NNC-711, a gamma-aminobutyric acid reuptake inhibitor.
NNC-711 [1-(2-((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride], a gamma-aminobutyric acid (GABA) reuptake inhibitor with anticonvulsant activity, was investigated with respect to its cognition-enhancing and neuroprotective potency. In the rat, administration of NNC-711 immediately prior to training prevented amnesia for a passive avoidance task induced by the acetylcholine receptor antagonist scopolamine. NNC-711 was also effective in protecting against ischemia-induced death of CA1 pyramidal neurons in a model of bilateral common carotid artery occlusion in the gerbil. In addition to a neuroprotective activity, NNC-711 exhibited significant cognition-enhancing actions. Daily administration of NNC-711, immediately prior to a spatial learning task, significantly reduced escape latencies in the water maze paradigm in both mature (postnatal day 80) and aged (28 months) rats. All of the above actions exhibited a bell-shaped response with an optimal dose of 0.5-1.0 mg/kg. These investigations with NNC-711 and previous clinical observations on the structurally related anticonvulsant tiagabine confirm the potential of GABA reuptake inhibitors as anti-amnesia and cognition-enhancing agents.
Amnesia↗
Linkage analysis of angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and systemic lupus erythematosus.
Previous studies have suggested an association between systemic lupus erythematosus (SLE) and an insertion/deletion polymorphism in the angiotensin-converting enzyme gene (ACE). This polymorphism consists of a 250-bp insertion/deletion of an alu repeat in the 16th intron of the ACE gene. Individuals homozygous for the deletion have a higher level of circulating enzyme. Due to the important role of this enzyme in regulating the renin--angiotensin and kallikrein--kininogen systems, it is possible that the ACE insertion/deletion may play a role in SLE, which can include vasculitis and vascular changes. Using primers flanking the insertion/deletion site, we have examined the ACE gene in lupus patients and family members using genomic DNA obtained from the Lupus Multiplex Registry and Repository (LMRR). We were unable to detect significant linkage or genetic association between the ACE gene and SLE.
Family Health↗
Expression of interleukin 7 (IL-7) mRNA and protein in the normal adult human liver: implications for extrathymic T cell development.
Interleukin-7 (IL-7) has been shown to play an essential role in T-cell development. Recombinase-activating gene (RAG)-1, RAG-2 and pre-TCR-alpha expression in the normal adult human liver (AHL), together with the presence of lymphoid-haematopoietic progenitors, is strong evidence that the AHL supports T cell maturation. We investigated IL-7 mRNA and protein levels in order to determine whether AHL could support T lymphocyte differentiation. Biopsies were snap frozen, powdered, and RNA/protein extracted. Reverse transcriptase polymerase chain reaction was used to detect IL-7 using primers that amplified 620 base pair (bp) fragments and other smaller transcripts. A sandwich enzyme-linked immunosorbent assay was developed to quantify IL-7 protein in homogenates. The anatomic distribution of IL-7-secreting cells was determined by immunohistochemistry. IL-7-specific product (620 bp) was detected in nine of ten samples, with six also positive for a smaller splice-variant (488 bp). Levels of the 620 bp product were 2.5 times greater than the 488 bp fragment. IL-7 protein was detected in all samples (range 18.47-76.93 pg/100 mg tissue). Immunohistochemistry demonstrated IL-7 protein in discrete cells of lymphoid morphology, widely distributed throughout the parenchyma and within portal tracts. Large populations of innate T cells are found in normal AHL, some of which may differentiate locally. The presence of IL-7 RNA and protein throughout normal hepatic tissue provides evidence that the normal AHL is a suitable microenvironment for T cell differentiation.
Adult↗
Lipovitellins derived from two forms of vitellogenin are differentially processed during oocyte maturation in haddock (Melanogrammus aeglefinus).
In the process of cloning vitellogenin (Vtg) cDNAs from haddock (Melanogrammus aeglefinus), two related, but distinct, mRNAs were identified. Full-length cDNA sequences were determined for both Vtg types (Had1 and Had2), and the deduced amino acid sequences were found to be 54% identical to each other and 48-58% identical to other teleost Vtgs. To investigate the expression of the two Vtg mRNAs, proteins from prehydrated oocytes and fertilized eggs were separated on SDS-polyacrylamide gels. Only a single lipovitellin I band was detected in each sample, and the egg lipovitellin I was smaller (97 vs. 110 kDa) than the oocyte protein, indicative of proteolytic processing during oocyte hydration. Mass spectrometric (MALDI-TOFMS and tandem mass spectrometry) analyses of tryptic fragments from the haddock oocyte and egg lipovitellin I revealed that the lipovitellin I from prehydrated oocytes contained tryptic fragments that matched the sequences of both types of Vtg, suggesting that there were two proteins in this band, while the egg lipovitellin I contained tryptic fragments that only matched the Had1 cDNA sequence, indicating that the Had2 lipovitellin had been degraded during hydration. Physiological data from haddock oocytes and eggs demonstrate that, as in other marine fish that spawn pelagic eggs, the free amino acid content increases during oocyte hydration and apparently contributes to hydration by driving the osmotic uptake of water. The correlation of the disappearance of one lipovitellin I with the increase of free amino acids in the oocyte suggests that this protein is a major source of the free amino acids for oocyte hydration.
Amino Acid Sequence↗
Polarization measurements in high-energy deuteron photodisintegration.
We present measurements of the recoil proton polarization for the d(gamma-->,p-->)n reaction at straight theta(c.m.) = 90 degrees for photon energies up to 2.4 GeV. These are the first data in this reaction for polarization transfer with circularly polarized photons. The induced polarization p(y) vanishes above 1 GeV, contrary to meson-baryon model expectations, in which resonances lead to large polarizations. However, the polarization transfer Cx does not vanish above 1 GeV, inconsistent with hadron helicity conservation. Thus, we show that the scaling behavior observed in the d(gamma,p)n cross sections is not a result of perturbative QCD. These data should provide important tests of new nonperturbative calculations in the intermediate energy regime.
Journal Article↗
Evidence in Escherichia coli that N3-methyladenine lesions induced by a minor groove binding methyl sulfonate ester can be processed by both base and nucleotide excision repair.
It has been previously reported that a neutral DNA equilibrium binding agent based on an N-methylpyrrolecarboxamide dipeptide (lex) and modified with an O-methyl sulfonate ester functionality (MeOSO(2)-lex) selectively affords N3-methyladenine lesions. To study the interaction of the neutral lex dipeptide with calf thymus DNA, we have prepared stable, nonmethylating sulfone analogues of MeOSO(2)-lex that are neutral and cationic. Thermodynamic studies show that both the neutral and monocationic sulfone compounds bind to DNA with K(b)'s of 10(5) in primarily entropy-driven reactions. To determine how the cytotoxic N3-methyladenine adduct generated from MeOSO(2)-lex is repaired in E. coli, MeOSO(2)-lex was tested for toxicity in wild-type E. coli and in mutant strains defective in base excision repair (tag and/or alkA glycosylases or apn endonuclease), nucleotide excision repair (uvrA), and both base and nucleotide excision repair (tag/alkA/uvrA). The results clearly demonstrate the cellular toxicity of the N3-methyladenine lesion, and the protective role of base excision glycosylase proteins. A novel finding is that in the absence of functional base excision glycosylases, nucleotide excision repair can also protect cells from this cytotoxic minor groove lesion. Interaction between base and nucleotide excision repair systems is also seen in the protection of cells treated with cis-diamminedichloroplatinum(II) but not with anti-(+/-)-r-7,t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
Linkage analysis of human systemic lupus erythematosus-related traits: a principal component approach.
OBJECTIVE: To identify chromosomal regions containing genes involved in the susceptibility to human systemic lupus erythematosus (SLE)-related traits. METHODS: In the context of a genome scan, we analyzed 101 SLE-affected sibpairs with respect to dermatologic, renal, immunologic, hematologic, neurologic, cardiopulmonary, and arthritic characteristics. Phenotypes were redefined in terms of principal components, which are synthetic variables composed of linear combinations of the original traits. Using 9 principal components obtained from these 7 traits plus age at SLE onset and race, we analyzed genome scan data with the multivariate version of the new Haseman-Elston regression model. RESULTS: The largest linkage for an individual trait was on chromosome 2 at 228 cM (immunologic; P = 0.00048). The most significant linkage to an individual principal component was on chromosome 4 at 208 cM (P = 0.00007). The largest multivariate linkage was on chromosome 7 at 69 cM (P = 0.0001). Of the individual organ systems, dermatologic involvement had the largest effect (P = 0.0083) at this peak at 7p13 on chromosome 7. Further analyses revealed that malar rash, a subtype of dermatologic involvement, was linked significantly (P = 0.00458) to this location. CONCLUSION: These results provide evidence of the presence and locations of genes that are involved in the genetic susceptibility to SLE-related traits in humans.
Adult↗
Phylogeny of lion tamarins (Leontopithecus spp) based on interphotoreceptor retinol binding protein intron sequences.
The evolutionary relationships of the lion tamarins (Leontopithecus) were investigated using nuclear interphotoreceptor retinol binding protein (IRBP) intron sequences. Phylogenetic reconstructions strongly support the monophyly of the genus, and a sister relationship between the golden lion tamarin, Leontopithecus rosalia, and the black lion tamarin, L. chrysopygus, to the exclusion of the golden-headed lion tamarin, L. chrysomelas. The most parsimonious evolutionary reconstruction suggests that the ancestral lion tamarin and the common ancestor of L. rosalia and L. chrysopygus had predominantly black coats. This reconstruction is not consistent with a theory of orthogenetic evolution of coat color that was based on coat color evolution in marmosets and tamarins. An alternative reconstruction that is consistent with metachromism requires that ancestral lion tamarins had agouti hairs.
Animals↗
Development of psychophysically-derived detection contours in L- and M-cone contrast space.
In order to investigate the development of color mechanisms in infants we fitted elliptical detection contours to psychophysically-derived contrast thresholds plotted in L- and M-cone contrast space. Detection ellipses were obtained for 47 infants (ages 2-5 months of age), and were compared to those of six adults tested under nearly identical conditions. The parameters of the fitted ellipses allowed us to address several aspects of color development. First, the lengths and widths were used to assess the relative development of chromatic, with respect to luminance, sensitivity. The results of these analyses revealed a sharp increase in chromatic sensitivity between 3 and 4 months of age, suggesting an accelerated development of chromatic mechanisms around this time. Second, the angles of the ellipses provided estimates of individual red/green isoluminance points. In line with previous reports, we found that isoluminance points do not vary significantly with age. Finally, our ellipse-fitting procedures were used to assess whether color sensitivity is best described by a model that assumes independence between post-receptoral chromatic and luminance mechanisms. Similar to previous results of Kelly and Chang [Kelly, J. P. & Chang, S. (2000). Vision Research 40, 1887-1906] obtained using steady-state visually evoked potentials, only a proportion (approximately half) of our infants exhibited detection contours that were consistent with independent mechanisms, a finding that most likely results from statistical noise in the infant data sets.
Adolescent↗
Cilomilast: pharmacokinetic and pharmacodynamic interactions with digoxin.
BACKGROUND: Cilomilast is an orally active, selective phosphodiesterase 4 inhibitor currently in clinical development for the treatment of chronic obstructive pulmonary disease. OBJECTIVE: The purpose of this study was to examine the tolerability and steady-state pharmacokinetics of cilomilast and digoxin when coadministered at standard therapeutic doses in healthy adults. METHODS: In an initial, open-label phase, healthy young adults received cilomilast 15 mg BID for 5 days. After a 7-day washout period, subjects entered a double-blind, crossover phase during which they received oral digoxin (375 microg once daily) for 2 consecutive 14-day periods with no intervening washout period. Cilomilast 15 mg BID or placebo was coadministered during the first 14-day period. Subjects then crossed over to the alternative treatment for the second 14-day period. Blood and urine samples were collected at appropriate times for evaluation of digoxin and cilomilast steady-state pharmacokinetic parameters. The size of the study was sufficient to achieve 90% power to correctly exclude an effect of cilomilast. RESULTS: Twelve of the 16 subjects enrolled completed the study. There were 4 withdrawals--1 due to noncompliance, 1 due to a positive drug screening, and 2 due to adverse events. At steady state, cilomilast 15 mg BID had no significant effect on the steady-state pharmacokinetic parameters of digoxin, with 90% CIs for both primary end points--area under the plasma concentration-time curve (AUC) over a 24-hour dosing interval and minimum plasma concentration--completely contained within the specified interval for equivalence (0.80-1.25). A mean reduction in maximum observed plasma concentration of digoxin of 11% was observed during coadministration with cilomilast, and time to maximum concentration was delayed by a median of 1 hour, suggesting a small reduction in the rate of digoxin absorption. Digoxin did not appear to markedly affect cilomilast steady-state pharmacokinetics. The most frequently reported adverse event was headache. CONCLUSIONS: Cilomilast 15 mg BID had no clinically significant effect on steady-state AUC or on predose trough plasma concentrations of digoxin (375 microg once daily). The steady-state pharmacokinetics of cilomilast 15 mg BID were similar whether administered alone or with digoxin at steady state (375 microg once daily).
Adolescent↗
Comparison of the statistical efficiency of case-crossover and case-control designs: application to severe cutaneous adverse reactions.
Although case-crossover analyses have lately emerged as an alternative to case-control analyses in epidemiological studies, it is not yet known in which situations they give reliable conclusions. In this work, the case-crossover and the case-control designs were first compared on the basis of a dataset from a published study of severe cutaneous adverse reactions resulting from drug exposures of various durations and prevalences of use (245 cases, 1147 controls, and exposures to 23 drug classes). Next, the statistical efficiency of each design was compared via Monte Carlo simulations. Eight of the 13 risk factors identified by case-control analysis of the published data were also identified by the case-crossover analysis, with fairly good agreement on ranks of risk estimates (Spearman's correlation coefficient = 0.71, P < 0.001 ). Simulation studies showed that for relative risks below 8, the case-crossover design (250 cases, 4 control periods/case) had a higher power than the case-control design (250 cases, 4 controls/case), and that the case-crossover design was more conservative than the case-control design for prevalences of drug use below 10%. We conclude that the case-crossover design is not suitable for long-term exposures, but is an appropriate alternative for assessing rare risks associated with transient to short-term exposures.
Case-Control Studies↗
The basis for IL-2-induced IL-2 receptor alpha chain gene regulation: importance of two widely separated IL-2 response elements.
The interleukin-2 receptor alpha (IL-2Ralpha) chain is an essential component of high-affinity IL-2 receptors. Accordingly, IL-2Ralpha expression helps to regulate T cell growth and other lymphoid functions. Lineage-restricted and activation-dependent IL-2Ralpha transcription is controlled by three upstream positive regulatory regions (PRRs). We now describe an additional IL-2 response element, PRRIV, within intron 1, in humans and mice. PRRIV activity requires GAS motifs that bind Stat5 proteins and additional upstream HMG-I(Y) binding sites. Moreover, IL-2 induces the binding of HMG-I(Y), Stat5a, and Stat5b in vivo to PRRIV and PRRIII, which also functions as an IL-2 response element. Thus, the IL-2 inducibility of the IL-2Ralpha gene is unexpectedly mediated by two widely separated regulatory Stat5-dependent elements, located both upstream and downstream of the transcription initiation sites.
Amino Acid Motifs↗
Elimination of early rehospitalization in a randomized, controlled trial of multidisciplinary care in a high-risk, elderly heart failure population: the potential contributions of specialist care, clinical stability and optimal angiotensin-converting enzyme inhibitor dose at discharge.
BACKGROUND: Despite a growing body of data demonstrating the benefits of multidisciplinary care in heart failure, persistently high rates of readmission, especially within the first month of discharge, continue to be documented. AIMS: As part of an ongoing randomized study on the value of multidisciplinary care in a high risk (NYHA Class IV), elderly (mean age 69 years) heart failure population, we examined the effects of this intervention on previously high (20%) 1-month readmission rates. METHODS: Unlike previous studies of this approach, both multidisciplinary (MC) and routine care (RC) populations were cared for by the cardiology service, complied with adherence to clinical stability criteria prior to discharge (100% of patients) and received at least target dose angiotensin-converting enzyme (ACE) inhibition with perindopril prior to discharge (94% of indicated patients). We analysed death and unplanned readmission for heart failure at 1 month. RESULTS: This early report from the first 70 patients (67% male, 71% systolic dysfunction with a mean ejection fraction of 31.0+/-6.7%) enrolled in this study demonstrates elimination of 1-month hospital readmission in both RC and MC groups. This unexpected result represents a dramatic improvement both for this patient cohort (20% 30-day readmission rate prior to enrollment reduced to 0% following the index admission in both care groups) and in comparison with available data. CONCLUSIONS: Critical contributors to this improvement appear to be specialist cardiology care, adherence to clinical stability criteria prior to discharge and routine use of target or high-dose ACE inhibitor therapy prior to discharge. Widespread application of this approach may have a dramatic improvement in morbidity of CHF while limiting the escalating costs of this condition.
Aged↗
Is stealing a gateway crime?
Stealing behaviors are common among youth and adolescents and often begin in early ages due to a variety of developmental, behavioral, and social factors. This study explores the prevalence of stealing behaviors in a South Texas juvenile detention facility. Researchers discovered stealing was the most frequently reported offense followed by the lack of supervision. Youth arrested for stealing were also more likely to be arrested prior to their twelfth birthday, have subsequent charges that may include assault, and have multiple charges. Results with implications for interventions are provided.
Adolescent↗