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Biomedical subjects

E Kelly

Publications and source records attributed to E Kelly.

At least 73 records · Page 4Linked to original sources
PubMed1993

Influence of implantable cardioverter-defibrillators on the long-term prognosis of survivors of out-of-hospital cardiac arrest.

BACKGROUND: Survivors of out-of-hospital cardiac arrest not associated with acute myocardial infarction are at high risk for recurrent cardiac arrest and sudden cardiac death. The impact of the implantable cardioverter-defibrillator on long-term prognosis in these patients is uncertain. METHODS AND RESULTS: Three hundred thirty-one survivors of out-of-hospital cardiac arrest (age, 56 +/- 13.7 years) underwent electrophysiologically guided therapy. Implantable defibrillators were placed in 150 patients (45.3%), and 181 patients (54.7%) received pharmacological and/or surgical therapy alone. Left ventricular ejection fraction was 35.2 +/- 16.6% in defibrillator recipients and 45.3 +/- 18.2% in nondefibrillator patients. Median patient follow-up was 24 months in the defibrillator group and 46 months in the nondefibrillator group. In a proportional hazards model, the independent predictors of total cardiac mortality were left ventricular ejection fraction of less than 0.40 (relative risk, 4.55; 95% confidence interval, 2.44 to 8.33; P = .0001), absence of an implantable defibrillator (relative risk, 2.70; confidence interval, 1.41 to 5.00; P = .017), and persistence of inducible sustained ventricular tachycardia (relative risk, 1.84; 95% confidence interval, 0.97 to 3.49; P = .045). The 1- and 5-year probabilities of survival free of cardiac mortality in patients with left ventricular ejection fraction of less than 0.40 were 94.3% and 69.6% with a defibrillator and 82.1% and 45.3% without a defibrillator, respectively. For patients with left ventricular ejection fraction of 0.40 or more, the 1- and 5-year probabilities of survival free of cardiac mortality were 97.7% and 94.6% with a defibrillator and 95.4% and 86.9% without a defibrillator, respectively. CONCLUSIONS: In survivors of out-of-hospital cardiac arrest, the implantable defibrillator is associated with a reduction in cardiac mortality, particularly in patients with impaired left ventricular function.

Anti-Arrhythmia Agents↗
PubMed1993

Pertussis toxin augments beta-adrenergic relaxation of muscarinic contraction in canine trachealis.

We studied the effect of pertussis toxin (PT) and partial muscarinic antagonism using pirenzepine (PIR) on beta-adrenergic relaxation of muscarinic contraction in 188 tracheal smooth muscle (TSM) preparations from 25 dogs in vitro. Strips of TSM were incubated for 4 h at 37 degrees C in Krebs-Henseleit (K-H) perfusate with or without 10 micrograms/ml of PT. In tissues contracted to target tension (TT; 50% of maximal response to 127 mM potassium-substituted K-H [KCl]) with acetylcholine (ACh), pretreatment with PT decreased the concentration of isoproterenol (ISO) causing 30% relaxation from TT (RC30) from 1.3 +/- 0.8 x 10(-7) M (control) to 2.8 +/- 0.7 x 10(-8) M (p = 0.013). Pretreatment with PT also augmented the maximal relaxation elicited by 10(-5) M ISO. In separate studies, strips of TSM were contracted with ACh; pretreatment with 10(-7) M PIR decreased the concentration of ISO causing 50% relaxation (RC50) from 3.4 +/- 0.6 x 10(-7) to 9.6 +/- 1.5 x 10(-8) M (p = 0.042). Pretreatment with PIR did not affect relaxation elicited by ISO for strips contracted equivalently with KCl. In addition, PIR increased both the potency and efficacy of ISO in relaxing muscarinic contraction in sham-incubated strips of TSM but had no effect after incubation with PT. Neither PT nor PIR affected beta-adrenergic relaxation of TSM contracted with KCl. Our data demonstrate that beta-adrenergic receptor relaxation of muscarinic contraction is augmented by (1) incubation with PT and (2) partial blockade of muscarinic receptors.

Acetylcholine↗
PubMed1993

The role of radiography and computed tomography in the diagnosis of acute dislocation of the proximal tibiofibular joint.

A cadaveric study was undertaken to determine the best radiographic method of diagnosing dislocation of the proximal tibio-fibular (PTFJ) joint. Three pairs of cadaver knees were used, the right side serving as a control in each case. Plain radiographs, antero-posterior (AP) lateral and 45 degrees oblique films, and axial computed tomography (CT) scans were obtained with the joints in each of three positions: (1) anatomical, (2) dislocated anteriorly and (3) dislocated posteriorly. Similar views were obtained in the control joints with the PTFJ undisturbed. The radiographs were assessed by eight independent observers and the results were analysed. The diagnostic accuracy with plain AP and lateral radiographs was 72.5%. This was unchanged with the addition of oblique views, but improved to 82% with the control films and 86% with the axial CT scans. The authors conclude that in the diagnosis of suspected dislocation of the PTFJ, axial CT scanning is the investigation of choice. Plain AP, lateral and comparison views are useful but less accurate, while oblique views are unhelpful and unnecessary.

Acute Disease↗
PubMed1993

Community health organizing: whom are we empowering?

Current strategies for initiating and operating community health programs rely on one of two approaches. One is a predetermined, operational process. The other comes from the grassroots, beginning with involvement of the recipients of the program. This editorial chronicles how one grassroots program, begun by volunteer mothers and one community health nurse, developed into a partnership for primary health care that advocates and empowers the entire community. In the end, the editorial challenges community health organizers to ask whom their programs are empowering--the community or the organizers themselves?

Community Health Services↗
PubMed1993

Involvement of adenosine in ethanol-induced changes in G-protein expression in NG108-15 cells?

Previous work has suggested that adenosine may be involved in ethanol-induced heterologous desensitization of adenylate cyclase in NG108-15 cells. It was proposed that chronic ethanol causes adenosine to accumulate extracellularly, activating adenosine A2 receptors and so leading to a reduction in Gs alpha mRNA and Gs alpha protein (Nagy et al., 1989). In this study we further investigated the effect of chronic ethanol on G-protein expression in NG108-15 cells. Pretreatment of NG108-15 cells with ethanol (200 mM, 48h) reduced membrane levels of Gs alpha and Gi alpha but increased Go alpha expression. The effects of ethanol on alpha-subunit expression were not reversed by adenosine deaminase and could not be mimicked by the adenosine agonist 5'- (n-ethyl)-carboxamidoadenosine (NECA). Chronic ethanol pretreatment did not appear to reduce the levels of Gs alpha or Gi alpha 2 mRNA. This same ethanol pretreatment reduced cell proliferation and increased differentiation without altering cell viability. Adenosine deaminase did not reverse any of these effects. These results indicate that ethanol differentially regulates G-protein alpha-subunit expression and induces morphological alterations in these cells independently of extracellular adenosine.

Adenosine↗
PubMed1993

Ethanol differentially regulates guanine nucleotide-binding protein alpha subunit expression in NG108-15 cells independently of extracellular adenosine.

Recent work has suggested that chronic ethanol treatment induces heterologous desensitization of adenylate cyclase in a number of cell lines maintained in culture and that this phenomenon is mediated by adenosine. It has been proposed that ethanol induces the accumulation of extracellular adenosine, which then down-regulates the Gs alpha protein and leads to heterologous desensitization. Here we investigated the effects of chronic ethanol treatment on the expression of Gs alpha, Gi alpha, and Go alpha, as well as cAMP signal transduction, in NG108-15 cells and further examined the role of adenosine in mediating these effects. Pretreatment of NG108-15 cells with 200 mM ethanol for 2 days reduced membrane levels of Gs alpha and Gi alpha and increased those of Go alpha. However, ethanol did not reduce the levels of Gs alpha and Gi alpha 2 mRNA in these cells. The ability of ethanol to alter alpha subunit expression was not reversed by removal of extracellular adenosine and could not be mimicked by an adenosine agonist. Chronic ethanol treatment increased both basal and agonist-stimulated cAMP accumulation in NG108-15 cells. Whereas the increase in basal cAMP was abolished by acute addition of adenosine deaminase, the increase in agonist-stimulated cAMP accumulation was not. Morphological examination of the cells indicated that ethanol inhibited cell division and promoted the apparent differentiation of the cells. These results indicate that ethanol induces complex alterations in guanine nucleotide-binding protein alpha subunit expression and cAMP signal transduction in NG108-15 cells and that it is unlikely that these effects are mediated simply by adenosine.

Adenosine↗
PubMed1992

Cloning of the gene coding for a human receptor for formyl peptides. Characterization of a promoter region and evidence for polymorphic expression.

Recently we reported that, in HL-60 cells, transcription of the formyl peptide receptor (FPR) gene can be up- and downregulated by agents that induce differentiation of HL-60 cells into neutrophils. To begin studying the mechanisms involved in regulation of FPR gene expression, we cloned two human cDNAs and the gene coding for FPR. The genomic clone (pINF14) contained a 14.5-kb insert. A 2.7-kb EcoRI fragment was obtained from pINF14 that hybridized with an FPR open reading frame probe. The EcoRI fragment was sequenced and found to contain an intronless FPR open reading frame. Sequence alignment of the EcoRI genomic fragment with the FPR cDNA revealed that the first 31 bases of 5' untranslated FPR cDNA were not represented in the genomic fragment. Furthermore, a splicing consensus sequence was present in the genomic fragment at the site of divergence with the cDNA sequence. Restriction mapping and Southern blot analysis identified a 121-bp fragment that contained the sequence corresponding to the first 31 bases of 5' untranslated FPR cDNA. An additional (previously undescribed) 15-bp cDNA sequence in the 5' end of FPR were identified using an anchored polymerase chain reaction. This sequence was also contained in the genomic 121-bp fragment. This 121-bp fragment was located 5.2 kb (intron) upstream of the FPR open reading frame. It contained an unusual TATA box and displayed transcriptional activity in vitro and in vivo. Potential binding sites for AP-1 and glucocorticoid receptor were identified upstream of the putative TATA box.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1992

Cloning of a cDNA encoding a receptor related to the formyl peptide receptor of human neutrophils.

We cloned a cDNA (RFP) encoding a receptor (RFP) related (70% overall nucleotide homology) to the formyl peptide receptor of human neutrophils (hFPR). RFP is a seven-transmembrane-domain receptor and its distribution is limited to myeloid cells. Domain sequence comparison with hFPR reveals highly conserved regions and provides clues to putative domains involved in ligand binding and receptor desensitization.

Amino Acid Sequence↗
PubMed1992

Cyclic AMP produces desensitization of prostacyclin and adenosine A2 receptors in hybrid cell lines but does not affect Gs function.

Prostacyclin and adenosine A2 receptors stimulate adenylate cyclase activity in the related somatic hybrid cell lines NG108-15 and NCB20. The role of cAMP in the desensitization of these receptors has been examined. Pretreatment for 17 h with forskolin or 8-bromo-cAMP had the same effect in both cell lines. There was no change in the response to sodium fluoride or forskolin, suggesting that the function of Gs and adenylate cyclase were unaffected by increased levels of cAMP. Receptor responses were affected however; the maximum response to N-ethylcarboxamidoadenosine (an A2 receptor agonist) was reduced by 30-40%, there was a small but consistent shift to the right of the dose-response curve for iloprost (a stable analogue of prostacyclin) and [3H]iloprost binding studies revealed a loss of prostacyclin receptors. However, the loss of receptor responsiveness was much smaller than that which occurs following pretreatment with prostacyclin or adenosine A2 receptor agonists (Keen et al. (1989) Biochem. Pharmacol. 38, 3827-3833; Kelly et al. (1990) Br. J. Pharmacol. 99, 309-316) suggesting that cAMP may not play a major role in agonist mediated desensitization.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

Regulation of formyl peptide receptor expression and its mRNA levels during differentiation of HL-60 cells.

When incubated with N6-2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (dbcAMP), HL-60 cells expressed formyl peptide receptor (FPR) (as assessed by ligand binding) and FPR transcripts in a time- and concentration-dependent fashion. Experiments using dbcAMP analogs modified at either the C-6 or C-8 position indicated that the process was mediated by a protein kinase A type I, and protein kinase A type I activity was isolated from undifferentiated HL-60 cells by DEAE-Sephacel chromatography. Forskolin mimicked the effects of dbcAMP. Forskolin and dbcAMP-dependent expression of FPR and FPR transcript was inhibited by staurosporine. Retinoic acid (but not retinal or retinol) was capable of inhibiting dbcAMP-dependent expression of FPR mRNA half-life. Dexamethasone enhanced the effects of dbcAMP and blocked the inhibitory effect of retinoic acid on expression of FPR and FPR transcripts. Phorbol 12-myristate 13-acetate (PMA) alone (1.5-15 nM) failed to induce HL-60 to express FPR and FPR transcripts. Low concentrations (1.5 nM) of PMA enhanced the ability of dbcAMP to induce HL-60 cells to express FPR and FPR transcript, whereas high (15 nM) concentrations of PMA inhibited dbcAMP effects. These results indicate that expression of FPR and FPR transcripts by HL-60 cells can be up- and down-regulated by agents that induce HL-60 cells to differentiate and that a "cross-talk" effect exists between protein kinase A and protein kinase C that modulates FPR gene transcription (and receptor expression) by these cells.

Alkaloids↗
PubMed1992

Very low birth weight and growth to age 8 years. II: Head dimensions and intelligence.

The occipitofrontal circumference was measured in all available children in the following cohorts at ages 2, 5, and 8 years: group 1, consisting of 79 children with birth weight between 500 and 999 g; group 2, with 111 children with birth weight between 1000 and 1499 g; and group 3 with 56 children with birth weight greater than 2500 g; all were white with no signs of moderate or severe cerebral palsy. National Center for Health Statistics reference values indicated substantially more children with an occipitofrontal circumference lower than the 10th percentile, particularly at age 2 years, compared with Nellhaus reference data. Occipitofrontal circumference was the head measurement best correlated with the Full Scale IQ on the Wechsler Intelligence Scale for Children-Revised. Dolichocephaly, often seen in very-low-birth-weight children was unrelated to IQ, and correction of occipitofrontal circumference for dolichocephaly was rarely of clinical importance.

Analysis of Variance↗
PubMed1992

Prospective study of the quality of survival of infants with critical fetal reserve detected by antenatal cardiotocography.

From 1981 to 1986 antenatal cardiotocographic monitoring was performed on 9,992 high-risk pregnancies selected from a total obstetrical population of 31,518 patients (31.7%). A critical fetal reserve pattern was detected in 89 patients (0.9%) whose pregnancies resulted in 68 surviving infants, 19 perinatal deaths and 2 sudden infant deaths. Since 47.4% of the infants who died in the perinatal period did so because of a related congenital malformation, such a defect should be excluded in the fetus with critical fetal reserve, by ultrasonography, before delivery (there is usually insufficient time for fetal karyotyping). Sixty-three (92.6%) of the surviving children were assessed at our Growth and Developmental Clinic and disabilities were detected in 16 (25.4%); however, the disability was major in only 5, including 2 children with Down syndrome. The quality of survival of infants born from pregnancies complicated by critical fetal reserve was satisfactory as 60 of 63 children (95.2%) had neither a major disability related to intrauterine hypoxia identified by the cardiotocographic pattern, or had one likely to significantly interfere with their quality of life. Our results suggest that pregnancies can be continued until the cardiotocographic pattern becomes critical in order to gain fetal maturity, without compromise to the fetal brain.

Cardiotocography↗
PubMed1991

Guanine nucleotide sensitivity of [3H]iloprost binding to prostacyclin receptors.

A component of the displaceable binding of the stable prostacyclin analogue, [3H]iloprost, to membranes from human platelets and the somatic hybrid cell lines NG108-15 and NCB20, was inhibited by guanine nucleotides. The order of potency of a range of nucleotides for this effect was GTP gamma S greater than GppNHp greater than GTP greater than GDP = GMP; ATP, UTP and CTP were ineffective at concentrations up to 1 mM. In the presence of 100 microM GppNHp, iloprost binding curves were displaced to the right of curves obtained in the absence of guanine nucleotide, and their Hill slopes were greater. This was consistent with a conversion of a minor population of high affinity agonist binding sites to lower affinity sites in the presence of guanine nucleotides. These effects of guanine nucleotides on the binding of the agonist ligand [3H]iloprost were consistent with an interaction with a G protein coupled receptor.

Cell Membrane↗
PubMed1991

Changing two-year outcome of infants weighing 500 to 999 grams at birth: a hospital study.

Survival and neurodevelopmental outcome to 2 years were determined for two cohorts of infants weighing 500 to 999 gm at birth, born in a tertiary maternity hospital. Live births increased over time from an annual average of 48.7 in the first era (January 1977 to March 1982) to 64.6 in the second era (January 1985 to December 1987), largely from referrals of additional mothers with pregnancy complications. In the first era, 33.6% (86/256) of infants survived to 2 years; the survival rate improved significantly to 45.9% (89/194) in era 2. After adjustment for birth weight, the odds ratio for survival in era 2 versus era 1 was 1.39 (95% confidence interval = 1.12, 1.73; p less than 0.01). One known survivor in each era was not seen at 2 years of age. In the first era, 59.3% (51/86) of 2-year-old children were free of disability compared with 68.5% (61/89) in era 2 (NS), but the Mental Development Index of the Bayley Scales improved significantly, from 90.0 in era 1 to 98.0 in era 2. For infants weighing less than 800 gm at birth, not only did the 2-year survival rate improve, adjusted for birth weight (odds ratio = 1.53; 95% confidence interval = 1.06, 2.20; p less than 0.05), but there was also a significant reduction in neurologic disabilities in survivors (p = 0.03). For infants weighing 800 to 999 gm at birth, there was a significant improvement in the survival rate, adjusted for birth weight (odds ratio = 1.37; 95% confidence interval = 1.04, 1.79; p less than 0.05), but the rate of neurologic disabilities was unchanged. Increased survival in our tertiary maternity center was achieved without increasing the annual number of severely disabled 2-year-old survivors.

Child, Preschool↗
PubMed1991

Octimibate, a potent non-prostanoid inhibitor of platelet aggregation, acts via the prostacyclin receptor.

1. Octimibate, 8-[(1,4,5-triphenyl-1H-imidazol-2-yl)oxy]octanoic acid, is reported to have antithrombotic properties. This is in addition to its antihyperlipidaemic effects which are due to inhibition of acylCoA:cholesterol acyltransferase (ACAT). The aim of this study was to investigate the mechanism of the antithrombotic effect of octimibate, and to determine whether the effects of octimibate are mediated through prostacyclin receptors. 2. In suspensions of washed (plasma-free) human platelets, octimibate is a potent inhibitor of aggregation; its IC50 is approx. 10 nM for inhibition of aggregation stimulated by several different agonists, including U46619 and ADP. The inhibitory effects of octimibate on aggregation are not competitive with the stimulatory agonist; the maximal response is suppressed but there is no obvious shift in potency of the agonist. In platelet-rich plasma, octimibate inhibits agonist-stimulated aggregation with an IC50 of approx. 200 nM. 3. Octimibate also inhibits agonist-stimulated rises in the cytosolic free calcium concentration, [Ca2+]i, in platelets. Both Ca2+ influx and release from intracellular stores are inhibited. The effects of octimibate on aggregation and [Ca2+]i are typical of agents that act via elevation of adenosine 3':5'-cyclic monophosphate (cyclic AMP). Similar effects are seen with forskolin, prostacyclin (PGl2) and iloprost (a stable PGl2 mimetic). 4. Octimibate increases cyclic AMP concentrations in platelets and increases the cyclic AMP-dependent protein kinase activity ratio. Octimibate stimulates adenylyl cyclase activity in human platelet membranes, with an EC50 of 200 nM. The maximal achievable activation of adenylyl cyclase by octimibate is 60% of that obtainable with iloprost. Octimibate has no effect on the cyclic GMP-inhibited phosphodiesterase (phosphodiesterase-ITI), which is the major cyclic AMP-degrading enzyme in human platelets.5. Octimibate inhibits, apparently competitively, the binding of [3H]-iloprost (a stable PGl2 mimetic) to platelet membranes; the estimated Ki is 150 nm. 6. The platelets of different species show considerable differences in the apparent potency of their inhibition of aggregation by octimibate; platelets from cynomolgus monkeys are 3 fold more sensitive than those from humans, while rat, cat and cow platelets are 50, 100, and 250 fold less sensitive than human platelets. The sensitivity of these different species to iloprost, however, varies over a range of only 10 fold with no obvious difference between primates and non-primates. 7. Octimibate appears to be a potent agonist (aggregation), or partial agonist (adenylyl cyclase), at prostacyclin receptors and is the first non-prostanoid agent of this type to be identified. The species differences in relative potency of octimibate and iloprost may reflect the existence of receptor subtypes.

Adenylyl Cyclases↗
PubMed1991

Second twin: quality of survival if born by breech extraction following internal podalic version.

The intrapartum management of the vertex-breech and vertex-transverse twin gestation is controversial. The fall in perinatal mortality rate to a low level has resulted in this parameter failing to be an adequate gauge of the safety of breech extraction and the answer lies in the quality of survival of the infants. Fifty-one twin pairs, collected over 12 years at the Mercy Hospital for Women, Melbourne, occurred where twin 2 was born by breech extraction following internal inversion and the control (twin 1) did not have this procedure performed. In 8 pairs either a stillbirth or neonatal death occurred; in one pair childhood death due to an accident (fire) occurred; in 4 pairs the parents refused entrance to the study as they perceived both twins to be similar; in 2 sets the assessment was incomplete; 11 sets were untraceable leaving 25 sets fully assessed as children ranging in age from 2 to 12 years. Growth, and psychological scores were not significantly different between twins 1 and 2 but 2 children had cerebral palsy and both were born by breech extraction following internal version at 29.2 and 30.1 weeks' gestation, respectively. Because of small numbers the results failed to achieve statistical significance and this study was unable to answer the question regarding the safety of breech extraction following internal version but did show that the majority of infants so born do well.

Apgar Score↗