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Biomedical subjects

J E Sullivan

Publications and source records attributed to J E Sullivan.

At least 19 recordsLinked to original sources
PubMed2001

Myelitis and ascending flaccid paralysis due to congenital toxoplasmosis.

A 4-week-old female newborn developed ascending flaccid paralysis and radiologic evidence of myelitis; the diagnosis of congenital toxoplasmosis was confirmed by the presence of Toxoplasma gondii-specific immunoglobulins in both mother and infant, and detection of Toxoplasma sequences in the infant's cerebrospinal fluid by polymerase chain reaction analysis. Treatment with pyrimethamine, sulfadiazine, and methylprednisolone resulted in improvement.

Animals↗
PubMed2001

Elevation of serum interleukin 8 levels in acetaminophen overdose in children and adolescents.

BACKGROUND: Elevations of inflammatory cytokines have been reported in animal models of acetaminophen (INN, paracetamol) toxicity. In addition, interleukin 8, a chemokine, has been found to be elevated in toxin-associated hepatic disease (ie, acute alcoholic hepatitis). The purpose of this study was to measure serum cytokine levels in children and adolescents with acetaminophen overdose and to evaluate relationships between cytokine elevation and hepatotoxicity. METHODS: Serum levels of tumor necrosis factor alpha, interleukin 1beta, interleukin 6, interleukin 8, and interleukin 10 were measured by ELISA in children and adolescents (n = 35) with acetaminophen overdose. Peak cytokine levels were examined relative to biochemical evidence of hepatocellular injury, nomogram risk assessment, and prothrombin time. RESULTS: Five patients had aspartate aminotransferase or alanine aminotransferase levels >1000 IU/L, and 4 patients had aspartate aminotransferase or alanine aminotransferase levels > or =100 IU/L and < or =1000 IU/L. No elevations of tumor necrosis factor alpha or interleukin 1beta were detected. Peak interleukin 8, but not interleukin 6 or interleukin 10, correlated with hepatotoxicity (Mann-Whitney exact test, P <.001). The peak interleukin 8 level was greater in patients at high risk by the nomogram combined with those presenting at >15 hours, as compared with other patients (Mann-Whitney U test, P <.01). The interleukin 8 level peaked before aspartate aminotransferase or alanine aminotransferase in 5 of the 9 patients with hepatotoxicity. In addition, interleukin 8 concentrations of >20 pg/mL were associated with peak prothrombin time values (Mann-Whitney exact test, P <.015). CONCLUSIONS: Interleukin 8 elevation in patients with acetaminophen hepatotoxicity corresponds with other common clinical measures that are predictive of hepatocellular injury. Further study is warranted to evaluate possible mechanistic relationships between inflammatory cytokines and acetaminophen hepatotoxicity in children and adults.

Acetaminophen↗
PubMed2001

Emotional outcome of adolescents and young adults with early and continuously treated phenylketonuria.

OBJECTIVE: To assess the emotional functioning of adolescents and young adults with early and consistently treated phenylketonuria (PKU). METHODS: Twenty PKU-affected participants, ages 14-25, were compared with age-matched chronically ill (n = 17) and peer (n = 16) controls on a structured clinical interview, the Minnesota Multiphasic Personality Inventory, and the Tennessee Self-Concept Scale-2. Affected participants and nonparticipants were assessed using a multidomain assessment of functioning interview. RESULTS: There were no significant differences between groups for observable psychiatric disorders or emotional and functional symptoms. No significant differences were found in self-concept. Although there were no differences between groups for IQ or treatment variables, PKU-affected participants were more likely than nonparticipants to have sought help for psychological concerns. CONCLUSIONS: Results suggest that early-treated PKU-affected adolescents and young adults do not show a higher risk for psychological disturbance than appropriate controls.

Adaptation, Psychological↗
PubMed2001

Measurement of acetaminophen-protein adducts in children and adolescents with acetaminophen overdoses. .

Acetaminophen-protein adducts are biomarkers of acetaminophen toxicity present in the centrilobular region of the liver of laboratory animals following the administration of toxic doses of acetaminophen. These biomarkers are highly specific for acetaminophen-induced hepatic injury and correlate with hepatic transaminase elevation. The objective of this prospective, multicenter study was to evaluate the clinical application of the measurement of acetaminophen-protein adducts in pediatric acetaminophen overdose patients. Serum samples were obtained from 51 children and adolescents with acetaminophen overdose at the time of routine blood sampling for clinical monitoring. Six subjects developed "severe" hepatotoxicity (transaminase elevation > 1,000 IU/L), and 6 subjects had transaminase elevation of 100 to 1,000 IU/L. Acetaminophen-protein adducts were detected in the serum of only 1 study subject, a patient with marked transaminase elevation (> 6,000 IU/L) and high risk for the development of hepatotoxicity according to the Rumack nomogram. While this study provides further support for the occurrence of covalent binding of acetaminophen to hepatic protein in humans following acetaminophen overdose, the detection of acetaminophen-protein adducts in serum with the current methodology requires significant biochemical evidence of hepatocellular injury.

Acetaminophen↗
PubMed2000

Radiovisiography in the detection of periapical lesions.

The periapical areas of 16 teeth from 6 human mandibular jaw specimens were randomly examined by 3 observers using conventional radiography with Kodak E-speed film and radiovisiography (with variable contrast and with fixed contrast). Each periapical area was examined preoperatively and after #2, #4, #6, and #8 sized bur periapical lesions were created in the cortical bone. The three radiographic methods were compared by repeated-measures ANOVA of the accuracy scores for the 16 periapical lesions. Accuracy increased with size of lesion, but did not vary by method. Repeated-measures ANOVA of the accuracy scores of only the smallest and no lesion condition showed that conventional radiography and radiovisiography (variable contrast) have opposite strengths. Conventional radiography tended to be more accurate in the no lesion condition, whereas radiovisiography using variable contrast was somewhat more accurate in the smallest lesion condition. The accuracy of radiovisiography with fixed contrast was not significantly different from the other two methods.

Analysis of Variance↗
PubMed1999

Super-EBA as an endodontic apical plug.

Forty extracted human single-rooted teeth were sequentially instrumented with nickel-titanium rotary files to a size 0.36 mm at the working length. Ten teeth were randomly assigned to the two control groups. The other 30 teeth were randomly divided into three groups and were obturated by a 5-mm apical plug of either Super-EBA, IRM, or laterally condensed gutta-percha and Roth's sealer. After 2 days, and at 1 month, the samples were tested for microleakage by the fluid filtration system under 15 psi. The negative controls were used to consider the time that it took the fluid filtration system to stabilize. A one-way analysis of variance showed that, at 1 month post obturation, there was no statistical difference in the ability of the three materials to seal the apex from coronal microleakage. However, at 2 days, Super-EBA gave a significantly better seal than IRM or laterally condensed gutta-percha and sealer.

Analysis of Variance↗
PubMed1999

Review: emotional and behavioral functioning in phenylketonuria.

OBJECTIVE: To examine 17 studies of the psychological sequelae of early-treated phenylketonuria (PKU) with emphasis on the impact of dietary control on functioning. Two questions are addressed: (1) What is the typical psychological profile associated with PKU? (2) Is emotional and behavioral disturbance more prevalent in PKU-affected individuals compared to appropriate controls? METHOD: Computerized searches of PsycINFO identified studies using behavioral, personality, and diagnostic measures. RESULTS: Findings converge upon a profile including attentional difficulties, depression, anxiety, and low self-esteem. Methodological constraints limit conclusions regarding the nature and severity of observed difficulties. A single study has used comparison groups appropriate for the simultaneous examination of the questions posed (Waisbren and Levy, 1991). CONCLUSIONS: We discuss results using a biopsychosocial framework, addressing the factors and processes that may influence emotional and behavioral functioning in this neurodevelopmental disorder. We outline potential lines of new investigation that address critical methodological factors.

Child↗
PubMed1998

The cloning expression and tissue distribution of human PP2Cbeta.

We have cloned a novel PP2Cbeta isoform from a human liver cDNA library which codes for a protein homologous to other mammalian PP2Cbetas at the N-terminus but with an extended C-terminus that is unique amongst the PP2Cs. The protein expressed in E. coli is indistinguishable from human recombinant PP2Calpha in its cation dependence and insensitivity to okadaic acid. Northern blot analysis of PP2Cbeta along with that of PP2Calpha shows that human PP2Cs are widely expressed and are most abundant in heart and skeletal muscle.

Amino Acid Sequence↗
PubMed1996

Biochemical characterization and deletion analysis of recombinant human protein phosphatase 2C alpha.

The use of protein phosphatase inhibitors has been instrumental in defining the intracellular roles of protein phosphatase 1 (PP1), PP2A and PP2B. Identification of the role of PP2C in vivo has been hampered, in part, by the unavailability of specific inhibitors. In order to facilitate the identification of novel and specific inhibitors of PP2C by random screening of compounds, and to further characterize this enzyme at the molecular level by site-directed mutagenesis and X-ray crystallography, we have expressed active recombinant human PP2C alpha (rPP2C alpha) in Escherichia coli. Biochemical characterization of rPP2C alpha showed that it could hydrolyse p-nitrophenyl phosphate (pNPP) although, in contrast with native PP2C, this was not stimulated by Mg2+. As with native PP2C, okadaic acid failed to inhibit rPP2C alpha, whereas 50 mM NaF dramatically inhibited its activity. An alignment of the amino acid sequence of AMP-activated protein kinase (AMPK) with those of other serine/threonine protein kinases around the regulatory phosphorylation site (subdomains VII-VIII) revealed a high degree of conservation. Phosphopeptides derived from this region of AMPK and containing the almost invariant threonine (Thr172 in AMPK) were found to be good substrates for rPP2C alpha. We also showed that rPP2C alpha can inactivate AMPK, but only in the presence of Mg2+. To define the regions of PP2C alpha important for catalytic activity, we expressed a number of truncated proteins based on the sequence and proposed domain structure of the PP2C alpha homologue from Paramecium tetraurelia. Deletion of 75 residues (9 kDa) from the C-terminus appeared to have little effect on the catalytic activity using pNPP, phosphopeptides or AMPK as substrates. This suggests that the residues important in catalysis lie elsewhere in the protein. A further deletion of the C-terminus led to a completely inactive and very poorly soluble protein.

AMP-Activated Protein Kinases↗
PubMed1996

Pharmacokinetics of bumetanide in critically ill infants.

OBJECTIVE: Define the pharmacokinetics of bumetanide after single intravenous doses in volume-overloaded critically ill infants. METHODS: A prospective, open-label study was carried out in a group of 58 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single dose of intravenous bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Hematologic and serum chemistry studies were performed before and at 6 and 24 hours after bumetanide administration. Determinations of urine volume and chemistries were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine collected at time 0 and at 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Data were evaluated by standard noncompartmental pharmacokinetic techniques. RESULTS: Peak serum bumetanide concentrations occurred at 5 minutes after bumetanide administration. Area under the curve and peak serum bumetanide concentrations showed linear increases over the twentyfold dose range; whereas beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time values were independent of dose. Peak urinary excretion rates of bumetanide increased linearly with increasing doses. The mean percent of bumetanide recovered in the urine from 0 to 12 hours was 40% +/- 15% of the administered dose. CONCLUSIONS: Distribution and elimination kinetics of bumetanide were similar in all patients. Elimination kinetics were first order over the dose range of 0.005 to 0.10 mg/kg. Pharmacokinetic parameter estimates (beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time) were independent of the dose of bumetanide administered. Single doses of bumetanide up to 0.10 mg/kg appear to be well tolerated in acutely ill volume-overloaded infants aged 0 to 6 months.

Area Under Curve↗
PubMed1996

Analysis of the variability in the pharmacokinetics and pharmacodynamics of bumetanide in critically ill infants.

OBJECTIVES: Account for the interindividual variability in the pharmacokinetics and pharmacodynamics of bumetanide after intravenous administration of single doses to critically ill infants. METHODS: This prospective open-label study was carried out in the pediatric intensive care unit of a university-based children's hospital. Fifty-three volume-overloaded critically ill infants (age range, 4 days to 6 months) were divided into two groups: those with heart disease (31 infants) and those with lung disease (22 infants). Each patient received a single intravenous bolus dose of bumetanide. Doses, selected in sequential order, ranged from 0.005 to 0.100 mg/kg. Age was used as a continuous variable to determine its effects on the variability in the pharmacokinetics and pharmacodynamics of bumetanide. Hierarchical multiple regression analyses were used to assess the effects of age, disease, and other drugs on the variability in the effects of bumetanide. RESULTS: Total clearance, renal clearance, and nonrenal clearance of bumetanide all increased with age (p < 0.05), but the ratio of renal clearance to total clearance remained constant at about 0.4. Half-life and mean residence time decreased markedly in the first month of life (p < 0.05). Bumetanide excretion rate normalized for dose also increased with increasing age. Patients with lung disease exhibited a significantly greater clearance and shorter half-life (p < 0.05) than those with heart disease, whereas volume of distribution was similar in both groups. The primary determinant of bumetanide excretion rate was the administered dose (73%). Dose-response curves for urine flow rate and electrolyte excretion were similar between disease groups. The time course of the effect of bumetanide excretion rate on pharmacodynamics responses was similar between disease groups, as was the duration of the diuretic effect. CONCLUSIONS: The pharmacokinetics of bumetanide were influenced significantly by age and disease. Differences in pharmacokinetics between patients with lung and heart disease were primarily due to differences in total clearance. The administered dose of bumetanide and age were positive determinants of bumetanide excretion rate and pharmacodynamic responses. Pharmacodynamic responses as a function of bumetanide excretion rate were not significantly different between disease groups.

Aging↗
PubMed1996

Dose-ranging evaluation of bumetanide pharmacodynamics in critically ill infants.

OBJECTIVES: Determine the diuretic effects of single intravenous doses of bumetanide in volume-overloaded critically ill infants. METHODS: A prospective, open-label study was carried out in 56 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single intravenous dose of bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Determinations of urine volume, electrolytes, creatinine levels, and osmolality were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine aliquots collected at time 0, 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Individual changes in urine flow rate and electrolyte excretion were plotted against corresponding bumetanide excretion rates, taken as the effective dose of the drug. RESULTS: Peak bumetanide excretion rates increased linearly with increasing doses of drug. Time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. Urine flow rate and electrolyte excretion increased linearly up to a bumetanide excretion rate of approximately 7 micrograms/kg/hr and either plateaued (urine flow rate) or declined at a bumetanide excretion rate of > 10 micrograms/kg/hr. Diuretic efficiency of bumetanide was maximal at doses of 0.005 to 0.010 mg/kg but decreased at higher doses. CONCLUSIONS: Maximal diuretic responses occurred at a bumetanide excretion rate of about 7 micrograms/kg/hr, corresponding to doses of 0.035 to 0.040 mg/kg. Higher doses produced a proportionately higher bumetanide excretion rate but no increased diuretic effect. Lower doses of bumetanide had the greatest diuretic efficiency, suggesting that continuous infusion of low doses of bumetanide or intermittent low-dose boluses may produce optimal diuretic responses in critically ill infants.

Bumetanide↗
PubMed1994

Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase.

In vivo, hormone-sensitive lipase (HSL) is known to be phosphorylated on two sites termed the regulatory and basal sites. However, the intracellular role of the basal site or the identity of the protein kinase phosphorylating this site has not been established. We show that 5-amino-4-imidazolecarboxamide ribonucleoside (AICAR) markedly activates cellular AMP-activated protein kinase (AMPK) in a time- and dose-dependent manner. As expected for an agent that activates AMPK intracellularly, AICAR had no effect on the basal activity of HSL. However, preincubation of adipocytes with AICAR led to a reduced response of these cells to the lipolytic agent isoprenaline. AICAR was also shown to profoundly inhibit lipogenesis through increased phosphorylation of acetyl-CoA carboxylase (ACC). Thus it appears that in addition to regulating lipogenesis, AMPK also plays an important antilipolytic role by regulating HSL in rat adipocytes.

AMP-Activated Protein Kinases↗
PubMed1994

Characterisation of 5'-AMP-activated protein kinase in human liver using specific peptide substrates and the effects of 5'-AMP analogues on enzyme activity.

A specific peptide (SAMS peptide) phosphorylation assay has previously been used to measure and subsequently purify rat liver 5'-AMP-activated protein kinase (AMPK). In this report, we show that this peptide and a peptide based on the sequence surrounding the site phosphorylated on 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase by AMPK (HMG peptide) can be used to measure human liver AMPK. Our data demonstrate that both human and rat AMPKs have a higher affinity for the HMG peptide compared to the SAMS peptide. We have used these peptide phosphorylation assays to identify novel activators of AMPK.

AMP-Activated Protein Kinases↗
PubMed1992

Xylem embolism in response to freeze-thaw cycles and water stress in ring-porous, diffuse-porous, and conifer species.

Vulnerability to xylem embolism by freeze-thaw cycles and water stress was quantified in ring-porous (Quercus gambelii Nutt.), diffuse-porous (Populus tremuloides Michx., Betula occidentalis Hook.), and conifer species (Abies lasiocarpa Nutt., Juniperus scopulorum Sarg.). Embolism was measured by its reduction of xylem hydraulic conductivity; it was induced by xylem tension (water-stress response) and by a tension plus a freeze-thaw cycle (freeze response). Conifers showed little (Juniperus) or no (Abies) freeze response even to repeated cycles. In contrast, Quercus embolized more than 90% by freezing at tensions below 0.2 MPa, whereas similar embolism without freezing required tensions above 4.5 MPa. Diffuse-porous trees (Betula, Populus) showed an intermediate freeze response. The magnitude of the freeze response was correlated with conduit volume but occurred at higher tensions than predicted from theory. Large early-wood vessels (2.8 x 10(-9) m(3)) in oak were most vulnerable to embolism by freezing, small vessels in Populus and Betula were intermediate (approximately 7 x 10(-11) m(3)), and tracheids in conifers (about 3 x 10(-13) m(3)) were most resistant. The same trend was found within a stem: embolism by freeze-thawing occurred preferentially in wider conduits. The water-stress response was not correlated with conduit volume; previous work indicates it is a function of interconduit pit membrane structure. Native embolism levels during winter corroborated laboratory results on freezing: Quercus embolized 95% with the first fall freeze, Populus and Betula showed gradual increases to more than 90% embolism by winter's end, and Abies remained below 30%.

Journal Article↗