Central and peripheral norepinephrine kinetics in heart failure, coronary artery disease, and hypertension.
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Central Nervous System↗
Biomedical subjects
G Lambert
Publications and source records attributed to G Lambert.
Metabolic activation of racemic and enantiomeric trans-8, 9-dihydroxy-8,9-dihydrodibenzo[a,l]pyrene (dibenzo[def,p]chrysene) to dibenzo[a,l]pyrene-bis-dihydrodiols by induced rat liver microsomes and a recombinant human P450 1A1 system: the role of the K-region-derived metabolic intermediates in the formation of dibenzo[a,l]pyrene-DNA adducts.
Metabolic activation studies of dibenzo[a,l]pyrene (DB[a,l]P) (dibenzo[def,p]chrysene), an extremely potent environmental carcinogen, have been focused on metabolism at the fjord region, a region associated with high mutagenic and carcinogenic activities of the corresponding fjord-region DB[a,l]P-11,12-diol-13,14-epoxides. DB[a,l]P is metabolized by beta-naphthoflavone (BNF)- and 3-methylcholanthrene-induced rat liver microsomes and a recombinant human P450 1A1 system to two major dihydrodiols, the K-region dihydrodiol, DB[a,l]P-8,9-dihydrodiol (DB[a,l]P-8,9-diol), and the fjord-region dihydrodiol, DB[a,l]P-11,12-dihydrodiol. We have investigated the further metabolic activation of DB[a,l]P-8,9-diol by BNF-induced rat liver microsomes and a recombinant human P450 1A1 system with epoxide hydrolase to DB[a,l]P-bis-diols and to DNA adducts. (+/-)-trans-DB[a,l]P-8,9-diol was synthesized and resolved into its enantiomers. Racemic trans-DB[a,l]P-8,9-diol was metabolized by BNF-induced rat liver microsomes to six metabolites: two diastereomers of trans,trans-DB[a,l]P-8,9:11,12-bis-diol, two diastereomers of trans,cis-DB[a,l]P-8,9:11,12-bis-diol, and two diastereomers of trans-DB[a,l]P-8,9:13,14-bis-diol as characterized by NMR, MS, and UV spectroscopy. Metabolic studies using both enantiomeric (-)- and (+)-trans-DB[a,l]P-8,9-diol further demonstrated that each diastereomer of trans,trans-DB[a,l]P-8,9:11, 12-bis-diol and trans-DB[a,l]P-8,9:13,14-bis-diol was comprised of two enantiomers. Similarly, incubations of enantiomeric or racemic trans-DB[a,l]P-8,9-diol with a recombinant human P450 1A1 system and epoxide hydrolase also gave the same two enantiomeric mixtures of diastereomers of trans,trans-DB[a,l]P-8,9:11,12-bis-diol and the same two enantiomeric mixtures of diastereomers of trans-DB[a,l]P-8, 9:13,14-bis-diol. This suggested that the microsomal oxidations of (-)- and (+)-trans-DB[a,l]P-8,9-diol were stereospecific. The stereospecific formation of enantiomers of trans-DB[a,l]P-8,9-diol from DB[a,l]P was examined using both BNF-induced rat liver microsomes and a recombinant human P450 1A1 system with epoxide hydrolase. Stereospecificity was observed as both metabolic systems favored the formation of (-)-trans-DB[a,l]P-8,9-diol by 8-9-fold. DNA adduct studies were undertaken using TLC/HPLC 32P-postlabeling techniques. In the presence of a recombinant human P450 1A1 system with epoxide hydrolase, DB[a,l]P gave two groups of calf thymus DNA adducts. The group of later-eluting adducts were identified as arising from syn- and anti-DB[a,l]P-11,12-diol-13,14-epoxides, while the more polar early-eluting adducts were derived, in part, from the further activation of trans-DB[a,l]P-8,9-diol. Our data indicate that, in P450 1A1-mediated microsomal incubations, DB[a,l]P is metabolized to trans-DB[a,l]P-8,9-diol which is further metabolized to DB[a,l]P-bis-diols. trans-DB[a,l]P-8,9-diol is metabolically activated to intermediates that can bind to DNA and give DNA adducts similar to those observed with DB[a,l]P. These results indicate that DB[a,l]P can be metabolically activated by both fjord-region and K-region pathways.
Animals↗
Association of human immunodeficiency virus (HIV) load early in life with disease progression among HIV-infected infants. New York City Perinatal HIV Transmission Collaborative Study Group.
The utility of RNA virus load to predict progression of human immunodeficiency virus (HIV)-1 disease was assessed in 89 HIV-1-infected children. Of 22 virus load values during week 1 of life, 17 were below the detection threshold. Geometric mean virus load increased to approximately 7 x 10(5) copies/mL by week 4, was sustained throughout the first 6 months of life, and then declined to 1.6 x 10(5) copies/mL during the third year. Samples from week 1 of life had little predictive value, but virus load during days 7-30 strongly predicted progression to CDC-3 classification or death (P = .024; risk ratio = 1.6), and virus load during months 2-3 predicted progression to CDC-C or death within the first 6 months of life (P = .002, risk ratio = 11). Virus load was highly associated with imminent vulnerability to CDC-C or death (P = .002) during the first 18 months of life. Except for values from the first week of life, virus load at any age through 18 months is strongly associated with risk of HIV disease progression.
Child, Preschool↗
Adrenergic nervous system in heart failure.
Recent demonstration that the level of sympathetic nervous drive to the failing heart in patients with severe heart failure is a major determinant of prognosis, and that mortality in heart failure is decreased by beta-adrenergic blockade with carvedilol, indicates the clinical relevance of cardiac neuroscience research. Important initial findings were observations that the plasma concentration of the sympathetic neurotransmitter, norepinephrine, is elevated in heart failure, and that overall clinical outcome is related to plasma norepinephrine concentration (although heart failure severity may be a confounder). Sympathetic nerve recording (clinical microneurography) and radiotracer methods measuring regional sympathetic activity in the heart (cardiac norepinephrine "spillover") have now largely supplanted antecubital venous norepinephrine measurements as research tools, with newer methods providing information on regional sympathetic function that was previously lacking. The cardiac sympathetic nerves are preferentially stimulated in severe heart failure, with norepinephrine release from the failing heart at rest in untreated patients increased up to 50-fold, which is similar to the level of release in healthy hearts during near maximal exercise. There is lesser stimulation of the sympathetic outflows to the kidneys and skeletal muscle. In early mild heart failure, it is only the cardiac sympathetic nerves that are activated. This preferential activation of cardiac sympathetic outflow contributes to arrhythmia development and probably to progression of heart failure and has been linked to mortality in mild and severe heart failure. The central nervous system mechanisms involved in the sympathetic nervous activation present in patients with heart failure remain uncertain. Increased intracardiac diastolic pressure seems to be one peripheral reflex stimulus with increased forebrain norepinephrine turnover being an important central mechanism.
Disease Progression↗
Regional sympathetic nervous activity and oxygen consumption in obese normotensive human subjects.
BACKGROUND: Disturbed sympathetic nervous function may be of importance in obesity; sympathetic underactivity could contribute to deficient thermogenesis, positive energy balance, and weight gain, while in contrast, sympathetic nervous overactivity would predispose to the development of obesity-related hypertension. Global indices of sympathetic nervous system (SNS) function such as plasma or urinary norepinephrine (NE) have been unable to define SNS status in obesity. Since regional SNS activity can be altered in the absence of global changes, we investigated SNS activity in the heart, kidneys, and hepatomesenteric bed in healthy human subjects across a wide body mass index (BMI) range of between 19.6 and 35.5. METHODS AND RESULTS: Whole-body and regional plasma NE kinetics using [3H]-labeled NE were assessed. Regional oxygen consumption was measured by combining arteriovenous differences in oxygen content and regional blood flow. Arterial plasma NE and whole-body plasma NE spillover were unrelated to BMI. With a BMI cutoff of 27, mean cardiac NE spillover was 46% lower in the obese subjects when compared with the lean subjects (P=.017). Renal NE spillover was significantly correlated with BMI (r=.668, P=.001), the mean value in the obese subjects being more than twice that in the lean subjects. Hepatomesenteric NE spillover was comparable in lean and obese subjects. Renal and hepatomesenteric oxygen consumption were both significantly higher in the obese subjects compared with lean subjects. CONCLUSIONS: Regional SNS activity is heterogeneous in the obese state. Important regional alterations, which may be clinically relevant, occur in the absence of changes in global indices of sympathetic nervous function. The enhanced renal NE spillover in obesity may have implications for the development of hypertension in this group, whereas the low cardiac sympathetic tone would be expected to be cardioprotective. Enhanced visceral oxygen consumption evident in the kidneys and hepatomesenteric circulation in proportion to body mass contributes to the greater resting oxygen consumption in obesity.
Adolescent↗
Timing of maternal-infant HIV transmission: associations between intrapartum factors and early polymerase chain reaction results. New York City Perinatal HIV Transmission Collaborative Study Group.
OBJECTIVE: To investigate the hypothesis that labour and delivery events, perinatal characteristics, and maternal factors are only associated with intrapartum HIV transmission, and not with intrauterine HIV transmission. METHODS: In the New York City Perinatal HIV Transmission Collaborative Study 276 infants of HIV-infected women were followed prospectively and had results of early polymerase chain reaction (PCR) tests available. Among infected children, intrauterine infection was presumed if HIV DNA was detected by PCR in samples collected from children aged < or = 3 days, and intrapartum infection was presumed if HIV DNA was not detected in these early samples. The proportion of infants with presumed intrauterine and intrapartum infections were compared by selected intrapartum, perinatal and maternal characteristics. RESULTS: Presumed intrapartum infection was found in 7% of infants delivered by Cesarean section and, among infants delivered vaginally, those with longer duration of membrane rupture (> 4 h) were significantly more likely to have presumed intrapartum HIV infection (22%) than those with shorter duration (9%; P = 0.02). There were no differences in presumed intrauterine HIV infection by mode of delivery or longer duration of membrane rupture. Infants born preterm and small for gestational age had significantly higher risks of presumed intrapartum infection, but only those who were small for gestational age had higher risks of intrauterine infection. CONCLUSION: Our results support the notion that selected intrapartum conditions, long duration of membrane rupture prior to delivery in particular, are independent risk factors for maternal-infant transmission, and suggest that preterm infants may be especially vulnerable to intrapartum HIV exposure.
Birth Weight↗
The effect of maternal viral load on the risk of perinatal transmission of HIV-1. New York City Perinatal HIV Transmission Collaborative Study Group.
OBJECTIVE: To determine the effect of maternal viral load at delivery on the risk of perinatal transmission of HIV-1. DESIGN: A nested case-control study within a prospectively followed cohort of HIV-1-infected pregnant women and their infants. SETTING: The multicenter New York City Perinatal HIV Transmission Collaborative Study. PARTICIPANTS: Fifty-one women who gave birth to HIV-1 infected infants were frequency-matched within CD4+ cell count quintiles with 54 non-transmitting mothers. MAIN OUTCOME MEASURES: Maternal quantity of HIV-1 viral RNA was assayed in plasma obtained near delivery using the nucleic acid sequence-based amplification assay system. RESULTS: Viral RNA was detected in 73 (70%) out of 105 women and the median viral load was 16,000 RNA copies/ml in transmitters and 6,600 in non-transmitters (P < 0.01). When adjusted for maternal CD4+ count near delivery, women with measurable viral load were nearly sixfold more likely to transmit HIV-1 than women with viral load below detection [adjusted odds ratio (AOR), 5.8; 95% confidence interval (CI), 2.2 15.5]. The odds ratio for perinatal transmission of log10 viral load, adjusted for CD4 count was 2.7 (95% CI, 1.5-5.1). When stratified by the stage of HIV-1 disease, the only group with significant association between log10 viral load and transmission were AIDS-free women with CD4+ count > 500 x 10(6)/l (AOR, 9.1; 95% CI, 2.6-31.5). CONCLUSIONS: High maternal viral load increases the likelihood of perinatal transmission of HIV-1 in women without AIDS and advanced immunosuppression. HIV-1 infected pregnant women without advanced disease, shown by others to have the lowest risk of perinatal transmission, may benefit the most from efforts to identify and decrease viral load at delivery.
Adult↗
Ascidian eggs block polyspermy by two independent mechanisms: one at the egg plasma membrane, the other involving the follicle cells.
Many ascidians live in clumps and usually release sperm before the eggs. Consequently, eggs are often spawned into dense clouds of sperm. Because fertilization by more than a single sperm is lethal, ascidians have evolved at least two successive blocks to polyspermy: the rapid release of a glycosidase that inhibits sperm binding to the vitelline coat (VC) and a subsequent change in membrane potential that prevents supernumerary sperm-egg fusion. This paper shows that (1) these two blocks can be uncoupled by the use of suramin, and (2) most of the glycosidase appears to be from the follicle cells, which are accessory cells on the outside of the egg VC. Phallusia mammillata eggs initially bind numerous sperm but, after the glycosidase is released, only a few additional sperm bind. Intact eggs in 20 microM suramin release glycosidase, but the electrical response is inhibited; sperm swim actively and bind to the VC but fail to penetrate. Suramin treatment is completely reversible; intact eggs exhibit the electrical response an average of 11 minutes after the drug is washed out. Sperm must contact the follicle cells before passing through the VC; eggs with the VC removed and fertilized in the presence of 20 microM suramin show the electrical response 35% of the time, thus VC removal enhances sperm entry. Like the intact eggs, 100% of the naked eggs respond electrically to fertilization after the drug is washed out. Follicle cells that are isolated by calcium magnesium free seawater and then returned to complete seawater release N-acetylglucosaminidase activity in response to sperm. Thus, these eggs have two blocks to polyspermy that operate in sequence: an early first block resulting from enzymatic modification of the VC by N-acetylglucosaminidase released primarily from follicle cells and a second electrical block operating at the egg plasma membrane level and requiring sperm-egg fusion.
Animals↗
Effect of maternal CD4+ cell count, acquired immunodeficiency syndrome, and viral load on disease progression in infants with perinatally acquired human immunodeficiency virus type 1 infection. New York City Perinatal HIV Transmission Collaborative Study Group.
Among a cohort of 152 infants perinatally infected with human immunodeficiency virus type 1, and their mothers, we correlated infant outcome with material CD4+ lymphocyte count and the presence of maternal acquired immunodeficiency syndrome near delivery. In a subset of 50 mother-infant pairs, we also correlated infant outcome with maternal quantitative viral burden as measured by the nucleic acid sequence based amplification system. We found that low maternal CD4+ cell count and high viral burden were associated with decreased time to category C disease or death in infants infected with human immunodeficiency virus type 1. In a multivariate analysis, high maternal viral load and maternal acquired immunodeficiency syndrome were independently associated with shorter time to category C disease or death in infants with human immunodeficiency virus type 1 infection. High viral load in pregnant women, independent of the presence of advanced maternal disease, appears to increase the risk of rapidly progressive disease in their infected offspring.
Acquired Immunodeficiency Syndrome↗
Testicular abscess due to Streptococcus pneumoniae in an infant with human immunodeficiency virus infection.
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Abscess↗
Early detection of perinatal human immunodeficiency virus (HIV) type 1 infection using HIV RNA amplification and detection. New York City Perinatal HIV Transmission Collaborative Study.
Early diagnosis of perinatally transmitted human immunodeficiency virus type 1 (HIV) infection can guide early interventions. HIV coculture and DNA polymerase chain reaction (DNA-PCR) detect few HIV-infected infants at birth and 90%-100% by age 3 months. Because extracellular HIV RNA may appear soon after infection, a plasma HIV RNA assay was compared with DNA-PCR for early detection of perinatally infected infants. Blood-draw specimens (108) obtained at the same time from 49 HIV-infected infants and 10 specimens from 8 uninfected infants were tested. HIV RNA and DNA-PCR positivity rates were 56% and 33%, respectively, in 36 specimens from 36 infants <28 days of age (binomial test, P = .001). Among 81 specimens obtained after age 14 days, 79 (98%) were positive by HIV RNA testing. No HIV-infected infant specimens were DNA-PCR-positive and HIV RNA-negative. All specimens from 8 uninfected infants were HIV RNA-negative. These results suggest that plasma HIV RNA was detectable earlier and more reliably than HIV DNA in perinatal infection.
Female↗
Origin of homovanillic acid in plasma.
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Alcoholism↗
Lipid-binding properties of synthetic peptide fragments of human apolipoprotein A-II.
Human apolipoprotein A-II (apo A-II) consists of three potential amphipathic helices of 17 residues each, which contribute to the lipid-binding properties of this apolipoprotein. The conformation and lipid-binding properties of these peptides, either as single-helix or as two-helix peptides, were investigated by turbidity, fluorescence, electron-microscopy and circular-dichroism measurements, and are compared in this article. The lipid affinity of shorter C-terminal segments of apo A-II was compared with those of the single-helix or two-helix peptides, to define the minimal peptide length required for stable complex formation. The properties of the apo-A-II-(13-48)-peptide were further compared with those of the same segment after deletion of the Ser31 and Pro32 residues, because the deleted apo-A-II-(13-30)-(33-48)-peptide, is predicted to form a long uninterrupted helix. The single helices of apo A-II could not form stable complexes with phospholipids, and the helix-turn-helix segment spanning residues 13-48 was not active either. The apo-A-II-(37-77)-peptide and the apo-A-II-(40-73)-peptide could form complexes with lipids, which appear as discoidal particles by negative-staining electron microscopy. The shortest C-terminal domain of apo A-II able to associate with lipids to form stable complexes was the apo-A-II-(40-73)-peptide, which consisted of the C-terminal helix, a beta-turn and part of the preceding helix. The shorter apo-A-II-(49-77)-peptide, and the helical apo-A-II-(13-30)-(33-48)-peptide, could also associate with phospholipids. The complexes formed were, however, less stable, as they dissociated outside the transition temperature range of the phospholipid. These data suggest that the C-terminal pair of helices of apo A-II, which is the most hydrophobic pair, is responsible for the lipid-binding properties of the entire protein. The N-terminal pair of helices of apo A-II at residues 13-48 does not associate tightly with lipids. The degree of internal similarity and the cooperativity between the helical segments of apo A-II is thus less pronounced than in apo A-I or apo A-IV. The N-terminal and C-terminal domains of apo A-II appear to behave as two distinct entities with regard to lipid-protein association.
Amino Acid Sequence↗
Effect of antimigraine drugs on dural blood flows and resistances and the responses to trigeminal stimulation.
The effects of 2 antimigraine drugs sumatriptan and dihydroergotamine on dilatation of the middle meningeal artery elicited by stimulation of the trigeminal ganglion at the entry point of the first and second divisions was investigated in cats. Carotid and middle meningeal arterial blood flows and resistances were measured in 9 cats anesthetised with chloralose. Electrical stimulation of either trigeminal ganglion produced a frequency-dependent decrease in resistance of the carotid artery ipsilaterally and the middle meningeal artery bilaterally. The intravenous injection of sumatriptan increased carotid and meningeal vascular resistance, but this response was not prolonged. The intravenous injection of dihydroergotamine produced a larger and more prolonged vasoconstriction in these 2 beds than did sumatriptan. Dihydroergotamine, but not sumatriptan, blocked some components of the vascular response induced by stimulation of the trigeminal ganglion. Dihydroergotamine and sumatriptan have a different spectrum of activity on cranial circulatory beds and neither of them is able to reduce trigeminal-induced vasodilatation by blocking antidromic activation of trigeminal nerve fibres in cats at the doses used in these experiments.
Animals↗
Zidovudine use to reduce perinatal HIV type 1 transmission in an urban medical center.
OBJECTIVE: To evaluate whether zidovudine treatment was accepted and used by pregnant women subsequent to the release of the results of a multicenter, randomized, placebo-controlled trial (AIDS Clinical Trial Group [ACTG] Protocol 076) that showed that zidovudine significantly reduced maternal-infant human immunodeficiency virus (HIV) type 1 transmission. DESIGN: Prospective study. SETTING: A community hospital with an integrated, multidisciplinary HIV-dedicated program located in an impoverished, HIV-endemic urban setting. PARTICIPANTS: All HIV-infected pregnant women identified after the release of the ACTG 076 results who were offered zidovudine therapy to reduce maternal-infant transmission. RESULTS: Only 49 of the 125 HIV-infected pregnant women delivering at our site during this study period were identified prenatally. Perinatal zidovudine therapy was chosen by 37 (75%) of 49 women. Women refusing zidovudine were more likely to report injection drug use as their HIV risk factor and to continue to use drugs during their pregnancy. Of women choosing zidovudine and delivering, 24 of 36 received all components of their elected therapy. The intrapartum dose was missed by 12 women, 4 of whom also missed their prescribed prenatal oral therapy. Lack of adherence to chosen therapy was associated with continued cocaine use during pregnancy. CONCLUSIONS: Zidovudine therapy to interrupt vertical transmission of HIV was not widely used by these HIV-infected pregnant women. Further studies evaluating factors affecting the acceptance and use of recently published public health recommendations are needed.
Adolescent↗
Cardiac sympathetic nerve function in congestive heart failure.
BACKGROUND: Increased availability of norepinephrine (NE) for activation of cardiac adrenoceptors (increased cardiac adrenergic drive) and depletion of myocardial NE stores may contribute to the pathophysiology and progression of congestive heart failure. This study used a comprehensive neurochemical approach to examine the mechanisms responsible for these abnormalities. METHODS AND RESULTS: Subjects with and without congestive heart failure received intravenous infusions of [(3)H]NE. Cardiac spillover, reuptake, vesicular-axoplasmic exchange, and tissue stores of NE were assessed from arterial and coronary venous plasma concentrations of endogenous and [(3)H]-labeled NE and dihydroxyphenylglycol. Tyrosine hydroxylase activity was assessed from plasma dopa, and NE turnover was assessed from measurements of NE metabolites. NE release and reuptake were both increased in the failing heart; however, the efficiency of NE reuptake was reduced such that cardiac spillover of NE was increased disproportionately more than neuronal release of NE. Cardiac NE stores were 47% lower and the rate of vesicular leakage of NE was 42% lower in the failing than in the normal heart. Cardiac spillover of dopa and NE turnover were increased similarly in congestive heart failure. CONCLUSIONS: Increased neuronal release of NE and decreased efficiency of NE reuptake both contribute to increased cardiac adrenergic drive in congestive heart failure. Decreased vesicular leakage of NE, secondary to decreased myocardial stores of NE, limits the increase in cardiac NE turnover in CHF. Decreased NE store size in the failing heart appears to result not from insufficient tyrosine hydroxylation but from chronically increased NE turnover and reduced efficiency of NE reuptake and storage.
Adolescent↗
Dietary intake estimates as a means to the harmonization of maximum residue levels for veterinary drugs. II. Proposed application to the Free Trade Agreement between the United States and Canada.
The Free Trade Agreement between the United States and Canada (FTA) went into effect January 1, 1989. To implement certain provisions of the agreement on technical regulations and standards, the United States Food and Drug Administration's Center for Veterinary Medicine, Health and Welfare Canada's Bureau of Veterinary Drugs, and Agriculture Canada established the Working Group on Veterinary Drug Tolerances. The progress of the working group and its continuing efforts to harmonize tolerances for approximately 15 veterinary drugs are discussed. This paper proposes use of the toxicologically determined acceptable daily intake (ADI) for the drug as the safety standard for reaching conclusions on the acceptability of residues in meat for human consumption. Specifically, the "equivalence" of different MRLs for the same veterinary drug would be determined by considering whether they are likely to result in dietary residues that exceed the other country's ADI for the drug. Estimates are made for the veterinary drugs lasalocid, fenbendazole, morantel tartrate, halofuginone, and tilmicosin. Based on these estimates, the U.S. and Canadian MRLs for each drug would be considered equivalent for trade purposes.
Animals↗
Pediatric HIV infection.
Developments in the prevention and treatment of HIV infection in pregnant women and their children are encouraging. Perinatal ZDV therapy can reduce the maternal-infant transmission rate by two thirds in select populations. New therapies and the development of diagnostic assays to monitor HIV viral burden have renewed hope that, by aggressively controlling viremia, the progressive immunodeficiency can be delayed or even prevented. The general pediatric approach of preventing illnesses through aggressive vaccination and education policies must be actively incorporated into an approach to this epidemic. Success in controlling the pediatric HIV epidemic requires a concerted, coordinated effort by public policy makers, health care providers, basic science researchers, and those who are HIV-infected.
AIDS-Related Opportunistic Infections↗