Shear stress platelet activation test and "rebleeding" in patients undergoing cardiopulmonary bypass.
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Cardiopulmonary Bypass↗
Biomedical subjects
J Butler
Publications and source records attributed to J Butler.
Studies on the molecular pharmacology of GR63178A. A novel pentacyclic pyrolloquinone anticancer drug.
GR63178A (NSC D611615) is the second pentacyclic pyrolloquinone to be evaluated clinically as an anticancer drug. Its mechanism of action is unknown but may be related either to its quinone group or planar ring system. In this report we have investigated the ability of GR63178A to bind non-covalently to DNA, inhibit topoisomerase II and undergo reduction to reactive free radical species. Using two DNA duplexes, a 12-mer oligonucleotide which is a preferred sequence for minor groove binders and a hexamer which is a preferred sequence for intercalators, no evidence of significant binding with GR63178A was found. Neither GR63178A nor GR54374X (its 9-hydroxy metabolite) inhibited purified human topoisomerase II in a decatenation assay. Free radical chemistry was studied by both pulse radiolysis and ESR spectroscopy as well as by in vitro drug incubations with NADPH-fortified rat liver microsomes and purified cytochrome P450 reductase. The one-electron reduction potential of GR63178A was -207 mV +/- 10 which is much more positive than other quinone-containing anticancer drugs such as doxorubicin, mitomycin C and mitozantrone. GR63178A underwent enzyme-catalysed quinone reduction more readily than doxorubicin but produced significantly fewer reactive oxygen species. No evidence was detected of drug-induced, radical-mediated DNA damage in vitro using pBR322 plasmid DNA. Disproportionation of the GR63178A semi-quinone free radical proceeded with a rate constant of 1 x 10(9) M-1 sec-1 under anaerobic conditions, one order of magnitude faster than doxorubicin. The preferential disproportionation of the semi-quinone may explain our inability to detect a free radical signal by ESR. The hydroquinone of GR63178A was stable and exhibited strong visible absorption with a bathochromic shift of 120 nm over the parent drug. These unusual properties may be due to the hydroquinone undergoing a form of keto-enol tautomerization. Thus, GR63178A free radical formation does not appear to result in significant drug activation. In conclusion, GR63178A is unlikely to mediate its antitumour activity by DNA binding, topoisomerase II inhibition or free radical formation in direct contrast to similar anthracycline- and anthraquinone-based anticancer drugs.
Animals↗
Alteration in DNA cross-linking and sequence selectivity of a series of aziridinylbenzoquinones after enzymatic reduction by DT-diaphorase.
DT-diaphorase (DTD) mediated reduction of a series of 2,5-bis-substituted-3,6-diaziridinyl-1,4-benzoquinones was found to increase the level of DNA interstrand cross-linking (ISC) formed at neutral pH with an enhancement observed as the pH was decreased to 5.8. The analogues used were symmetrically alkyl-substituted carbamoyl ester analogues of AZQ (D1-D7), 3,6-diaziridinyl-1,4-benzoquinone (DZQ), the 2,5-dimethyl derivative (MeDZQ), and a 2,5-bis[(2-hydroxyethyl)amino] analogue (BZQ). At pH 5.8, the level of DNA ISC induced by enzymatic reduction was as follows: DZQ greater than MeDZQ much greater than D1 (methyl) greater than D3 (n-propyl) greater than D2 (AZQ; ethyl) greater than D5 (n-butyl) greater than D7 (sec-butyl) greater than D4 (isopropyl) D6 greater than (isobutyl). A similar trend was observed at pH 7.2. The level of DNA ISC induced by BZQ, which is not a substrate for DTD, was not increased by enzymatic reduction. Dicumarol, a known inhibitor of DTD, was capable of inhibiting the DNA ISC induced by these quinones upon enzymatic reduction. MeDZQ and DZQ reacted with guanines, as measured by Maxam and Gilbert sequencing, with a sequence selectivity similar to that of the nitrogen mustard class of antitumor agents. Enzymatic reduction of DZQ and MeDZQ by DTD was found to alter their sequence-selective alkylation. Reduced DZQ showed enhanced guanine alkylation in 5'-GC-3' sequences and new sites of adenine alkylation in 5'-(A/T)AA-3' sequences. Reduced MeDZQ only showed new sites of adenine alkylation at 5'-(A/T)AA-3' sequences but no enhancement of guanine alkylation. The new sites of adenine alkylation were found to be inhibited in the presence of magnesium and rapidly converted into apurinic sites.(ABSTRACT TRUNCATED AT 250 WORDS)
Alkylation↗
Cytokine responses to cardiopulmonary bypass with membrane and bubble oxygenation.
The systemic inflammatory response to cardiopulmonary bypass was assessed in 20 patients who underwent elective coronary artery bypass grafting with flat-sheet membrane oxygenation (group I; n = 10; age, 59 +/- 5 years) or bubble oxygenation (group II; n = 10; age, 62 +/- 8 years). The duration of cardiopulmonary bypass was 46 +/- 12 minutes in group I and 47 +/- 15 minutes in group II. Plasma interleukin-6, plasma interleukin-1 beta, transpulmonary leukocyte counts, pulmonary hemodynamic variables, and respiratory index were determined in all patients perioperatively. The plasma interleukin-6 response (median [range]) was similar in both groups at the end of the operation, peaked 4 hours postoperatively (99 [30 to 320] pg/mL in group I; 123 [21 to 300] pg/mL in group II; p greater than 0.05), and remained elevated 48 hours postoperatively (76 [9 to 140] pg/mL in group I; 65 [25 to 159] pg/mL in group II; p greater than 0.05). No significant interleukin-1 beta response was demonstrated. Pulmonary neutrophil and lymphocyte sequestration was observed on commencement of cardiopulmonary bypass in group II but did not occur in either group on discontinuation of cardiopulmonary bypass. Pulmonary vascular resistance at the end of the operation (82 [48 to 320] dynes.s.cm-5 in group I; 119 [54 to 385] dynes.s.cm-5 in group II; p greater than 0.05) was similar to preoperative values (151 [30 to 327] dynes.s.cm-5 in group I; 185 [62 to 291] dynes.s.cm-5 in group II; p greater than 0.05). The respiratory index at the end of the operation was similarly and significantly increased in both groups (1.26 [0.92 to 4.17] in group I; 1.44 [0.73 to 3.30] in group II).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
The Galway Study of Panic Disorder. II: Changes in some peripheral markers of noradrenergic and serotonergic function in DSM III-R panic disorder.
Sixty six patients with panic disorders, fulfilling the DSM III criteria for panic attack, together with a group of age and sex matched controls, were studied for changes in their peripheral noradrenergic and serotonergic status before treatment and during six months treatment with either clomipramine or lofepramine. The results of this study suggest that, despite clinical improvement, the peripheral markers of both adrenergic (platelet aggregation to noradrenaline, platelet alpha 2 receptor density and lymphocyte beta receptor density) and serotonergic (platelet aggregation to serotonin, 3H-ketanserin binding to platelet 5HT2 receptors and 3H-5HT uptake into platelets) function largely remained abnormal. It is concluded that such abnormalities are trait markers of biogenic amine function in patients with panic attack. Further studies are needed to determine whether or not these parameters eventually normalize in those patients showing prolonged remission of symptoms.
Adult↗
Redox cycling of potential antitumor aziridinyl quinones.
The formation of reactive oxygen intermediates (ROI) during redox cycling of newly synthesized potential antitumor 2,5-bis (1-aziridinyl)-1,4-benzoquinone (BABQ) derivatives has been studied by assaying the production of ROI (superoxide, hydroxyl radical, and hydrogen peroxide) by xanthine oxidase in the presence of BABQ derivatives. At low concentrations (< 10 microM) some BABQ derivatives turned out to inhibit the production of superoxide and hydroxyl radicals by xanthine oxidase, while the effect on the xanthine-oxidase-induced production of hydrogen peroxide was much less pronounced. Induction of DNA strand breaks by reactive oxygen species generated by xanthine oxidase was also inhibited by BABQ derivatives. The DNA damage was comparable to the amount of hydroxyl radicals produced. The inhibiting effect on hydroxyl radical production can be explained as a consequence of the lowered level of superoxide, which disrupts the Haber-Weiss reaction sequence. The inhibitory effect of BABQ derivatives on superoxide formation correlated with their one-electron reduction potentials: BABQ derivatives with a high reduction potential scavenge superoxide anion radicals produced by xanthine oxidase, leading to reduced BABQ species and production of hydrogen peroxide from reoxidation of reduced BABQ. This study, using a unique series of BABQ derivatives with an extended range of reduction potentials, demonstrates that the formation of superoxide and hydroxyl radicals by bioreductively activated antitumor quinones can in principle be uncoupled from alkylating activity.
Antineoplastic Agents↗
Reactions of glutathione and glutathione radicals with benzoquinones.
The reactions of glutathione (GSH) and glutathione radicals with a series of methyl-substituted 1,4-benzoquinones and 1,4-benzoquinone have been studied. It was found that by mixing excess benzoquinone with glutathione at pH above 6.5, the products formed were complex and unstable. All of the other experiments were carried out at pH 6.0, where the main product was stable for several hours. Stopped-flow analysis allowed the measurement of the rates of the rapid reactions between GSH and the quinones, and the products were monitored by High Performance Liquid Chromatography (HPLC). The rates of the reactions vary by five orders of magnitude and must be influenced by steric factors as well as changes in the redox states. It was observed that simple hydroquinones were not formed when the different benzoquinones were mixed with excess GSH and suggests that the initial reaction is addition/reduction rather than electron transfer. In the presence of excess quinone, the hydroquinone of the glutathione conjugate is oxidized back to its quinone. The rates of the reaction were measured. By using the technique of pulse radiolysis, it was possible to measure the reduction of the quinones by GSSG.- and the oxidation of hydroquinones by GS(.). It is proposed that the appearance of GSSG in reactions of quinones with glutathione could be due to oxidation of the hydroquinone by oxygen and the subsequent superoxide or H2O2 promoting the oxidation of GSH to GSSG.
Benzoquinones↗
Risk of viral hepatitis among military personnel assigned to US Navy ships.
A prevalence study of 2072 male US shipboard military personnel scheduled for deployment to South America/West Africa and the Mediterranean was conducted to determine whether serologic evidence of prior hepatitis A, B, or C infection is associated with exposure in foreign countries. There were 210 subjects (10.1%) who had antibodies to hepatitis A virus (anti-HAV), 76 (3.7%) to hepatitis B core antigen (anti-HBc), and 9 (0.4%) to hepatitis C virus (anti-HCV). By multivariate analysis, anti-HAV seropositivity was independently associated with age, non-white racial/ethnic groups, birth outside of the United States, and prior Caribbean deployment for less than 1 year. Anti-HBc seropositivity was independently associated with black and Filipino race/ethnicity, foreign birth, a history of a sexually transmitted disease, South Pacific/Indian Ocean deployment (less than 12 months), and South Pacific or Mediterranean duty for (greater than 1 year). No geographic risk factors were associated with anti-HCV positivity. These data indicate that military personnel deployed outside the United States are at increased risk of viral hepatitis infection and should be considered for vaccination.
Adult↗
T cell receptor alpha-chain pairing determines the specificity of residue 262 within the Kb-restricted, ovalbumin257-264 determinant.
Ovalbumin-specific, Kb-restricted T cells recognize the minimal fully active synthetic peptide ovalbumin (OVA)257-264. This sequence coincides with the eight residue, allele-specific peptide binding motif previously predicted from direct sequencing of naturally occurring Kb-associated peptides (Falk, K., Rotzscke, O., Stevanovic, S., Jung, G., and Rammensee, H.-G., Nature 351:290, 1990). T cell recognition of a panel of analogs with single residue substitutions between the two putative Kb anchor residues at OVA261 and OVA264 suggested that at least one residue, Glu at position 262, is involved in TCR interaction. OVA-specific cytotoxic T lymphocytes (CTL) derived from TCR beta-chain transgenic mice, where the beta-chain originates from an OVA-specific, Kb-restricted CTL B3, showed that differences in TCR alpha-chain pairing determined the specificity for OVA residue 262. These data support the notion that residue 262 of the OVA T cell determinant, corresponding to position 6 within the Kb-binding motif, represents a contact site for TCR. This residue interacts directly with the TCR alpha-chain or with a site on the TCR beta-chain whose conformation is affected by TCR alpha-chain pairing.
Amino Acid Sequence↗
Influence of lung volume and alveolar pressure on reverse pulmonary venous blood flow.
We have reported that left atrial blood refluxes through the pulmonary veins to gas-exchanging tissue after pulmonary artery ligation. This reverse pulmonary venous flow (Qrpv) was observed only when lung volume was changed by ventilation. This was believed to drive Qrpv by alternately distending and compressing the alveolar and extra-alveolar vessels. Because lung and pulmonary vascular compliances change with lung volume, we studied the effect of positive end-expiratory pressure (PEEP) on the magnitude of Qrpv during constant-volume ventilation. In prone anesthetized goats (n = 8), using the right lung to maintain normal blood gases, we ligated the pulmonary and bronchial arterial inflow to the left lung and ventilated each lung separately. A solution of SF6, an inert gas, was infused into the left atrium. SF6 clearance from the left lung was determined by the Fick principle at 0, 5, 10, and 15 and again at 0 cmH2O PEEP and was used to measure Qrpv. Left atrial pressure remained nearly constant at 20 cmH2O because the increasing levels of PEEP were applied to the left lung only. Qrpv was three- to fourfold greater at 10 and 15 than at 0 cmH2O PEEP. At these higher levels of PEEP, there were greater excursions in alveolar pressure for the same ventilatory volume. We believe that larger excursions in transpulmonary pressure during tidal ventilation at higher levels of PEEP, which compressed alveolar vessels, resulted in the reflux of greater volumes of left atrial blood, through relatively noncompliant extra-alveolar veins into alveolar corner vessels, and more compliant extra-alveolar arteries.
Animals↗
Growth hormone binding protein in patients with renal failure.
To investigate changes in the growth hormone binding protein (GH-BP) in renal disease, gel chromatography was used to separate free and bound hormone after incubation with 125I-GH, the results being expressed as a percentage of radioactive GH eluting in a high molecular weight (70-80 kD) peak. In 26 normal individuals, binding was 39.3 +/- 8.0%, while in 11 patients with renal disease who were off dialysis binding was reduced to 16.8 +/- 5.6%. Similarly, in 9 patients undergoing hemodialysis binding was reduced to 24.6 +/- 6.8%, in 8 patients undergoing chronic ambulatory peritoneal dialysis binding was reduced to 25.7 +/- 7.6%, and in 9 patients within three months of a renal transplant binding was reduced to 25.1 +/- 8.6%. Scatchard analysis showed that these changes were not a result of decreased affinity of GH-BP for GH, and receptor binding studies showed that uremic serum was not inhibiting binding. The decreased concentration of GH-BP may indicate decreased expression of the GH receptor in target tissues, and hence diminished responsiveness to GH in renal failure.
Adult↗
Relationship between DT-diaphorase-mediated metabolism of a series of aziridinylbenzoquinones and DNA damage and cytotoxicity.
A series of 2,5-bis-substituted 3,6-diaziridinyl-1,4-benzoquinones have been tested for their ability to be reduced by the two-electron NAD(P)H:(quinone acceptor) oxidoreductase [DT-diaphorase (DTD); EC 1.6.99.2]. Symmetrically alkyl-substituted carbamoyl ester analogs of 2,5-ethyl(carboethoxyamino)3,6-diaziridinyl-1,4- benzoquinone [AZQ], 3,6-diaziridinyl-1,4-benzoquinone (DZQ), and its 2,5-dimethyl derivative (MeDZQ) were tested. The rate of reduction by DTD was DZQ greater than MeDZQ greater than n-butyl- (D5) greater than sec-butyl- (D7) greater than n-propyl- (D3) greater than methyl- (D1) greater than ethyl- (AZQ) greater than i-butyl- (D6) greater than i-propyl- (D4) substituted derivatives. The hydroxyethylamino analog (BZQ) was not a substrate for DTD. The order of toxicity to HT-29 human colon carcinoma cells (at 1-log cell kill) was MeDZQ greater than DZQ greater than BZQ greater than D1 greater than D5 greater than AZQ greater than D7 greater than D3 greater than D6 greater than D4. Dicumarol, a known inhibitor of DTD, was capable of inhibiting the cytotoxicity of DZQ, MeDZQ, AZQ, D3, D4, D5, D6, and D7, with little inhibition of D1 cytotoxicity. Alkaline elution assays suggested that DZQ induced DNA strand breaks, whereas MeDZQ induced DNA interstrand crosslinks in HT-29 cells. The formation of both classes of lesions was inhibited by dicumarol. DZQ and MeDZQ were 5-6-fold less cytotoxic to the DTD-deficient BE cell line, whereas BZQ was more cytotoxic to this cell line than the HT-29 cell line. BZQ was capable of inducing dicumarol-insensitive DNA interstrand crosslinks in both cell lines. In summary, these data show a trend between the rate of reduction by DTD of an analog and its ability to induce cytotoxicity in HT-29 cells, and they support a role for DTD in the bioreductive activation of AZQ and its analogs.
Animals↗
Assessment of gall bladder dynamics, cholecystokinin release and the development of gallstones during octreotide therapy for acromegaly.
The development of gallstones is a well recognized complication of therapy with the long-acting somatostatin analogue, octreotide in patients with acromegaly. A group of nine acromegalic patients was treated with octreotide at doses of 300-600 micrograms daily for 8 months and the changes in fasting and post-prandial cholecystokinin release, and gall bladder motor function (determined by a radiosotopic technique) were assessed at regular intervals. In addition the development of any gallstones was determined by serial ultrasonography. Fasting cholecystokinin levels showed no significant change over 6 months, whereas the post-prandial levels demonstrated a significant decrease (p less than 0.01) during therapy, yet remained significantly higher than fasting levels. Twenty-four hours after commencing therapy gall bladder ejection fraction was decreased by 57 +/- 23 per cent and gall bladder ejection rate decreased by 63 +/- 19 per cent compared to the pretreatment values, whereas after 6 months' therapy a marked reduction in gall bladder ejection fraction (greater than 35 per cent) and gall bladder ejection rate (greater than 40 per cent) persisted in only four of nine patients. Three of these four patients with persistently impaired gall bladder motor function were subsequently shown to have developed either gallstones or biliary sludge during the course of therapy. We conclude that treatment with octreotide is associated with an impaired post-prandial release of cholecystokinin in all acromegalic patients, but gallstones only develop in those patients who, in addition, have evidence of a persistently impaired gall bladder motor response to cholecystokinin.
Acromegaly↗
DNA cross-linking and sequence selectivity of aziridinylbenzoquinones: a unique reaction at 5'-GC-3' sequences with 2,5-diaziridinyl-1,4-benzoquinone upon reduction.
Several bifunctional alkylating agents of the aziridinylbenzoquinone class have been evaluated as potential antitumor agents. 3,6-Bis[(2-hydroxyethyl)amino]-2,5- diaziridinyl-1,4-benzoquinone (BZQ), 2,5-diaziridinyl-1,4-benzoquinone (DZQ), 3,6-bis(carboxyamino)-2,5-diaziridinyl- 1,4-benzoquinone (AZQ), and six analogues of AZQ have been studied for their ability to induce DNA interstrand cross-linking, as measured by an agarose gel technique, and to determine whether they react with DNA in a sequence-selective manner, as determined by a modified DNA sequencing technique. At an equimolar concentration (10 microM), only DZQ and BZQ showed any detectable cross-linking at pH 7 without reduction. Cross-linking was enhanced in both cases at low pH (4). Reduction by ascorbic acid at both pH's increased the cross-linking, which was particularly striking in the case of DZQ. In contrast, AZQ and its analogues only produced a significant level of cross-linking under both low-pH and reducing conditions, the extent of cross-linking decreasing as the size of the alkyl end group increased. The compounds reacted with all guanine-N7 positions in DNA with a sequence selectivity similar to other chemotherapeutic alkylating agents, such as the nitrogen mustards, although some small differences were observed with BZQ. Nonreduced DZQ showed a qualitatively similar pattern of reactivity to the other compounds, but on reduction (at pH 4 or 7) was found to react almost exclusively with 5'-GC-3' sequences, and in particular, at 5'-TGC-3' sites. A model to explain this unique reaction is proposed.
Antineoplastic Agents↗
Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus.
BACKGROUND: Data on human fetal thyroid function have largely been derived from histologic studies or studies of cord-blood samples obtained at hysterotomy or delivery. These data may not represent true normal values. Cordocentesis (ultrasound-guided blood sampling from the umbilical cord) is a technique that allows investigation of physiologic processes in fetuses not under stress. METHODS: We measured serum thyroid-stimulating hormone, total and free thyroxine (T4), total and free triiodothyronine (T3), and thyroxine-binding globulin in blood samples from 62 fetuses. The samples were obtained by cordocentesis (n = 58) or cardiocentesis (n = 4) at 12 to 37 weeks of gestation. Maternal serum samples were obtained immediately before fetal blood sampling. RESULTS: Fetal serum thyroid-stimulating hormone, thyroxine-binding globulin, and total and free T4 and T3 concentrations increased significantly with the length of gestation (P less than 0.001). The only significant association among these variables, independent of the length of gestation, was between thyroid-stimulating hormone and free T4 (P less than 0.0001). Maternal serum concentrations of these variables did not change during gestation, and there was no significant relation between fetal and maternal values. Most fetal serum concentrations of thyroid-stimulating hormone were higher, whereas most serum total and free T3 concentrations were lower than the respective values for normal adults. The fetal serum total T4, free T4, and thyroxine-binding globulin values reached the level of the mean adult values at approximately 36 weeks of gestation. CONCLUSIONS: The increases in fetal serum concentrations of thyroid-stimulating hormone, thyroxine-binding globulin, and total and free T4 and T3 during gestation reflect increasing maturation of the pituitary, thyroid, and liver. The finding of increasing fetal serum concentrations of thyroid-stimulating hormone in the presence of increasing thyroid hormone concentrations suggests that the sensitivity of the fetal pituitary gland to negative feedback is limited or is counterbalanced by increasing stimulation by thyrotropin-releasing hormone from the hypothalamus.
Female↗
Fetal thyroid-stimulating hormone response to maternal administration of thyrotropin-releasing hormone.
Thyroid-stimulating hormone was measured in fetal blood samples obtained by cordocentesis before and after blood transfusion in Rh-affected pregnancies at 25 to 37 weeks' gestation. In eight of 26 study subjects thyrotropin-releasing hormone was given to the mothers immediately after the pretransfusion samples were obtained. In this group the fetal thyroid-stimulating hormone concentrations in the posttransfusion samples were significantly higher than those before the transfusion.
Blood Transfusion, Intrauterine↗
Diaphragm paralysis following cardiac surgery: role of phrenic nerve cold injury.
Diaphragm paralysis has been reported radiologically after cardiac surgery with an incidence ranging from 30% to 75% of patients. We studied 100 consecutive patients undergoing open heart operations, half of whom received ice/slush topical hypothermia (group 1) and half of whom did not (group 2). Chest radiology and diaphragm screening were performed at 1 week, 1 month, and every 6 months thereafter in all patients with an elevated diaphragm. Phrenic nerve conduction time was measured in all patients in whom there was radiological evidence of diaphragm paralysis 1 week postoperatively. The two groups were similar in terms of age and sex. Aortic cross-clamp time was less in group 1 (61.5 +/- 15.6 minutes) compared with group II (74.4 +/- 20.8 minutes), although this difference was not significant. Significant differences, however, were found for radiological evidence of partial left lower lobe collapse (82% in group 1 versus 32% in group 2; p less than 0.01) and for radiological evidence of diaphragm paralysis (32% in group 1 versus 2% in group 2; p less than 0.001) within the first postoperative week. Unilateral diaphragm paralysis developed in 16 group 1 patients (15 left sided, 1 right sided) compared with only 1 patient in group 2. In these 16 group 1 patients, diaphragm paralysis was still present in 12 (75%) at 1 month and in 5 (31.3%) at 1 year postoperatively. There were no significant differences between the two groups in terms of postoperative arrhythmias, myocardial infarction, or mortality. Phrenic nerve conduction time was found to be a sensitive indicator of phrenic nerve cold injury and recovery.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiac Surgical Procedures↗