A normal coronary artery: what size is it?
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Animals↗
Biomedical subjects
M R Johnson
Publications and source records attributed to M R Johnson.
Coronary angioplasty in cardiac transplant patients. Results of a multicenter study.
BACKGROUND: Accelerated allograft atherosclerosis is the main cause of death of cardiac transplant recipients after the first year after transplantation. Because no medical therapy is known to prevent or retard graft atherosclerosis and transplantation is associated with a shortened allograft survival, alternative, palliative therapy with percutaneous transluminal coronary angioplasty (PTCA) has been attempted. Because no single medical center has performed angioplasty in a large number of cardiac transplant recipients, representatives of 11 medical centers retrospectively analyzed their complete experience of coronary angioplasty in cardiac transplant patients to determine the safety, efficacy, limitations, and long-term outcome of angioplasty in allograft coronary vascular disease. METHODS AND RESULTS: Thirty-five patients underwent 51 angioplasty procedures for 95 lesions 46 +/- 5 months (mean +/- SEM) after transplantation. The primary indications for angioplasty included angiographic coronary disease in 22 cases (43%) and noninvasive evidence of ischemia in 18 procedures (35%). Angiographic success, defined as less than or equal to 50% post-PTCA stenosis, occurred in 88 of 95 lesions (93%). Mean pre-PTCA stenosis was 83 +/- 1.1%; mean post-PTCA stenosis was 29 +/- 2.1% (p less than 0.0001). Periprocedural complications included myocardial infarction and late in-hospital death in one patient and three groin hematomas. Twenty-three of the 35 patients (66%) had no major adverse outcome such as death, retransplantation, or myocardial infarction at 13 +/- 3 months after angioplasty. Four patients died less than 6 months after angioplasty, and four died more than 6 months after angioplasty (range, 6-23 months). Two patients had retransplantation 2 months after PTCA, and one patients had retransplantation 18 months after angioplasty. CONCLUSIONS: Coronary angioplasty may be applied in selected cardiac transplant recipients with comparable success and complication rates to routine angioplasty. Whether angioplasty prolongs allografts survival remains to be determined by a prospective, controlled trial.
Angioplasty, Balloon, Coronary↗
Effect of food deprivation and altered thyroid status on the hypothalamic-pituitary-thyroid axis in the rat.
Propylthiouracil (PTU) was administered to rats for different lengths of time with or without food deprivation on the last 2 days. Within 4 days of PTU treatment peripheral 3,5,3'-tri-iodothyronine (T3) fell to low levels and beta-subunit of thyroid-stimulating hormone (beta-TSH) mRNA increased significantly in the anterior pituitary. Pro-thyrotrophin-releasing hormone (pro-TRH) mRNA in the hypothalamic paraventricular nucleus (PVN) increased significantly in the control group of animals by 8 days and in the food-deprived group by day 12; the increment of pro-TRH mRNA in the food-deprived group on day 12 was significantly less than that in the control group. In a second study, animals were treated with intraperitoneal injections of T3 with or without the food deprivation. After 4 days of T3 treatment, peripheral T3 levels were markedly increased and pro-TRH mRNA in the PVN and beta-TSH mRNA in the anterior pituitary were significantly reduced. Food deprivation had no additional suppressive effect. These studies confirm that the predominant effect of food deprivation on the thyroid axis is at the hypothalamic or suprahypothalamic level and that it can, at least in part, overcome the increase in TRH mRNA due to diminished T3 feedback.
Animals↗
Distribution of relaxin between human maternal and fetal circulations and amniotic fluid.
Relaxin was measured in maternal blood and amniotic fluid samples at 9-40 weeks and in fetal blood samples at 19-41 weeks of pregnancy. In amniotic fluid, concentrations of relaxin rose from 58 ng/l (geometric mean) at 10 weeks to 142 ng/l at 14 weeks and declined subsequently to 55 ng/l at 22 weeks. In maternal blood, mean relaxin concentrations were ten times greater than in amniotic fluid, and concentrations decreased with gestation. Since there was no significant association between the relaxin concentrations in the two compartments, relaxin in the amniotic fluid may be derived from the decidualized endometrium rather than the maternal circulation, alternatively its metabolism may be different in the two compartments. The absence of detectable concentrations of relaxin in any of the fetal blood samples demonstrates that there is no significant placental transfer or fetal synthesis of this peptide.
Amniotic Fluid↗
Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents.
Opening of the pyran ring of delta 9-tetrahydrocannabinol (THC) produces cannabidiol, a bicyclic cannabinoid devoid of many pharmacological properties produced by delta 8-THC or delta 9-THC. Interestingly, the bicyclic compound CP-47,497 (VI) has been described as producing many of the pharmacological effects produced by delta 9-THC, and another related bicyclic analog CP-55,940 (XIV) has been used to successfully define a cannabinoid binding site. A series of 16 bicyclic analogs of VI and XIV were evaluated and compared with the pharmacological profile of cannabidiol, delta 8-THC and delta 9-THC. The goals of the studies described herein were to determine whether these bicyclic analogs possess similar pharmacological properties of delta 9-THC, to compare pharmacological activity after s.c. and i.v. administration, and to evaluate the structure-activity relationship of this series of analogs for further insight into cannabinoid mechanism of action. Each analog was evaluated for its ability to produce hypoactivity, hypothermia, antinociception and catalepsy in mice. The ED50 values generated from these assays were averaged to provide an index of activity. The ED50 values for delta 9-THC varied from 1.0 to 1.5 mg/kg, giving an overall index of activity of 1.3. The index for delta 8-THC was 6.0, making this isomer 4-fold less potent. Although several bicyclic analogs (V, VI, VII, VIII, XI, XII, XIV and XVI) proved to be truly cannabimimetic, three (IV, IX and X) were sufficiently unique to be classified as noncannabimimetic. The index of activity of cannabimimetic bicyclic analogs varied from 0.2 to 2.2, although some minor differences between the bicyclics and delta 9-THC exist.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenylyl Cyclases↗
Development of a library-based information service for the subject of workers' compensation: a proposal.
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Humans↗
Photopheresis versus corticosteroids in the therapy of heart transplant rejection. Preliminary clinical report.
BACKGROUND: Photopheresis is a technique in which reinfusion of mononuclear cells exposed to UV-A light ex vivo after in vivo treatment with 8-methoxypsoralen initiates host-immunosuppressive responses. METHODS AND RESULTS: To determine if photopheresis safely reverses International Society for Heart and Lung Transplantation (ISHLT) rejection grades 2, 3A, and 3B without hemodynamic compromise, 16 heart transplant patients with ISHLT rejection grades 2, 3A, and 3B were randomized to photopheresis or corticosteroid therapy. The average number of mononuclear cells treated with each photopheresis procedure was 9.8 +/- 9.1 x 10(9) (mean +/- SD). Photopheresis and corticosteroids reversed eight of nine and seven of seven episodes of rejection, respectively. The median time from initiation of treatment to rejection reversal was 25 days (range, 6-67 days) in the photopheresis group and 17 days (range, 8-33 days) in the corticosteroid group. Hemodynamics were normal before either treatment and did not change after reversal of rejection. No adverse reactions occurred with photopheresis, and all patients in either treatment group are alive. CONCLUSIONS: These preliminary, short-term results in prospectively randomized patients indicate that photopheresis may be as effective as corticosteroids for treating ISHLT rejection grades 2, 3A, and 3B. The apparently low toxicity and potential efficacy of photopheresis warrant further analysis of its role in the prevention and treatment of heart transplant rejection.
Adult↗
The cannabinoid receptor-pharmacologic identification, anatomical localization and cloning.
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Animals↗
Identification of bile acid-CoA: amino acid N-acyltransferase in rat kidney.
A novel location of the bile-acid-conjugating enzyme bile acid-CoA:amino acid N-acyltransferase (BAT) has been discovered in the cytosolic fraction of rat kidney. Both taurine and glycine were utilized as substrates. Formation of bile acid N-acyl amidates was verified by h.p.l.c. by comparison with authentic standards and by specific hydrolysis using cholylglycine hydrolase. Immunoblot analysis using a human liver anti-BAT polyclonal antibody indicated that rat kidney BAT has the same molecular mass as rat liver BAT. These findings suggest that the kidney has a role in bile acid metabolism and physiology.
Acyltransferases↗
Purification and characterization of bile acid-CoA:amino acid N-acyltransferase from human liver.
The bile acid-conjugating enzyme, bile acid-CoA: amino acid N-acyltransferase, was purified 480-fold from the soluble fraction of homogenized frozen human liver. Purification was accomplished by a combination of anion exchange chromatography, chromatofocusing, glycocholate-AH-Sepharose affinity chromatography, and high performance liquid chromatography (HPLC) gel filtration. Following purification, the reduced, denatured enzyme migrated as a single 50-kDa protein band by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A similar molecular mass was obtained for the native enzyme by HPLC gel filtration. Elution from the chromatofocusing column suggested an apparent isoelectric point of 6.0 (+/- 0.2). Using a rabbit polyclonal antibody raised against the purified enzyme, Western blot analysis using 100,000 x g human liver supernatant confirmed that the affinity-purified polyclonal antibody was specific for human liver bile acid-CoA:amino acid N-acyltransferase. The purified enzyme utilized glycine, taurine, and 2-fluoro-beta-alanine (a 5-fluorouracil catabolite), but not beta-alanine, as substrates. Kinetic studies revealed apparent Km values for taurine, 2-fluoro-beta-alanine, and glycine of 1.1, 2.2, and 5.8 mM, respectively, with corresponding Vmax values of 0.33, 0.19, and 0.77 mumol/min/mg protein. These data demonstrate that a single monomeric enzyme is responsible for the conjugation of bile acids with glycine or taurine in human liver.
Acyltransferases↗
Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs.
Numerous cannabinoids have been synthesized that are extremely potent in all of the behavioral assays conducted in our laboratory. An important feature in increasing potency has been the substitution of a dimethylheptyl (DMH) side chain for the pentyl side chain. Our previous studies have shown that (-)-11-OH-delta 8-THC-dimethylheptyl was 80-1150 times more potent than delta 9-THC. Stereospecificity was demonstrated by its (+)-enantiomer which was more than 1400-7500 times less potent. A related series of DMH cannabinoid analogs has recently been synthesized and preliminary evaluations reported here. (-)-11-OH-delta 9-THC-DMH was found to be equipotent with (-)-11-OH-delta 8-THC-DMH. The aldehyde (-)-11-oxo-delta 9-THC-DMH was 15-50 times more potent than delta 9-THC. Surprisingly, (-)-11-carboxy-delta 9-THC-DMH was also active, being slightly more potent than delta 9-THC. In the bicyclic cannabinoid series, the length and bulk of the side chain were found to be equally important. Aminoalkylindoles, which are structurally dissimilar from classical cannabinoids, have been found to exhibit a pharmacological profile similar to delta 9-THC. Though not extremely potent in vivo, they appear to represent an entirely new approach to studying the actions of the cannabinoids. The structural diversity and wide-ranging potencies of the analogs described herein provide the opportunity to develop a pharmacophore for the cannabinoids using molecular modeling techniques.
Analgesics↗
A comparative study of bile acid CoA:amino acid:N-acyltransferase (BAT) from four mammalian species.
1. Bile acid CoA:amino acid:N-acyltransferase (BAT) was partially purified from dog, human, pig and rat livers. The interspecies variation in substrate specificity and kinetics were determined for glycine and taurine. 2. BAT activity from dog liver formed bile acid conjugates with taurine exclusively, whereas BAT activity from each of the other species formed conjugates with both taurine and glycine. 3. Biliary composition of glycine and taurine bile acid conjugates could partly be accounted for by substrate affinity (Km) and turnover number (Vmax) of BAT activity. 4. A monospecific anti-human BAT polyclonal antibody reacted on Western blot analysis with a 40 kDa band in a 100,000 g supernatant fraction from rat liver. 5. Immunoabsorption chromatography using an anti-human BAT antibody-Sepharose affinity column showed that both the immunoreactive protein band and BAT activity were removed from the 100,000 g supernatant fraction from human and rat livers.
Acetyltransferases↗
Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics.
In an effort to discover a potent ultrashort-acting mu opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent mu opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinepropanoi c acid alkyl esters, were evaluated in vitro in the guinea pig ileum for mu opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent mu agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.
Analgesics↗
The effect of human chorionic gonadotropin and pregnancy on the circulating level of relaxin.
The effect of hCG and pregnancy on the circulating levels of relaxin was investigated in 48 women undergoing in vitro fertilization and embryo transfer (ET) for the treatment of infertility. Subjects were allocated randomly to receive hCG (Profasi; 2000 IU, im) or placebo on the day of ET (day 0) and on day 3 after ET (day 3). Samples of peripheral blood were taken on days -4, 6, and 10. An additional sample was taken on day 22 from women who became pregnant. The subjects were allocated retrospectively to 1 of 4 groups: no pregnancy, no hCG (NP); pregnancy, no hCG (P); no pregnancy, hCG (NPH); and pregnancy, hCG (PH). Two patients with blighted ova and one with a tubal pregnancy were excluded from the analysis. The concentrations of relaxin were similar and rose significantly in all groups at each time point (P less than 0.05). On day 6 there was no significant difference in the increment between the groups, but by day 10, circulating levels in the P compared to the NP and those in the PH compared to the NPH group were significantly greater (P less than 0.05). By day 22 the difference between the PH and the P groups was significant (P less than 0.05). Relaxin levels correlated with progesterone levels on day 10 in the NP and P groups (r = 0.633; P less than 0.05 and r = 0.697; P less than 0.05, respectively) and with estradiol levels in the P group only on days 6 and 22 (r = 0.659; P less than 0.05 and r = 0.783; P less than 0.05, respectively). These data demonstrate that in women undergoing in vitro fertilization, relaxin levels increase during the luteal phase, and in those women who establish a pregnancy, the values are significantly greater by day 10. The administration of hCG in the early luteal phase, before implantation, to women who subsequently become pregnant significantly increased the level of circulating relaxin on day 22. The positive correlation between relaxin levels and ovarian steroid levels in the groups not receiving exogenous hCG suggests that a common factor may control the release of both.
Chorionic Gonadotropin↗
Effect of tryptic or peptic digestion or mechanical isolation on the extraction of proteins, antigens, and ribonucleic acids from Sarcocystis muris bradyzoites.
Various methods have been used for the isolation of bradyzoites of Sarcocystis species. Using Sarcocystis muris as a model, the effect of 3 methods, trypsin digestion, pepsin digestion, and mechanical isolation, on the subsequent extraction of S. muris proteins, antigens, and RNA was examined. Although some quantitative differences were found among the proteins, antigens, and RNA extracted after the 3 isolation methods, qualitative differences were not evident. The overall isoelectric focusing protein profile showed approximately 30 bands in the pH range of 3-9 and was dominated by 5 bands with pI values of approximately 5.3, 6.3, 6.8, 7.0, and 7.4. In experimentally infected mice, antibodies were recorded from 35 days postinoculation (PI) until the end of examination (130 days PI). The S. muris RNA appeared to consist of at least 10 subunits in the range of 200-4,200 nucleotides. A Toxoplasma gondii DNA fragment specific for small subunit ribosomal RNA (rRNA) hybridized mainly to the S. muris 1,900-nucleotide subunit and a range of smaller subunits, and a probe specific for large subunit rRNA hybridized mainly to the 4,200-nucleotide subunit and a range of smaller subunits. All 3 methods of bradyzoite isolation gave good yields of intact messenger RNAs that showed similar in vitro translation curves.
Animals↗
Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study.
A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
Animals↗
Relaxin levels in ovum donation pregnancies.
STUDY OBJECTIVE: To investigate the relative contributions of the corpus luteum (CL) and the placenta to the circulating levels of relaxin during pregnancy. PATIENTS: Forty-one patients in whom pregnancy had been achieved by ovum donation. RESULTS: Relaxin was not detected in the serum of 36 patients; in the remaining 5, although it was detectable, the levels were markedly reduced when compared with those in normal pregnancies. CONCLUSION: These results demonstrate that the CL is essential for the maintenance of normal circulating levels of relaxin during pregnancy.
Corpus Luteum↗
Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients.
BACKGROUND: A sudden increase in the incidence of post-transplantation lymphoproliferative disorder among the patients in our cardiac-transplantation program was temporally related to introduction of the immunosuppressive drug OKT3. This monoclonal antibody has come to be widely used in recent years both to prevent and to treat rejection after cardiac transplantation. METHODS: In order to identify variables that predict the development of post-transplantation lymphoproliferative disorder, we analyzed retrospectively a series of 154 consecutive cardiac-transplant recipients at a single institution. Univariate analyses and multivariate analysis by logistic regression were performed. RESULTS: Among 75 patients who did not receive OKT3, post-transplantation lymphoproliferative disorder developed in 1 (1.3 percent), as compared with 9 of 79 patients who received the drug (11.4 percent); the incidence among the OKT3-treated patients was ninefold higher (odds ratio, 9.5; 95 percent confidence interval, 1.6 to 54.7). According to multivariate analysis, the only factor significantly associated with the development of post-transplantation lymphoproliferative disorder was the use of OKT3 (P = 0.001). A significant increase in risk with increasing doses was also apparent: 4 of 65 patients who received a cumulative dose of 75 mg of OKT3 or less (6.2 percent) had post-transplantation lymphoproliferative disorder, whereas 5 of 14 patients who received more than 75 mg had the disorder (35.7 percent; P less than 0.001). CONCLUSION: The addition of OKT3 to the immunosuppressive regimen increases the incidence of post-transplantation lymphoproliferative disorder after cardiac transplantation, and the risk increases sharply after cumulative doses greater than 75 mg. We suggest that the risks and benefits of prophylactic OKT3 administration be reassessed in the light of these findings, particularly since the value of prophylactic immunotherapy in cardiac-transplant recipients remains to be clearly established.
Antibodies, Monoclonal↗