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Biomedical subjects

M R Johnson

Publications and source records attributed to M R Johnson.

At least 109 records · Page 6Linked to original sources
PubMed1998

Outpatient inotropic therapy in heart transplant candidates: should its use influence waiting list priority status?

BACKGROUND: The use of outpatient intravenous inotropic therapy in heart transplant candidates is contentious. In addition to concerns about morbidity and mortality rates, the current United Network for Organ Sharing (UNOS) heart allocation system presently grants no waiting list priority status benefit to candidates who receive intravenous inotropic therapy in the outpatient setting (UNOS status 2), whereas identical therapy given in an intensive care unit setting does increase priority status (UNOS status 1). The goal of this study was to determine whether an increase in UNOS waiting list priority status is justified in heart transplant candidates receiving outpatient intravenous inotropic therapy by comparing the waiting list mortality of UNOS status 2 candidates on such therapy with that of UNOS status 2 candidates maintained on oral heart failure agents alone. METHODS: This is a retrospective analysis of the pretransplantation outcomes of heart transplant candidates initially listed as UNOS status 2, comparing 29 candidates receiving intravenous outpatient inotropic therapy (group 1) to 109 candidates maintained on oral heart failure agents alone (group 2). RESULTS: The waiting list mortality was not significantly different between the two groups (group 1=7% vs group 2=20%, p=.18); however, group 1 patients had greater morbidity rates while awaiting transplantation than group 2 patients. A greater percentage of group 1 than group 2 patients clinically deteriorated to UNOS status 1 while awaiting transplantation (45% vs 11%), resulting in more group 1 patients undergoing transplantation overall, (59% vs 33%, p=.01) and more group 1 than group 2 patients undergoing transplantation at a higher priority status, UNOS status 1 (76% vs 33%, p=.003). Group 1 patients had more pretransplantation heart failure admissions (1.2 vs 0.6 admissions/total waiting period, p=.02) and longer hospital stays (26+/-39 vs 8.8+/-16 days, p=.03), spent a greater percentage of their total waiting time hospitalized (7% vs 2%, p=.003), and were more likely than group 2 patients to receive intravenous inotropic therapy during hospitalization (70% vs 25%, p=.001). CONCLUSION: This study suggests that heart transplant candidates who require maintenance outpatient intravenous inotropic therapy represent a subgroup of UNOS status 2 candidates with greater waiting list morbidity, but no greater waiting list mortality than candidates who can be maintained on oral heart failure agents alone. However, the current UNOS heart allocation system provides for this increased illness acuity by assigning a higher priority status when necessary. A larger, prospective study is necessary to determine whether a true difference in waiting list mortality rates exists and if an increase in priority status is justified for UNOS status 2 candidates requiring maintenance inotropic therapy.

Administration, Oral↗
PubMed1998

The use of APACHE II scores to select candidates for left ventricular assist device placement. Acute Physiology and Chronic Health Evaluation.

BACKGROUND: The growth in left ventricular assist device (LVAD) use has been hampered by high morbidity and mortality rates and cost. The purpose of this study was to help improve patient selection for LVAD placement by determining whether the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system, a multiparameter, physiology-based predictor of outcome, could be used to predict outcome after LVAD placement and thus help determine optimum timing of LVAD placement. METHODS: This was a retrospective analysis of a prospective cohort observational study consisting of 2 groups: (1) 50 patients with severe heart failure who did not receive LVAD placement after initial evaluation and (2) 31 patients who did receive LVAD placement. Patients included in the study were in severe heart failure on the basis of 3 of the following: lung crackles, S3, peripheral edema, ejection fraction < 0.30, systolic blood pressure < 80 mm Hg, progressive prerenal azotemia, altered level of consciousness, gastrointestinal ischemia or congestion, or persistent although reversible pulmonary hypertension in spite of maximal medical therapy, including intravenous inotropes. The decision for LVAD placement was at the discretion of the attending physician. RESULTS: Both LVAD- and non-LVAD-treated patients were similar in cause of heart failure, APACHE II scores, and other baseline laboratory parameters. Survival time with a log-logistic model was better for LVAD-treated patients, p=.0266. Although Kaplan Meier analysis showed a trend toward better survival rates in the LVAD-treated patient, the Cox proportional hazards revealed that LVAD-treated patients had better survival (relative risk ratio, 95% confidence interval=0.305, 0.110 to 0.892; p=.0219) after adjustment for APACHE II score. Each unit increase in APACHE II independently predicted death (relative risk ratios, 95% confidence interval=1.139, 1.055 to 1.231; p=.0009). Patients with medium APACHE II (11 to 20) scores in particular benefitted from LVAD treatment. CONCLUSION: LVAD placement for severe heart failure (not restricted to cardiogenic shock) improves survival. APACHE II can aid in deciding the timing of LVAD placement in patients with heart failure who may not have attained conventional hemodynamic criteria for LVAD placement. Patients who had APACHE II scores between 11 and 20 derived the greatest benefit from LVAD placement.

APACHE↗
PubMed1997

Semi-automated radioassay for determination of dihydropyrimidine dehydrogenase (DPD) activity. Screening cancer patients for DPD deficiency, a condition associated with 5-fluorouracil toxicity.

Dihydropyrimidine dehydrogenase (DPD) catalyzes the reduction of the naturally occurring pyrimidines, uracil and thymine, and the fluoropyrimidine anticancer drug, 5-fluorouracil (FUra) to 5,6-dihydropyrimidines. Previous studies have demonstrated that cancer patients who are DPD deficient exhibit severe toxicity (including death) following treatment with FUra. To date, the direct measurement of DPD enzyme activity has been the only reliable method to identify DPD deficient cancer patients. We now report a semi-automated radioassay for measuring DPD activity in human peripheral lymphocytes. Following incubation of lymphocyte cytosol (at a fixed protein concentration of 200 micrograms) with [6-14C]FUra at timepoints ranging from 0 to 30 min, samples are ethanol precipitated, filtered and analyzed by HPLC. Determination of radioactivity is accomplished using an in-line flow scintillation analyzer with automatic quantitation of peaks. This method provides the first specific assay for DPD enzyme activity which is rapid, reproducible and sensitive enough to be used in the routine screening of cancer patients for DPD deficiency prior to treatment with FUra.

Antimetabolites, Antineoplastic↗
PubMed1997

Structural organization of the human dihydropyrimidine dehydrogenase gene.

Deficiency of the pyrimidine catabolic enzyme, dihydropyrimidine dehydrogenase (DPD), has been shown to be responsible for a pharmacogenetic syndrome in which administration of 5-fluorouracil is associated with severe and potentially life-threatening toxicity. Following the recent availability of the cDNA for DPD, there were initial reports of several molecular defects (point mutations, deletions due to exon skipping) that were suggested as a potential molecular basis for DPD deficiency, even before the complete physical structure of the DPD gene was known. To understand the mechanism responsible for DPD deficiency, we have determined the genomic structure and organization of the human DPD gene. The gene is approximately 150 kb in length, and it consists of 23 exons, ranging in size from 69 to 1404 bp. The sequences of intronic regions flanking the exon boundaries have been determined. The physical map of the DPD gene should permit development of rapid assays to detect point mutations or small deletions in the DPD gene associated with 5-fluorouracil toxicity.

Dihydrouracil Dehydrogenase (NADP)↗
PubMed1997

Role of maximal oxygen consumption in establishment of heart transplant candidacy for heart failure patients with intermediate exercise tolerance.

Maximal exercise oxygen consumption (VO2max) was measured in patients with chronic congestive heart failure undergoing evaluation for heart transplantation. Although VO2max correlated with survival for the group as a whole, it did not demonstrate survival discrimination for patients in the intermediate range (VO2max = 12 to 17 ml/kg/min) and should therefore not be used as a benchmark test for determination of appropriateness for cardiac transplantation in this group of patients.

Adult↗
PubMed1997

Serum concentrations of steroid hormones during reproduction in the Atlantic stingray, Dasyatis sabina.

The Atlantic stingray, Dasyatis sabina, has a well-defined annual reproductive cycle in Florida. We collected adult specimens over 12 months and evaluated reproductive parameters and serum levels of five steroid hormones, 17beta-estradiol (E2), progesterone (P4), testosterone (T), dihydrotestosterone (DHT), and corticosterone (CS). Female E2 peaked twice, once in mid-March to early April in association with ovulation and again in mid-June to mid-July in association with the enlargement of a second group of ovarian follicles. Female P4 peaked in early March and early April, coincident with the peak in E2. Female DHT was variable but exhibited a pattern not clearly associated with known events in the reproductive cycle. Female T and CS levels did not vary significantly through time. In males, T, DHT, and CS increased progressively through winter and spring, peaking in March when females were ovulating and when copulation probably took place. DHT concentrations were usually at least twice T levels. These three hormones peaked long after the November/December peak in gonadosomatic index. E2 was measurable in males and was highest during the period of testicular development. Male P4 varied in a pattern not clearly associated with known reproductive events.

Animals↗
PubMed1997

Echocardiography for hemodynamic assessment of patients with advanced heart failure and potential heart transplant recipients.

OBJECTIVES: This study sought to assess the accuracy of Doppler echocardiographic techniques for the determination of right heart catheterization hemodynamic variables in patients with advanced heart failure and in potential heart transplant recipients. BACKGROUND: Doppler echocardiographic techniques permit the noninvasive acquisition of hemodynamic variables traditionally used for the assessment of patients with advanced heart failure and potential heart transplant candidates. However, the accuracy of these techniques has not been sufficiently well documented for clinical application in individual patients. METHODS: Echocardiographic data required for estimation of mean right atrial, pulmonary artery and mean left atrial pressures and cardiac output were obtained. Right heart catheterization was performed immediately after Doppler echocardiographic data were acquired, before any intervention that might have altered the subject's hemodynamic status. RESULTS: A complete Doppler echocardiographic hemodynamic data set was acquired in 21 (84%) of 25 subjects. For all variables, invasive and noninvasive hemodynamic values were highly correlated (p < 0.001), with minimal bias and narrow 95% confidence limits. An algorithm constructed from the noninvasive hemodynamic variable values identified all patients with adverse pulmonary vascular hemodynamic variables (i.e., transpulmonary gradient > or = 12 mm Hg, pulmonary vascular resistance > or = 3 Wood units or pulmonary vascular resistance index > or = 6 Wood units x m2). This algorithm identified 12 (71%) of 19 patients for whom right heart catheterization was unnecessary. CONCLUSIONS: Doppler echocardiographic estimates of hemodynamic variables in patients with advanced heart failure are accurate and reproducible. This noninvasive methodology may assist with monitoring and optimization of medical therapy in patients with advanced heart failure and may obviate the need for routine right heart catheterization in potential heart transplant candidates.

Algorithms↗
PubMed1997

Characterization of the human extracellular matrix protein 1 gene on chromosome 1q21.

Ecm1, the mouse gene encoding extracellular matrix protein 1, is highly expressed in bone and cartilage as well as in osteogenic, preosteoblastic and chondroblastic cell lines. Ecm1 was recently localized to a chromosomal region in mouse syntenic to human chromosome 1q21, establishing this gene as a prime candidate gene for pycnodysostosis, a rare, autosomal recessive sclerosing skeletal dysplasia. Shortly thereafter, it was determined that cathepsin K is the pycnodysostosis gene. We now report the radiation hybrid mapping of human ECM1 to 1q21, and the gene structure and coding sequence of human ECM1.

Amino Acid Sequence↗
PubMed1997

Serological survey for diseases in free-ranging coyotes (Canis latrans) in Yellowstone National Park, Wyoming.

From October 1989 to June 1993, we captured and sampled 110 coyotes (Canis latrans) for various diseases in Yellowstone National Park, Wyoming (USA). Prevalence of antibodies against canine parvovirus (CPV) was 100% for adults (> 24 months old), 100% for yearlings (12 to 24 months old), and 100% for old pups (4 to 12 months old); 0% of the young pups (< 3 months old) had antibodies against CPV. Presence of antibodies against canine distemper virus (CDV) was associated with the age of the coyote, with 88%, 54%, 23%, and 0% prevalence among adults, yearlings, old pups, and young pups, respectively. Prevalence of CDV antibodies declined over time from 100% in 1989 to 33% in 1992. The prevalence of canine infectious hepatitis (ICH) virus antibodies was 97%, 82%, 54%, and 33%, for adults, yearlings, old pups, and young pups, respectively. The percentage of coyotes with ICH virus antibodies also declined over time from a high of 100% in 1989 to 31% in 1992, and 42% in 1993. Prevalence of antibodies against Yersinia pestis was 86%, 33%, 80%, and 7%, for adults, yearlings, old pups, and young pups, respectively, and changed over time from 57% in 1991 to 0% in 1993. The prevalence of antibodies against Francisella tularensis was 21%, 17%, 10%, and 20%, for adults, yearlings, old pups, and young pups, respectively. No coyotes had serologic evidence of exposure to brucellosis, either Brucella abortus or Brucella canis. No coyotes were seropositive to Leptospira interrogans (serovars canicola, hardjo, and icterohemorrhagiae). Prevalence of antibodies against L. interrogans serovar pomona was 7%, 0%, 0%, and 9%, for adults, yearlings, old pups, and young pups, respectively. Antibodies against L. interrogans serovar grippotyphosa were present in 17% of adults and 0% of yearlings, old pups, and young pups. Many infectious canine pathogens (CPV, CDV, ICH virus) are prevalent in coyotes in Yellowstone National Park, with CPV influencing coyote pup survival during the first 3 months of life; eight of 21 transmitted pups died of CPV infection in 1992. The potential impact of these canine pathogens on wolves (C. lupus) reintroduced to Yellowstone National Park remains to be documented.

Adenoviruses, Canine↗
PubMed1997

Serologic survey for infectious pathogens in free-ranging American bison.

From November 1991 through March 1992, we evaluated 101 free-ranging American bison (Bison bison) from Yellowstone National Park, Wyoming (USA) for exposure to infectious organisms that commonly infect cattle. No titers were detected for bluetongue virus, bovine leukemia virus, or Campylobacter fetus in these 101 bison. Detectable antibodies occurred against Anaplasma marginale (eight of 76, 11%), bovine respiratory syncytial virus (31 of 101, 31%), bovine viral diarrhea (31 of 101, 31%), bovine herpesvirus 1 (29 of 76, 38%), Leptospira interrogans icterohaemorrhagiae (four of 101, 4%), L interrogans hardjo (seven of 101, 7%), L interrogans autumnalis (one of 101, 1%), L interrogans bratislava (seven of 101, 7%), L interrogans australis (one of 101, 1%), and parainfluenza 3 virus (27 of 75, 36%). The low antibody titers and the lack of gross lesions are evidence that while previous exposure to infectious organisms may have occurred, none appeared to have active infections.

Anaplasma↗
PubMed1997

Effects of methotrexate on acute rejection and cardiac allograft vasculopathy in heart transplant recipients.

BACKGROUND: In heart transplant recipients methotrexate has been shown to reverse recurrent/persistent acute rejection refractory to intensified conventional immunosuppression. This study sought to determine whether methotrexate produces a sustained decline of heart allograft rejection rates and renders rejection rates of patients with a history of recurrent/persistent rejection similar to those of heart transplant recipients without such history. METHODS: Rejection, infection, and cardiac allograft vasculopathy were compared in 35 patients treated with methotrexate (12 +/- 9 mg/week for 34 +/- 54 weeks) and 236 patients never given methotrexate. Because the mean time from transplantation to initiation of methotrexate was 9.4 months, patients treated without methotrexate were analyzed for events < or = 9.4 versus > 9.4 months after heart transplantation. RESULTS: Demographics, perioperative and maintenance immunosuppression, and postoperative follow-up time (58 +/- 32 vs 57 +/- 33 months) were similar in the two groups. Rejection rates decreased in both groups but remained significantly higher in the patients treated with methotrexate after initiation of therapy than in the patients treated without methotrexate more than 9.4 months after transplantation (0.15 +/- 0.16 vs 0.06 +/- 0.12 episodes/patient/month; p = 0.0014). Infection rates were higher in patients after methotrexate initiation than in patients treated without methotrexate more than 9.4 months after heart transplantation (0.17 +/- 0.24 vs 0.06 +/- 0.13 episodes/patient/month; p = 0.015). At the end of the follow-up period methotrexate- and non-methotrexate-treated groups did not differ in the percentage of patients with angiographically detectable cardiac allograft vasculopathy (17.1% and 21.2%, respectively) and survival (71.4% and 64.0%, respectively). CONCLUSIONS: Even after reversal of rejection by methotrexate, patients requiring methotrexate for the treatment of persistent/recurrent rejection continued to have higher rejection rates than patients not requiring methotrexate. In spite of persistently higher rejection rates, patients treated with methotrexate did not have higher rates of cardiac allograft vasculopathy. This finding raises the question whether methotrexate provides a protective influence on the development of cardiac allograft vasculopathy in this high-risk group.

Acute Disease↗
PubMed1997

The incremental risk of female sex in heart transplantation: a multiinstitutional study of peripartum cardiomyopathy and pregnancy. Cardiac Transplant Research Database Group.

BACKGROUND: Controversy remains regarding the reason females seem to be at increased risk for rejection after heart transplantation. Therefore this study was performed to define the effect of a pretransplantation diagnosis of peripartum cardiomyopathy and the effect of previous pregnancy on the outcome (incidence of rejection and death) of females after heart transplantation. METHODS: In this multiinstitutional study of 3244 adult (greater than 13 years of age) heart transplant recipients, (a) the outcome of 40 females who underwent transplantation for peripartum cardiomyopathy was compared with that of 200 females of childbearing age (13 to 45 years) who underwent transplantation for other indications and (b) the posttransplantation outcome of 543 females with a history of pregnancy was compared with that of 101 nulliparous adult females and 2562 adult males. RESULTS: The posttransplantation outcome of females with a history of peripartum cardiomyopathy was similar to that of females of childbearing age who underwent transplantation for other indications. However, parous females had a significantly shorter time to first rejection (p < 0.0001) and greater cumulative rejection than nulliparous females or males. By multivariable analysis, the risk factors for cumulative rejection at 1 year were a history of pregnancy (p < 0.0001), younger recipient age (p < 0.0001), induction therapy (p < 0.0001), and the number of human leukocyte antigen-DR mismatches (p = 0.007). CONCLUSION: Our data suggest that it is previous pregnancy, and not sex per se, that is associated with an increased frequency of rejection in females after heart transplantation.

Actuarial Analysis↗
PubMed1996

The nonreceptor protein tyrosine phosphatase corkscrew functions in multiple receptor tyrosine kinase pathways in Drosophila.

Corkscrew (csw) encodes a nonreceptor protein tyrosine phosphatase (PTPase) that has been implicated in signaling from the Torso receptor tyrosine kinase (RTK). csw mutations, unlike tor mutations, are associated with zygotic lethality, indicating that Csw plays additional roles during development. We have conducted a detailed phenotypic analysis of csw mutations to identify these additional functions of Csw. Our results indicate that Csw operates positively downstream of other Drosophila RTKs such as the Drosophila epidermal growth factor receptor (DER), the fibroblast growth factor receptor (Breathless), and likely other RTKs. This model is substantiated by specific dosage interactions between csw and DER. It is proposed that Csw is part of the evolutionarily conserved "signaling cassette" that operates downstream of all RTKs. In support of this hypothesis, we demonstrate that SHP-2, a vertebrate PTPase similar to Csw and previously implicated in RTK signaling, encodes the functional vertebrate homologue of Csw.

Alleles↗
PubMed1996

(Aminoalkyl)indole isothiocyanates as potential electrophilic affinity ligands for the brain cannabinoid receptor.

A series of (aminoalkyl)indole compounds, naphthalene analogs of pravadoline (1), has been shown to exhibit cannabinoid agonist activities such as antinociception in animals, inhibition of adenylate cyclase in brain membranes, and binding to the cannabinoid receptor. These pravadoline analogs were selected for the preparation of potential electrophilic affinity ligands based on the synthesis of isothiocyanate derivatives. One isothiocyanatonaphthalene derivative (8) displaced [3H]CP-55940 binding to a rat brain P2 membrane preparation with an IC50 of 690 nM, which was 10-fold less potent than the parent molecule (IC50 = 73 nM). Isothiocyanate substitution at various positions on the naphthalene moiety of the desmethyl analog 10 gave compounds that displaced [3H]CP-55940 with IC50 values between 400 and 1000 nM, compared with 46 nM for the parent compound 10. However, 6-isothiocyanato substitution on the indole ring of the desmethyl analog provided isothiocyanate 12 that displaced [3H]CP-55940 binding with an IC50 and 160 nM. After pretreatment of brain membranes with this high-affinity isothiocyanato ligand followed by washing out the ligand, the membranes were depleted of 90% of the cannabinoid receptor binding capacity. Loss of receptor binding capacity was half-maximal at 300 nM of the derivative under standard assay conditions. As a control, pretreatment with the parent compound at concentrations that were 20 times the Kd failed to alter subsequent binding activity. This study demonstrates that an isothiocyanato (aminoalkyl)-indole (12) can behave as an affinity ligand which binds irreversibly to the cannabinoid receptor in brain and which precludes subsequent binding of the cannabinoid ligand [3H]CP-55940.

Adenylyl Cyclases↗
PubMed1996

Nitric oxide synthase activities in human myometrium and villous trophoblast throughout pregnancy.

OBJECTIVE: To study the changes in nitric oxide synthase activities in human myometrium and trophoblast throughout pregnancy and around delivery. METHODS: Samples of villous trophoblast were collected from women undergoing elective cesarean delivery at term (n = 12) or voluntary termination of pregnancy in the first (n = 27) or second (n = 11) trimesters of pregnancy. Myometrial samples were obtained from nonpregnant women undergoing hysterectomy (n = 5) and pregnant women both before (n = 7) and after (n = 7) the onset of spontaneous labor at term. Nitric oxide synthase activity was quantified for homogenized samples using the L-citrulline assay in the presence and absence of calcium. RESULTS: The highest levels of nitric oxide synthase activity were found in first-trimester villi (range 2-29 nmol L-citrulline/minute/g protein), with a significant fall in activity in the third trimester (range 2-10 nmol L-citrulline/minute/g protein; P < .001 for both calcium-dependent and calcium-independent activity). Myometrial activities were relatively low compared with those in the trophoblast (0-2 nmol L-citrulline/minute/g protein), with no significant differences in calcium-dependent activities between subgroups. Myometrial calcium-independent activities were lower in pregnant than in nonpregnant women (P = .007), with those in labor having levels higher than those not in labor (P = .048). CONCLUSION: Levels of nitric oxide synthase activity are relatively high in villous trophoblast, particularly during the first trimester. Although the contribution to total nitric oxide production in the uterus by myometrial nitric oxide synthase appears to be relatively small, nitric oxide produced by the trophoblast may play a role in maintaining uterine quiescence by a paracrine effect. Further work is needed to test this hypothesis and explore other possible roles for trophoblast-derived nitric oxide in early pregnancy.

Female↗