Mycophenolate mofetil without antibody induction in pediatric renal transplantation.
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Adolescent↗
Biomedical subjects
D Cutler
Publications and source records attributed to D Cutler.
Hard metal-induced disease: effects of metal cations in vitro on guinea pig isolated airways.
Inhalation of dust from hard metal (HM), a mixture of tungsten carbide, cobalt, and other metals, can cause interstitial alveolitis, fibrosis, and asthma in the workplace. Some effects of HM could occur after the metals dissolve in the lung. We examined whether chloride salts of metals in HM alloys can elicit responses or modify reactivity to methacholine (MCh) or responses to electric field stimulation (EFS) in guinea pig tracheal strips. In unstimulated strips, Co(2+), Cd(2+), and Ni(2+) evoked contractions (>3 x 10(-6) M), while Ta(5+), Zn(2+), Cr(2+), and Cr(3+) caused weak relaxations (>10(-5) M). In strips contracted with MCh (3 x 10(-7) M), Co(2+) and Ni(2+) also caused relaxation in lower concentrations while the other metals caused weak relaxation only in high concentrations (>10(-4) M). The metals were generally without effect on reactivity to MCh, except that Cd(2+) inhibited and Ni(2+) potentiated some responses. The effects of selected metals (10(-6) M; Cr(3+), Ni(2+), Cd(2+), and Co(2+)) on EFS-induced contractile and relaxant responses were examined (+/-MCh; +/-10(-6) M indomethacin (Indo), 30 min). No metal had any effect on the excitatory nonadrenergic, noncholinergic-mediated contraction phase. Cd(2+) and Ni(2+) inhibited cholinergically mediated contractions of unstimulated strips (+Indo), whereas Cr(3+) both inhibited (-MCh, -Indo) and potentiated (-Indo,+MCh; +Indo, +MCh) contractile responses. Cr(3+) was the only metal to inhibit the inhibitory nonadrenergic, noncholinergic-mediated relaxation phase (+/-MCh; -Indo). Co(2+) had no effect at all. The results suggest that smooth muscle tone and nerves in the airways could be targets of cationic metals after they dissolve in the lung.
Alloys↗
Clone database unveiled.
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Cloning, Molecular↗
Conference fast-tracking.
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Congresses as Topic↗
Acupuncture and opioids.
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Acupuncture Therapy↗
Tightening tobacco legislation.
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Europe↗
On the mechanism of Cr (VI)-induced carcinogenesis: dose dependence of uptake and cellular responses.
Cr (VI) compounds are widely used industrial chemicals and are recognized human carcinogens. The mechanisms of carcinogenesis associated with these compounds remain to be investigated. The present study focused on dose-dependence of Cr (VI)-induced uptake and cellular responses. The results show that Cr (VI) is able to enter the cells (human lung epithelial cell line A549) at low concentration (< 10 microM) and that the Cr (VI) uptake appears to be a combination of saturable transport and passive diffusion. Electron spin resonance (ESR) trapping measurements showed that upon stimulation with Cr (VI), A549 cells were able to generate reactive oxygen species (ROS). The amount of ROS generated depended on the Cr (VI) concentration. ROS generation involved NADPH-dependent flavoenzymes. Cr (VI) affected the following cellular parameters in a dose-dependent manner, (a) activation of nuclear transcription factors NF-kappaB, and p53, (b) DNA damage, (c) induction of cell apoptosis, and (d) inhibition of cell proliferation. The activation of transcription factors was assessed by electrophoretic mobility shift assay and western blot analysis, DNA damage by single cell gel electrophoresis assay, cell apoptosis by DNA fragmentation assay, and cell proliferation by a non-radioactive ELISA kit. At the concentration range used in the present study, no thresholds were found in all of these cell responses to Cr (VI). The results may guide further research to better understand and evaluate the risk of Cr (VI)-induced carcinogenesis at low levels of exposure.
Antioxidants↗
Clinical outcome 10 years after infant heart transplantation.
The feasibility of heart transplantation for infants has now been established. Clinical outcome data is necessary to assist in targeting areas for improvement and for counseling families considering this option. This report describes clinical outcome in 29 infant heart transplant recipients who have survived at least 10 years. A query of the transplant database, referring physicians and parental questionnaire was performed. Patient survival for the overall infant population is 64% at 13 years. Parents of 19/29 (55%) children described them as developmentally normal. Three children have had a severe developmental outcome. Sixteen of 29 children are in mainstream school environments. Four have repeated one grade in school. Speech delay was present in 10/26 (38%). Somatic growth is normal in 88%. All children are NYHA class I. Renal function shows only modest insufficiency with most recent BUN (mean+/-S.D.)=25+/-7 mg/dl and serum creatinine=0.8+/-0.2 mg/dl. Only four children have creatinine levels >1 mg/dl. No child requires dialysis. No children have developed post-transplant lymphoproliferative disease beyond 10 years. Four children have experienced rejection beyond 10 years with one mortality due to rejection and transplant coronary artery disease. Conclusion: Heart transplantation during infancy is technically feasible and results in good survival. Many children have some degree of learning disability but most are mild and the children function well in society. Improvements in surgical techniques may improve developmental outcome. Other side-effects of immunosuppression are manageable and most survivors have a good functional outcome.
Journal Article↗
Interleukin 10-induced thrombocytopenia in normal healthy adult volunteers: evidence for decreased platelet production.
Recombinant human interleukin 10 (rhuIL-10) inhibits the production of proinflammatory cytokines and has shown promise in the treatment of inflammatory bowel disease. Clinical trials have been accompanied by a reversible decline in platelet counts. We conducted a randomized, double-blinded, placebo-controlled, parallel group trial in 12 healthy volunteers to investigate the aetiology of rhuIL-10-induced thrombocytopenia. Eight volunteers received 8 microg/kg/d of rhuIL-10 subcutaneously, while four subjects received a placebo alone for 10 d. A reversible decline in the platelet counts from a mean of 275 x 10(9)/l to 164 x 10(9)/l was observed in the IL-10-treated cohort (P = 0.012). A fall in the haemoglobin mean levels was also observed in the IL-10-treated cohort from 13.7 to 11.7 g/dl (P = 0.011). No significant change was observed in the bone marrow cellularity or myeloid/erythroid ratio or in the number of megakaryocytes per high-powered field (HPF). A fall was observed in the number of megakaryocyte colony-forming units (CFU-MKs) after the administration of IL-10 compared with those receiving the placebo (P = 0.068). No difference in the change in granulocyte-macrophage CFUs (CFU-GMs), mixed lineage CFUs (CFU-GEMMs) or erythroid burst-forming units (BFU-Es) was observed when comparing the IL-10- vs. placebo-treated groups (P > 0.465). Serum cytokine levels of thrombopoietin (TPO). IL-6 and granulocyte-macrophage colony stimulating factor (GM-CSF) were not decreased following IL-10 administration. In fact, both TPO and GM-CSF appeared to be slightly increased in the serum. All subjects underwent In111-labelled platelet survival studies with liver/spleen scans to assess splenic sequestration prior to and then on day 7 of treatment. A significant reduction in splenic sequestration of platelets (P =0.012) was observed in the IL-10-treated group, but not in the placebo-treated subjects.
Adult↗
Effect of ozone treatment on airway reactivity and epithelium-derived relaxing factor in guinea pigs.
Ozone (O(3)) is toxic to respiratory epithelium and causes airway inflammation and hyperreactivity. To evaluate the role of the epithelium in the development of hyperreactivity, we examined in guinea pigs the effects of inhaled O(3) (3 ppm for 1 h; 0-24 h after exposure) on 1) reactivity to inhaled methacholine (MCh), 2) reactivity of the isolated, perfused trachea (IPT) to MCh, 3) epithelium-derived relaxing factor (EpDRF)-mediated relaxations of IPT induced by mucosal hyperosmolar solutions, 4) neurogenic contraction and relaxation responses, 5) transepithelial potential difference, and 6) microscopic analysis of nitrotyrosine immunofluorescence, substance P fiber density, and tracheal morphology. At 0 h, O(3) caused hyperreactivity to inhaled MCh and mucosally but not serosally applied MCh in IPT (only in the presence of the epithelium) and a decrease in transepithelial potential difference. Inhibition of EpDRF-induced relaxation responses occurred at 2 h. All of these changes returned to control by 12 to 18 h. O(3) had no effect on neurogenic responses. Nitrotyrosine immunofluorescence appeared in the trachea at 0 h in detached epithelial cell ghosts and in intrapulmonary airways by 6 h. Substance P fiber density was elevated in smooth muscle at 0 and 18 h but not in epithelium or lamina propria of intrapulmonary and extrapulmonary bronchi. Loss of cilia and mucosubstances in the mucosa occurred at 0 h; the epithelium became markedly attenuated over 12 to 24 h. A reversible increase in epithelial permeability and a decrease in EpDRF production may contribute to O(3)-induced hyperreactivity to MCh.
Animals↗
Queuing for coronary angiography during severe supply-demand mismatch in a US public hospital: analysis of a waiting list registry.
CONTEXT: Adverse cardiac events have been reported in patients waiting for either coronary surgery or angioplasty. However, data on the risk of adverse events while awaiting coronary angiography are limited, and none are available from a US population. OBJECTIVE: To quantify cardiac outcomes in patients waiting for elective coronary angiography. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study of 381 adult outpatients (mean [SD] age, 55 [12] years; 64% male; 61% white) on a waiting list for coronary angiography at a US tertiary care public teaching hospital during 1993-1994. MAIN OUTCOME MEASURES: Rates of cardiac death, nonfatal myocardial infarction, and hospitalizations for unstable angina or heart failure as a function of amount of time spent on a waiting list. RESULTS: Sixty-six patients were dropped from the waiting list but were included in the study analysis. During a mean (SD) follow-up of 8.4 (6.5) months, cardiac death, myocardial infarction, and hospitalization occurred in 6 (1.6%), 4 (1.0%), and 26 (6.8%) patients, respectively. The probability of events was minimal in the first 2 weeks and increased steadily between 3 and 13 weeks. By Cox multivariate analysis, 2 variables independently identified an increased risk of adverse events: a strongly positive treadmill exercise electrocardiogram or positive stress imaging result at referral (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.22-4.16; P=.01) and the use of 2 to 3 anti-ischemic medications (OR, 1.98; 95% CI, 1.19-3.96; P=.04). Among 311 patients who ultimately underwent angiography, those with adverse events had a higher prevalence of coronary disease (96% vs 60%; P<.001), more frequently required revascularization (93% vs 53%; P<.001), and had longer hospital stays (mean [SD], 6.2 [4.3] vs 1.3 [0.7] days; P=.001). CONCLUSION: Our data suggest that in a cohort referred for coronary angiography, delaying the procedure places some patients at risk for death, myocardial infarction, unplanned hospitalization, a longer hospital stay, and, potentially, a poorer prognosis. Waits longer than 2 weeks should be avoided, and patients with strongly positive stress test results and those who require 2 to 3 anti-ischemic medications should be prioritized for early intervention.
Aged↗
Comparing practice patterns of consumer and non-consumer mental health service providers.
The practice patterns of consumer and non-consumer providers of assertive community treatment are compared using both quantitative and qualitative data collected as part of a randomized trial. Activity log data showed that there were few substantive differences in the pattern of either the administrative or direct service tasks performed by the two teams. In contrast, the qualitative data revealed that there were discernable differences in the "culture" of the two teams. The consumer team "culture" emphasized "being there" with the client while the non-consumer team was more concerned with accomplishing tasks.
Case Management↗
Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies.
Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug's safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100-250 mg m(-2) was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m(-2) day(-1). Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean Tmax approximately 1 h) and eliminated (mean t1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m(-2) day(-1) for 5 days, every 28 days, is recommended for phase II studies.
Administration, Oral↗
Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer.
The purpose of this study is to characterize the absorption, metabolism, and excretion of carbon 14-labeled temozolomide (14C-TMZ) administered p.o. to adult patients with advanced solid malignancies. On day 1 of cycle 1, six patients received a single oral 200-mg dose of 14C-TMZ (70.2 microCi). Whole blood, plasma, urine, and feces were collected from days 1-8 and on day 14 of cycle 1. Total radioactivity was measured in all samples. TMZ, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), and 4-amino-5-imidazole-carboxamide (AIC) concentrations were determined in plasma, and urine and plasma samples were profiled for metabolite/degradation products. Maximum TMZ plasma concentrations were achieved between 0.33 to 2 h (mean, 1.2 h), and half-life, apparent volume of distribution, and oral clearance values averaged 1.9 h, 17 liters/m2, and 104 ml/min/m2, respectively. A first-order absorption, one-compartment linear model, which included first-order formation of MTIC from TMZ and elimination of MTIC via degradation to AIC, and a peripheral distribution compartment for AIC, adequately described the plasma TMZ, MTIC, and AIC concentrations. MTIC systemic clearance was estimated to be 5384 ml/min/m2, and the half-life was calculated to be 2.5 min. Metabolite profiles of plasma at 1 and 4 h after treatment showed that 14C-derived radioactivity was primarily associated with TMZ, and a smaller amount was attributed to AIC. Profiles of urine samples from 0-24 h revealed that 14C-TMZ-derived urinary radioactivity was primarily associated with unchanged drug (5.6%), AIC (12%), or 3-methyl-2,3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxyl ic acid (2.3%). The recovered radioactive dose (39%) was principally eliminated in the urine (38%), and a small amount (0.8%) was excreted in the feces. TMZ exhibits rapid oral absorption and high systemic availability. The primary elimination pathway for TMZ is by pH-dependent degradation to MTIC and further degradation to AIC. Incomplete recovery of radioactivity may be explained by the incorporation of AIC into nucleic acids.
Absorption↗
Osmotic regulation of airway reactivity by epithelium.
Inhalation of nonisotonic solutions can elicit pulmonary obstruction in asthmatic airways. We evaluated the hypothesis that the respiratory epithelium is involved in responses of the airways to nonisotonic solutions using the guinea pig isolated, perfused trachea preparation to restrict applied agents to the mucosal (intraluminal) or serosal (extraluminal) surface of the airway. In methacholine-contracted tracheae, intraluminally applied NaCl or KCl equipotently caused relaxation that was unaffected by the cyclo-oxygenase inhibitor, indomethacin, but was attenuated by removal of the epithelium and Na+ and Cl- channel blockers. Na+-K+-2Cl- cotransporter and nitric oxide synthase blockers caused a slight inhibition of relaxation, whereas Na+,K+-pump inhibition produced a small potentiation. Intraluminal hyperosmolar KCl and NaCl inhibited contractions in response to intra- or extraluminally applied methacholine, as well as neurogenic cholinergic contractions elicited with electric field stimulation (+/- indomethacin). Extraluminally applied NaCl and KCl elicited epithelium-dependent relaxation (which for KCl was followed by contraction). In contrast to the effects of hyperosmolarity, intraluminal hypo-osmolarity caused papaverine-inhibitable contractions (+/- epithelium). These findings suggest that the epithelium is an osmotic sensor which, through the release of epithelium-derived relaxing factor, can regulate airway diameter by modulating smooth muscle responsiveness and excitatory neurotransmission.
Animals↗