Extensive troponin I and T modification detected in serum from patients with acute myocardial infarction.
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Humans↗
Biomedical subjects
D L Morris
Publications and source records attributed to D L Morris.
In vitro and in vivo suppression of growth of hepatocellular carcinoma cells by albendazole.
Tubulin protein is a major target of drug molecules, and consequently, tubulin inhibitors have attracted great attention as antimitotic antitumor agents for chemotherapeutic use. It has been shown that, the benzimidazole carbamate group of antiparasitics including albendazole act by inhibiting tubulin polymerization. In this study, albendazole was tested in culture against a range of human, rat and mice hepatocellular carcinoma (HCC) cells and in vivo against human SKHEP-1 tumor growth in nude mice. Albendazole induced a dose-dependent inhibition of [(3)H]thymidine incorporation in all cell lines examined and a dramatic decline in cell numbers in SKHEP-1 cells. The inhibitory effect of albendazole was evident at the 100 nM concentration and at 1000 nM, proliferation in all cell lines examined was inhibited by more than 80%, while, proliferation of HepG2, Hep3B and SKHEP-1 were suppressed by more than 90%, compared to control. Cell cycle analysis revealed that, depending on the dose employed, albendazole can arrest SKHEP-1 cells at both G0-G1 (250 nM) and G2-M (1000 nM) phases of the cycle. Albendazole treatment (300 mg/kg per day oral for 20 days) of nude mice inoculated subcutaneously with SKHEP-1, led to profound suppression of tumor growth. Immunohistochemical analysis of these tumors revealed that compared to control, those treated with albendazole have lower growth fractions. These findings demonstrate that albendazole strongly suppresses both in vitro and in vivo proliferation of HCC cells.
Albendazole↗
Reduction in recurrence risk for involved or inadequate margins with edge cryotherapy after liver resection for colorectal metastases.
HYPOTHESIS: The usefulness of additional edge cryotherapy after liver resection for liver metastases from colorectal cancer to improve involved or inadequate (less than 1 cm) margins is uncertain. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Department of surgery at a university hospital. PATIENTS: Eighty-six consecutive patients with hepatic metastases from colorectal cancer in whom we applied additional edge cryotherapy to involved or inadequate margins. This group was compared with 134 patients who underwent resection without edge cryotherapy (control group) during the same period. INTERVENTION: Potentially curative treatment was achieved by adding edge cryotherapy to insufficient resection sites in patients not eligible for further resection. MAIN OUTCOME MEASURES: Edge recurrence rate in the study group; validation of an additional treatment to improve curative resectability; and comparison of morbidity and local recurrence rates with the control group. RESULTS: At a median follow-up of 39 months, 47 patients were alive and 39 had died. Local recurrence at the resection site was diagnosed in 9 patients (10%), of which 7 occurred in patients with involved margins and 2 in patients with resection margin less than 1 cm. Thirty-six patients (42%) experienced recurrence in the remnant liver. Extrahepatic recurrence occurred in 38 patients (44%), the lungs being the most common site (22 patients [26%]). CONCLUSIONS: Edge cryotherapy is a potent additional surgical treatment option in patients with liver metastases from colorectal cancer. The percentage of patients who can be treated for cure can be increased, especially if complex liver surgery is demanded.
Adult↗
Hepatic arterial and intravenous administration of 1,25-dihydroxyvitamin D3--evidence of a clinically significant hepatic first-pass effect.
PURPOSE: We have previously shown that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits the proliferation of a number of human cancers, including colorectal and hepatocellular carcinoma, both of which affect the liver and are major causes of cancer death. However, the clinical use of 1,25(OH)2D3 and analogues has been restricted by the development of hypercalcaemia upon systemic administration. We hypothesized that a clinically significant hepatic first-pass effect may exist upon the administration of 1,25(OH)2D3 as a hepatic arterial infusion, and that such an effect may allow high levels of 1,25(OH)2D3 to be delivered to the liver whilst avoiding high systemic levels. METHODS: To examine this hypothesis, two groups of Landrace pigs were given identical doses of 1,25(OH)2D3 as continuous infusions, one group systemically, the other as a hepatic arterial infusion. Serum levels of 1,25(OH)2D3, calcium, phosphate and a number of liver and kidney function tests were performed regularly. RESULTS: Concentrations of 1,25(OH)2D3 and calcium remained normal in the hepatic arterial infusion animals, in contrast to the intravenous infusion animals which developed elevated levels of 1,25(OH)2D3 and hypercalcaemia. Hepatic arterial infusion of 1,25(OH)2D3 did not produce any adverse effects upon renal or hepatic function. CONCLUSION: The present findings support the existence of a clinically significant hepatic first-pass effect when 1,25(OH)2D3 is administered as a continuous hepatic arterial infusion. Hepatic arterial infusion of 1,25(OH)2D3 has great potential in the treatment of hepatic cancers.
Alanine Transaminase↗
Recurrent symptoms: well-being and management.
Although most older adults report one or more symptoms of a chronic health problem, little attention has been paid to the report of these symptoms over time and whether different symptom patterns affect well-being and symptom management in community-dwelling elders. Therefore, this study examined whether community-dwelling older adults in Ohio, U.S.A. who experience consistently recurring (a) arthritis or (b) cardiopulmonary symptoms report more depression and worse self-assessed health and show more symptom management than those who report inconsistent symptoms and if there are differences in well-being and symptom management over time. This secondary analysis used longitudinal data collected from a random sample of 387 older adults who reported their health complaints in four interviews over 27 months time. Subjects were included in this analysis if they reported either arthritis (n = 321) or cardiopulmonary (n = 232) symptoms at one or more times during 27 months, and then were classified as having either consistent (occurring at all four time points) or intermittent/inconsistent (occurring at three or fewer time points) symptoms. Data analysis included t-tests, chi-square tests, and Repeated Measures ANOVA. Results indicate that those with consistent symptoms reported greater depression and worse self-assessed health than those with less consistent symptoms. Specifically, those with consistent cardiopulmonary symptoms became more depressed over time. Those with consistent cardiopulmonary complaints were more likely than those with an inconsistent pattern to use an illness label to describe their symptoms. Those with consistent arthritis symptoms tended to use more self-care at all time points, to label their symptoms as an illness, and were more likely to consult a physician as their symptoms persisted. The implications of symptom recurrence on well-being, symptom management and the concept chronicity are discussed.
Aged↗
A method for measuring potency of narasin extracts using near-IR spectroscopy.
We present a method for extracting the active component from granulated narasin samples using chloroform with subsequent quantitation by near-infrared absorption spectroscopy (NIRS). A multiple linear regression (MLR) calibration equation was developed using a set of 41 calibration samples. The potencies obtained using NIR analysis exhibit no larger than an 8% (3.03 mg/g) error when compared to results based on the primary HPLC reference method. We estimate the detection limit using this method to be 400 ppm narasin (20 mg/g potency), and the standard deviation for five independent extractions of the same sample is approximately 24 ppm (approximately 1.2 mg/g potency or approximately 1%). We also present the results from a robustness study based upon a full factorial experimental design in which we varied extraction and measurement parameters. This study indicates that sample mass causes the most variation in the results. Bottle-to-bottle variations in the chloroform used for the extraction also proved significant. Variations in sample batch, number of spectral scans, and the interactions between sample hatch*soneration time, no. Scans*time in NIR, and sample batch*sample mass were borderline significant.
Calibration↗
Concordance of stroke symptom onset time. The Second Delay in Accessing Stroke Healthcare (DASH II) Study.
PURPOSE: This study examines the concordance between symptom onset obtained during an interview in the emergency department (ED) compared to that recorded in the medical record among patients with stroke-like symptoms and characterizes the frequency of missing symptom onset information in the medical record. METHODS: Interviews with patients presenting with signs and symptoms of acute stroke were completed in the ED of seven hospitals to determine symptom onset time. Symptom onset recorded in the medical record was abstracted after the patient was discharged. RESULTS: Among the patients who presented to the ED with stroke-like symptoms, 60.2% overall and 61.9% among stroke patients had a symptom onset date and time recorded in the medical record. The Pearson correlation of prehospital delay time, comparing symptom onset obtained by interview to that obtained by the medical record was 0.80 and among stroke patients was 0.91. Concordance of prehospital delay time for stroke within +/- 1 h between the interview and the medical record was 60.1%. For stroke patients, concordance was more likely for those who had higher functional status prior to the acute episode. CONCLUSIONS: Symptom onset time was often missing from the medical record. Standardized and systematic recording of delay time in the medical record could increase its utility as a clinical measure and as a research tool for acute stroke.
Adult↗
Chronic rhinosinusitis.
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Antifungal Agents↗
Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA.
The major histocompatibility complex (MHC) class I homolog, MICA, is a stress-inducible ligand for NKG2D, a C-type lectin-like activating immunoreceptor. The crystal structure of this ligand-receptor complex that we report here reveals an NKG2D homodimer bound to a MICA monomer in an interaction that is analogous to that seen in T cell receptor-MHC class I protein complexes. Similar surfaces on each NKG2D monomer interact with different surfaces on either the alpha1 or alpha2 domains of MICA. The binding interactions are large in area and highly complementary. The central section of the alpha2-domain helix, disordered in the structure of MICA alone, is ordered in the complex and forms part of the NKG2D interface. The extensive flexibility of the interdomain linker of MICA is shown by its altered conformation when crystallized alone or in complex with NKG2D.
Amino Acid Sequence↗
1alpha,25-Dihydroxyvitamin D3 and its analogues, EB1089 and CB1093, profoundly inhibit the in vitro proliferation of the human hepatoblastoma cell line HepG2.
BACKGROUND: 1alpha,25-dihydroxyvitamin D3 (1,25[OH]2D3) has been shown to inhibit the proliferation of various cancer cells including colon, prostate, melanoma, osteosarcoma and breast cancer. METHODS: The human hepatoma cell line (HepG2) was cultured with 1,25(OH)2D3 or one of two analogues EB1089 or CB1093 for various durations. Cellular proliferation was measured by uptake of [3H]thymidine, and cell numbers were determined by trypan blue exclusion counting. RESULTS: 1,25(OH)2D3, EB1089 and CB1093 all inhibited proliferation of HepG2 by up to 90% after 5 days of treatment, compared to the untreated controls. Decreased proliferation was associated with an approximately 50% reduction in cell numbers at concentrations of up to 10(-10) mol/L after 5 days of treatment with 1,25(OH)2D3. Cell proliferation rapidly recovered in cultures treated with lower concentrations of 1,25(OH)2D3 (10(-10) and 10(-11) mol/L) when 1,25(OH)2D3 was removed from the cultures by placing cells in serum containing medium without 1,25(OH)2D3. When HepG2 cells were treated with 10(-8) mol/L 1,25(OH)2D3 for 5 weeks, there was still significant inhibition of proliferation, although at week 5 there was 66% inhibition compared to 93% at the end of week 1. CONCLUSIONS: 1,25(OH)2D3, EB1089 and CB1093 all significantly inhibit the proliferation of HepG2 hepatoblastoma cells, with EB1089 being the most potent at lower concentrations. Inhibition can be maintained for at least 4 weeks, but is reversed after removal of vitamin D3.
Antineoplastic Agents↗
A phase one study of the hepatic arterial administration of 1,25-dihydroxyvitamin D3 for liver cancers.
BACKGROUND AND AIMS: It is well established that exposure to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits the proliferation of human colorectal cancer and hepatoma cell lines, both in vitro and in vivo. However, clinical trials of the administration of 1,25(OH)2D3 and analogs for the treatment of malignancy have been limited by the development of hypercalcemia. 1,25-dihydroxyvitamin D3 is principally excreted in bile following hepatic catabolism. This suggested the hypothesis that hepatic regional administration may allow high doses of 1,25(OH)2D3 to be administered for the treatment of liver cancers without producing hypercalcemia, caused by a clinically significant first pass effect. This phase one study investigates the effect of hepatic regional administration of 1,25(OH)2D3 on serum calcium levels, together with other markers of renal and liver function. METHODS: Six subjects with hepatic colorectal cancer metastases and one with primary hepatocellular cancer were given continuous hepatic arterial infusions of 1,25(OH)2D3, for periods of 1-4 weeks. Blood samples were taken regularly and assayed for calcium levels, liver function tests and urea and electrolyte levels. RESULTS: Patients remained normocalcemic at dosages of up to 10 mcg/day. No patient experienced any side-effects from the treatment. CONCLUSIONS: Administration of 1,25(OH)2D3 as a continuous hepatic arterial infusion allows a high dosage to be administered without inducing hypercalcemia. This route of administration may allow the potential of 1,25(OH)2D3 in the treatment of hepatic cancers to be realized.
Adult↗
Morphological transformation of Syrian hamster embryo cells at pH 6.7 by bemitradine, a nongenotoxic carcinogen.
Bemitradine is a compound that was intended for use as a diuretic antihypertensive drug. In the preclinical safety assays, it was found to be nongenotoxic in five in vitro assays (Ames, mouse lymphoma, CHO/HGPRT, CHO chromosome aberration, and UDS) and in one in vivo assay (mouse bone marrow micronucleus). In a subsequent long-term bioassay using Sprague-Dawley rats, this compound was found to be a rodent carcinogen at multiple sites. Because of the carcinogenicity, further development of this compound as a drug was halted. Because the Syrian hamster embryo (SHE) cell transformation assay at pH 6.7 has been demonstrated to be a good predictor of carcinogenic activity in animals, this nongenotoxic compound was used to determine if this in vitro assay system could be utilized to predict the potential for the carcinogenicity in rodents. The SHE cell transformation assay was validated initially for use in this laboratory using genotoxic and nongenotoxic carcinogens including benzo(a)pyrene, 20-methylcholanthrene, 2-acetylaminofluorene, methapyrilene, and phenobarbital. Each of these chemicals induced a statistically significant increase in morphological transformation frequency. Bemitradine was initially tested in a range-finding cytotoxicity assay at 10-250 microg/mL for treatment periods of 7 days. Doses used in the 7-day treatment transformation assay were 1.25, 2.5, 5.0, 7.5, and 10.0 microg/mL. Statistically significant increases in morphological transformation frequencies were observed at 1.25, 2.5, and 7.5 microg/mL, indicating a positive response. The experiment was repeated with similar results confirming the previous conclusion. These data provide additional evidence that the pH 6.7 SHE cell transformation assay may be a valuable in vitro tool to detect nongenotoxic rodent carcinogens.
Animals↗
Emergency department management of patients with seizures: a multicenter study.
OBJECTIVES: Patients with seizure disorders are common in the emergency department (ED), yet little is known regarding the management of these patients. This study was performed to define the frequency of patients with seizure disorders in the ED patient population and to determine possible seizure etiologies, characteristics of diagnostic activities, treatments, and dispositions. METHODS: Twelve EDs monitored all patients with a chief complaint related to seizure disorders presenting over 18.25 days (5% of the calendar year) in late 1997. Retrospective chart review was used to gather specific data regarding these consecutive cases. RESULTS: Of the 31,508 patients who presented to these 12 EDs during the study period, 368 (1.2%) had complaints related to seizures. Three hundred sixty-two charts were available for analysis and make up the study population. Two hundred fifty-seven (71%) utilized emergency medical services (EMS) for transport and care. Advanced care, including intravenous access, laboratory work, cardiac monitoring, or oxygen administration, was utilized in 304 (84%) patients. Antiepileptic drugs were given in 199 (55%) patients. Ethanol withdrawal or low antiepileptic drug levels were implicated as contributing factors in 177 (49%) of patients. New-onset seizures were thought to be present in 94 (26%) patients. Status epilepticus occurred in only 21 (6%) patients. Ninety-eight (27%) of all patients were admitted to the hospital. CONCLUSIONS: Patients with presenting complaints related to seizures are frequent in the ED population and make considerable demands on EMS and ED resources. Six percent of patients with seizure-related presentations were in status epilepticus and more than a fourth of all patients required hospitalization.
Adolescent↗
Inflammatory bowel disease and laterality: is left handedness a risk?
BACKGROUND: Left handedness has been associated with inflammatory bowel disease (IBD) and autoimmune diseases. AIMS: To determine whether left handedness is associated with IBD in two prospective national birth cohorts. METHODS: Subjects with Crohn's disease (CD) and ulcerative colitis (UC) were identified from two national longitudinal birth cohorts at age 26 years (1970 British Cohort Study (BCS70), born in 1970) and age 33 years (National Child Development Study (NCDS), born in 1958). Laterality was determined at age 10 (BCS70) or seven (NCDS) years, based on hand preference for writing and foot preference for kicking a ball (BCS70 only). Multiple logistic regression was used to assess the relationship of handedness with CD, UC, and IBD in the cohorts combined and adjusted for sex. RESULTS: Both cohorts combined showed increased adjusted relative odds of 2.13 (95% confidence interval (CI) 0.97--4.65; p=0.059), 2.13 (95% CI 0.92--4.91; p=0. 077), and 2.13 (95% CI 1.20--3.78; p=0.010) for CD, UC, and IBD, respectively in left handers. CONCLUSIONS: The study suggests a link between IBD and left handedness which may be genetic and/or environmental in origin.
Adult↗
Prehospital and in-hospital delays in acute stroke care.
Current guidelines emphasize the need for early stroke care. However, significant delays occur during both the prehospital and in-hospital phases of care, making many patients ineligible for stroke therapies. The purpose of this study was to systematically review and summarize the existing scientific literature reporting prehospital and in-hospital stroke delay times in order to assist future delivery of effective interventions to reduce delay time and to raise several key issues which future studies should consider. A comprehensive search was performed to find all published journal articles which reported on the prehospital or in-hospital delay time for stroke, including intervention studies. Since 1981, at least 48 unique reports of prehospital delay time for patients with stroke, transient ischemic attack, or stroke-like symptoms were published from 17 different countries. In the majority of studies which reported median delay times, the median time from symptom onset to arrival in the emergency department was between 3 and 6 h. The in-hospital times from emergency department arrival to being seen by an emergency department physician, initiation and interpretation of a computed tomography (CT) scan, and being seen by a neurologist were consistently longer than recommended. However, prehospital delay comprised the majority of time from symptom onset to potential treatment. Definitions and methodologies differed across studies, making direct comparisons difficult. This review suggests that the majority of stroke patients are unlikely to arrive at the emergency department and receive a diagnostic evaluation in under 3 h. Further studies of stroke delay and corresponding interventions are needed, with careful attention to definitions and methodologies.
Brain↗
Pilot study of albendazole in patients with advanced malignancy. Effect on serum tumor markers/high incidence of neutropenia.
Our preclinical studies have shown that the widely used antiparasitic drug albendazole has potent antiproliferative activity against colorectal cancer (CRC) and hepatocellular carcinoma (HCC). This trial was designed to evaluate albendazole in a small number of patients (n = 7) with either HCC or CRC and hepatic metastases refractory to other forms of therapy. Albendazole was given at 10 mg/kg/day orally in two divided doses for a period of 28 days. To follow the effect of treatment, tumor markers, carcinoembryonic antigen (CEA) or alpha-feto protein (AFP), were measured routinely in these patients. A range of hematological and biochemical indices were also serially measured to monitor bone marrow, kidney or liver toxicity. Albendazole therapy resulted in a decrease in CEA in 2 patients. In the remaining 5 with measurable tumor markers, serum CEA or AFP was stabilized in 3 patients, while in the other 2, after an initial stabilization (5-10 days), the markers began to increase. In the 7 patients completing the trial, albendazole was well tolerated and there were no significant changes in any hematological, kidney or liver function tests, but 3 patients were withdrawn for severe neutropenia which was probably contributory to the death of 1 patient. These data support our previous experimental results demonstrating that albendazole has antitumor effects.
Adult↗
Addressing Healthy People 2010 objectives for stroke.
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Emergency Treatment↗
Characteristics of an Albumin Cobalt Binding Test for assessment of acute coronary syndrome patients: a multicenter study.
BACKGROUND: The ability of the N-terminal region of human albumin to bind cobalt is diminished by myocardial ischemia. The characteristics of an assay based on albumin cobalt binding were assessed in suspected acute coronary syndrome patients and in a control reference population. The ability of the Albumin Cobalt Binding (ACB) Test measurement at presentation to predict troponin-positive or -negative results 6-24 h later was also examined. METHODS: We enrolled 256 acute coronary syndrome patients at four medical centers. Blood specimens were collected at presentation and then 6-24 h later. The dichotomous decision limit and performance characteristics of the ACB Test for predicting troponin-positive or -negative status 6 h-24 h later were determined using ROC curve analysis. Results for 32 patients could not be used because the time of onset of ischemia appeared to have been >3 h before presentation or was uncertain. The reference interval was determined by parametric analysis to estimate the upper 95th percentile of a reference population (n = 109) of ostensibly healthy individuals. RESULTS: Increased cTnI was found in 35 of 224 patients. The ROC curve area for the ACB Test was 0.78 [95% confidence interval (CI), 0.70-0.86]. At the optimum decision point of 75 units/mL, the sensitivity and specificity of the ACB Test were 83% (95% CI, 66-93%) and 69% (95% CI, 62-76%). The negative predictive value was 96% (95% CI, 91-98%), and the positive predictive value was 33% (95% CI, 24-44%). The within-run CV of the ACB Test was 7.3%. Results for the reference population were normally distributed; the one-sided parametric 95th percentile was 80.2 units/mL. CONCLUSIONS: This exploratory study suggests that the ACB Test has high negative predictive value and sensitivity in the presentation sample for predicting troponin-negative or -positive results 6-24 h later.
Acute Disease↗