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Biomedical subjects

W C Small

Publications and source records attributed to W C Small.

At least 19 recordsLinked to original sources
PubMed2000

Multicentre dose-ranging study on the efficacy of USPIO ferumoxtran-10 for liver MR imaging.

AIM: A dose ranging multicentre phase-II clinical trial was conducted to evaluate the efficacy of ultrasmall superparamagnetic iron oxide (USPIO) ferumoxtran-10 for magnetic resonance (MR) imaging of focal hepatic lesions. MATERIAL AND METHODS: Ninety-nine patients with focal liver lesions received USPIO at a dose of 0.8 (n = 35), 1.1 (n = 32), or 1.7 (n = 32) mg Fe/kg. Liver MR imaging was performed before and after USPIO with T1-weighted and T2-weighted pulse sequences. Images were analysed by two independent readers for additional information (lesion detection, exclusion, characterization and patient management). Signal intensity (SI) based quantitative measurements were also taken. RESULTS: Post-contrast medium MR imaging showed additional information in 71/97 patients (73%) for reader one and 83/96 patients (86%) for reader two. The results with all three doses were statistically significant (P < 0.05). Signal intensity analysis revealed that all three doses increased liver SI on T1-weighted images and decreased liver SI on T2-weighted images. On T2-weighted images metastases increased in contrast relative to normal hepatic parenchyma whereas haemangiomas decreased in contrast. On T2-weighted images there was statistically improved efficacy at the intermediate dose, which did not improve at the highest dose. CONCLUSION: Ultrasmall superparamagnetic iron oxide was an effective contrast agent for liver MR imaging at all doses and a dose of 1.1 mg Fe/kg was recommended for future clinical trials.

Adult↗
PubMed1999

Safety profile of ultrasmall superparamagnetic iron oxide ferumoxtran-10: phase II clinical trial data.

The safety data from the phase II clinical trial of ferumoxtran-10, an ultrasmall superparamagnetic iron oxide contrast agent, are presented. One hundred and four patients with focal liver or spleen pathologies underwent ferumoxtran-10-enhanced magnetic resonance (MR) imaging at doses of 0.8, 1.1, and 1.7 mg Fe/kg. Overall, 15% patients reported a total of 33 adverse events, regardless of causality. The adverse events most frequently seen were dyspnea (3.8%), chest pain (2.9%), and rash (2.9%). No serious adverse events were reported during the 48 hour observation period. There were no clinically significant effects on vital signs, physical examination, and laboratory results. Ferumoxtran-10 is a safe and well tolerated MR contrast agent.

Contrast Media↗
PubMed1999

A multisite phase III study of the safety and efficacy of a new manganese chloride-based gastrointestinal contrast agent for MRI of the abdomen and pelvis.

The purpose of this study was to evaluate the safety and efficacy of a manganese chloride-based oral magnetic resonance (MR) contrast agent during a Phase III multisite clinical trial. Two hundred seventeen patients were enrolled who were already scheduled for MRI of the abdomen and/or pelvis. In this group of patients, it was postulated that the use of an oral agent would better allow discrimination of pathology from bowel. Patients with known gastrointestinal pathology including peptic ulcer disease, inflammatory bowel disease, obstruction, or perforation were excluded to minimize confounding variables that could affect the safety assessment. Of these 217 patients, 18 received up to 900 mL of placebo, and 199 patients were given up to 900 mL of a manganese chloride-based oral contrast agent, LumenHance (Bracco Diagnostics, Inc.). Safety was determined by comparing pre- and post-dose physical examinations, vital signs, and laboratory examinations and by documenting adverse events. Efficacy was assessed by unblinded site investigators and two blinded reviewers who compared pre- and post-dose T1- and T2-weighted MRI scans of the abdomen and/or pelvis. In 111 (57%) of the 195 cases evaluated for efficacy by site investigators (unblinded readers), MRI after LumenHance provided additional diagnostic information. Increased information was found by two blinded readers in 52% and 51% of patients, respectively. In 44/195 cases (23%) unblinded readers felt the additional information would have changed patient diagnosis and in 50 patients (26%), it would have changed management and/or therapy. Potential changes in patient diagnosis or management/therapy were seen by the two blinded readers in 8-20% of patients. No clinically significant post-dose laboratory changes were seen. Forty-eight patients (24%) receiving LumenHance and four patients (22%) receiving placebo experienced one or more adverse events. Gastrointestinal tract side effects were most common, seen in 29 (15%) of LumenHance patients and in 3 (17%) of the placebo patients. LumenHance is a safe and efficacious oral gastrointestinal contrast agent for MRI of the abdomen and pelvis.

Abdomen↗
PubMed1998

Identification of a cytosolically directed NADH dehydrogenase in mitochondria of Saccharomyces cerevisiae.

The reoxidation of NADH generated in reactions within the mitochondrial matrix of Saccharomyces cerevisiae is catalyzed by an NADH dehydrogenase designated Ndi1p (C. A. M. Marres, S. de Vries, and L. A. Grivell, Eur. J. Biochem. 195:857-862, 1991). Gene disruption analysis was used to examine possible metabolic functions of two proteins encoded by open reading frames having significant primary sequence similarity to Ndi1p. Disruption of the gene designated NDH1 results in a threefold reduction in total mitochondrial NADH dehydrogenase activity in cells cultivated with glucose and in a fourfold reduction in the respiration of isolated mitochondria with NADH as the substrate. Thus, Ndh1p appears to be a mitochondrial dehydrogenase capable of using exogenous NADH. Disruption of a closely related gene designated NDH2 has no effect on these properties. Growth phenotype analyses suggest that the external NADH dehydrogenase activity of Ndh1p is important for optimum cellular growth with a number of nonfermentable carbon sources, including ethanol. Codisruption of NDH1 and genes encoding malate dehydrogenases essentially eliminates growth on nonfermentable carbon sources, suggesting that the external mitochondrial NADH dehydrogenase and the malate-aspartate shuttle may both contribute to reoxidation of cytosolic NADH under these growth conditions.

Amino Acid Sequence↗
PubMed1997

Metabolic effects of altering redundant targeting signals for yeast mitochondrial malate dehydrogenase.

Eukaryotic cells contain highly homologous isozymes of malate dehydrogenase which catalyze the same reaction in different cellular compartments. To examine whether the metabolic functions of these isozymes are interchangeable, we have altered the cellular localization of mitochondrial malate dehydrogenase (MDH1) in yeast. Since a previous study showed that removal of the targeting presequence from MDH1 does not prevent mitochondrial import in vivo, we tested the role of a putative cryptic targeting sequence near the amino terminus of the mature polypeptide. Three residues in this region were changed to residues present in analogous positions in the other two yeast MDH isozymes. Alone, these replacements did not affect activity or localization of MDH1 but, in combination with deletion of the presequence, prevented mitochondrial import in vivo. Measurable levels of the resulting cytosolic form of MDH1 were low with expression from a centromere-based plasmid but were comparable to normal cellular levels with expression from a multicopy plasmid. The cytosolic form of MDH1 restored the ability of a deltaMDH1 disruption strain to grow on ethanol or acetate, suggesting that mitochondrial localization of MDH1 is not essential for its function in the TCA cycle. This TCA cycle function observed for the cytosolic form of MDH1 is unique to that isozyme since overexpression of MDH2 and of a cytosolic form of MDH3 in a deltaMDH1 strain failed to restore growth. Finally, only partial restoration of growth of a deltaMDH2 disruption mutant was attained with the cytosolic form of MDH1, suggesting that MDH2 may also have unique metabolic functions.

Amino Acid Sequence↗
PubMed1997

Differentiation of liver hemangiomas from metastases and hepatocellular carcinoma at MR imaging enhanced with blood-pool contrast agent Code-7227.

PURPOSE: To evaluate differentiation of liver lesions at magnetic resonance (MR) imaging enhanced with Code-7227. MATERIALS AND METHODS: Thirty-five patients with 38 proved liver lesions (15 hemangiomas, 17 metastases, six hepatocellular carcinomas [HCCs]) underwent T1-weighted gradient-echo and T2-weighted fast-spin-echo MR imaging at 1.5 T before and after intravenous administration of Code-7227 (1.1 mg iron per kilogram of body weight). RESULTS: In hemangiomas, the mean contrast-to-noise ratio on precontrast and postcontrast images, respectively, increased from -4.51 +/- 4.7 (standard deviation) to 5.19 +/- 6.3 on T1-weighted images and decreased from 14.73 +/- 7.4 to 0.64 +/- 5.1 on T2-weighted images. In comparison, metastases remained hypointense to liver on T1-weighted images (from -5.77 +/- 5.9 to -7.8 +/- 6.8) and hyperintense on T2-weighted images (from 8.73 +/- 5.4 to 12.61 +/- 6.1). Although HCC enhanced more than metastases, they also remained hypointense to liver on T1-weighted images (from -4.87 +/- 6.1 to -1.79 +/- 5.7) and hyperintense on T2-weighted images (from 10.12 +/- 7.9 to 8.7 +/- 6.4). The degree of enhancement on T1-weighted images and of signal intensity drop on T2-weighted images were significantly lower in malignant liver masses than in hemangiomas (P < .001). CONCLUSION: Distinctly different enhancement patterns with Code-7227 helped accurate differentiation of liver lesions.

Adult↗
PubMed1995

Enzymatic and metabolic studies on retrograde regulation mutants of yeast.

Two nuclear genes, RTG1 and RTG2, which sense the functional state of yeast mitochondria, have been described recently. Yeast strains with null alleles of either of these two genes (delta rtg1, delta rtg2) cannot grow on acetate as the sole carbon source and are auxotrophic for glutamate and aspartate. We report here a series of metabolic experiments and enzyme activity measurements that were made in an attempt to determine the reason for the acetate- phenotype and the glutamate/aspartate auxotrophy. Decreases in the activities (approximately 50%) in mitochondrial citrate synthase (CS1), acetyl-CoA synthetase, NAD isocitrate dehydrogenase, and pyruvate carboxylase were noted. When CS1 was overexpressed in the delta rtg1 and delta rtg2 mutants, these strains could grow on acetate but were still auxotrophic for glutamate/aspartate. We propose that, in the mutant strain, CS1 activity becomes limiting for efficient acetate utilization, but that other complex metabolic interactions are affected, limiting production of intermediates that would allow synthesis of glutamic and aspartic acids.

Acetate-CoA Ligase↗
PubMed1995

Case report: haemangiopericytoma of the oesophagus.

Haemangiopericytomas are rare, vascular soft tissue sarcomas typically located in the retroperitoneum, pelvis or lower extremities. To our knowledge this neoplasm within the oesophagus has not been reported previously. We present a patient with a haemangiopericytoma of the oesophagus and discuss the radiographic and pathological findings.

Aged↗
PubMed1994

Metabolic studies on Saccharomyces cerevisiae containing fused citrate synthase/malate dehydrogenase.

We have constructed two different fusion proteins consisting of the C-terminal end of CS1 fused in-frame to the N-terminal end of MDH1 and HSA, respectively. The fusion proteins were expressed in mutants of Saccharomyces cerevisiae in which CS1 and MDH1 had been deleted and the phenotypes of the transformants characterized. The results show that the fusion proteins are transported into the mitochondria and that they restore the ability for the yeast mutants CS1-, MDH1-, and CS1-/MDH1- to grow on acetate. Determination of CS1 activity in isolated mitochondria showed a 10-fold increase for the strain that expressed native CS1, relative to the parental. In the transformant with CS1/MDH1 fusion protein, parental levels of CS1 were observed, while one-fifth this amount was observed for the strain expressing the CS1/HSA conjugate. Oxygen consumption studies on isolated mitochondria did not show any significant differences between parental-type yeast and the strains expressing the different fusion proteins or native CS1. [3(-13)C]Propionate was used to study the Krebs TCA cycle metabolism of yeast cells containing CS1/MDH1 fusion constructs. The 13C NMR study was performed in respiratory-competent parental yeast cells and using the genetically engineered yeast cells consisting of CS1- mutants expressing native CS1 and the fusion proteins CS1/MDH1 and CS1/HSA, respectively. [3(-13)C]Propionate is believed to be metabolized to [2(-13)C]succinyl-CoA before it enters the TCA cycle in the mitochondria. This metabolite is then oxidized through two symmetrical intermediates, succinate and fumarate, followed by conversion to malate, oxalacetate, and other metabolites such as alanine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1994

Preparation and kinetic characterization of a fusion protein of yeast mitochondrial citrate synthase and malate dehydrogenase.

We have expressed the DNA of the fusion of CS1 to MDH1 in Escherichia coli gltA-. The fusion protein (CS1/MDH1) is the C-terminus of CS1 linked in-frame to the N-terminus of MDH1 with a short linker of glycyl-seryl-glycyl. The fusion protein produced was isolated and purified. Gel filtration studies indicated that CS1/MDH1 had a M(r) of approximately 170,000. Western blotting analysis with SDS gel indicated a M(r) of approximately 90,000-95,000 (theoretical M(r) = 87,000). This is the expected M(r) for the fusion protein subunit. The kinetics of CS1 and MDH1 activities of the fusion protein were compared to those of the free enzymes. In addition, the effect of AAT reaction, as a competitor for the intermediate OAA of the coupled MDH-CS reaction, was examined. It was observed that AAT was a less effective competitor for OAA when the CS1/MDH1 fusion protein is used than when the separate enzymes are employed. In addition, the transient time for the coupled reaction sequence was less for the fusion protein than for the free enzymes.

Aspartate Aminotransferases↗
PubMed1994

Contrast-enhanced spiral CT of the liver: effect of different amounts and injection rates of contrast material on early contrast enhancement.

OBJECTIVE: Spiral CT allows rapid hepatic imaging during a single breath-hold. The increase in imaging speed potentially allows contrast material to be used more efficaciously than with conventional dynamic CT, perhaps allowing a decrease in the volume of required contrast agent. To determine how this can be accomplished, we studied the effect of different bolus IV injection rates and amounts of contrast material on early hepatic enhancement during dynamic bolus spiral CT. SUBJECTS AND METHODS: A group of 20 healthy male volunteers were divided into four groups of five each. The groups received 75, 100, 125, or 150 ml of contrast material (Omnipaque 300, 300 mg l/ml). Each person within each group was scanned as contrast material was injected at rates of 3, 4, and 5 ml/sec. Hepatic enhancement was evaluated by comparing quantitative regions of interest before and after bolus injection of contrast material. Variations in enhancement produced by changes in volume and injection rate of contrast material were evaluated on early, middle, and late sections of the spiral, corresponding to 32-34, 41-43, and 51-53 sec, respectively, after the injection of contrast material was begun. RESULTS: Hepatic enhancement increased more rapidly when the bolus of contrast material was given at a rate of 5 ml/sec than at the slower rates of 3 or 4 ml/sec. Enhancement of the liver was greatest at the late portion of the spiral (51-53 sec after start of the bolus injection), averaging 73 and 79 H for volumes of 125 and 150 ml, respectively, at 5 ml/sec, and the enhancement was still increasing at that time. Enhancement curves predict 50- and 70-H mean increases in hepatic attenuation on initial slices with scan delays of approximately 40 and 50 sec, respectively, for these two protocols. CONCLUSION: Our results demonstrate that there is a marked dependence on early hepatic enhancement produced by variations in volume and injection rate of contrast material. We found no difference in the results produced by 125- and 150-ml volumes. These results are important for maximizing the effectiveness of IV contrast material during rapid hepatic spiral CT scanning.

Adult↗
PubMed1993

Dual contrast enhancement of both T1- and T2-weighted sequences using ultrasmall superparamagnetic iron oxide.

BMS 180549 (previously AMI-227), an ultrasmall superparamagnetic iron particulate agent, was investigated to determine its utility as a contrast agent on T1-weighted, as well as T2-weighted sequences, as a function of route of administration, (intravenous versus selective arterial) and concentration. Twelve farm pigs were divided into three groups of four each by route of administration (intravenous, selective superior mesenteric, or selective hepatic arterial injection). 10 mumol/kg and 20 mumol/kg dosages were given and evaluated both immediately after and 20-24 hr after contrast infusion, using both spin-echo and gradient-echo T1 and T2-weighted sequences. Significant postcontrast liver and spleen enhancement was noted at both concentrations, regardless of route of administration on both T1- and T2-weighted sequences. The earliest postcontrast T1-weighted sequence obtained during the 1-3 min interval following IV administration of high dose (20 mumol/kg) contrast demonstrated an average of +42.8% liver and +249.0% spleen enhancement; 24 hr later this decreased to 0 and 7.2%, respectively. The earliest postcontrast T2-weighted sequence obtained during the 8-17 min interval post high-dose IV contrast showed an average of -75.8% decrease in liver and -28.7% decrease in spleen signal intensity; 24 hr later the magnitude of these changes diminished to -33.1% and +2.5%, respectively. No significant difference was noted in liver or spleen enhancement, regardless of route of contrast administration (intravenous versus intraarterial).

Animals↗
PubMed1993

Preoperative determination of the resectability of hepatic tumors: efficacy of CT during arterial portography.

OBJECTIVE: A multiinstitutional study was performed to evaluate the efficacy of CT during arterial portography for determining the resectability of hepatic tumors. The impact of findings from CT during arterial portography on patients' treatment (i.e., surgical vs nonsurgical) was assessed. In patients considered to have resectable tumors, the accuracy of CT during arterial portography for predicting surgical findings was also evaluated. MATERIALS AND METHODS: A retrospective study was done of 404 patients from three institutions who had CT during arterial portography during the period 1985-1991 as part of preoperative staging to determine the resectability of hepatic tumors. The tumors included metastases from colorectal carcinoma in 197 patients (49%); other hepatic metastases, mostly from adenocarcinoma of the stomach, pancreas, and biliary tree in 123 (30%); and primary hepatocellular carcinoma in 84 (21%). Imaging results were correlated with results of percutaneous biopsy of at least one hepatic lesion in patients whose tumors were considered unresectable. In patients whose tumors were considered resectable, results were correlated with preoperative percutaneous biopsy (obtained in almost all cases) and pathologic examination of a surgical specimen (all cases). Although each case was considered individually, four criteria were used for resectability: (1) accessibility of all lesions to lobar or wedge resection that would yield clear margins, (2) anticipation that residual liver tissue after resection would provide sufficient function, (3) the absence of invasion of central hepatic vascular or biliary structures, and (4) the absence of extrahepatic disease. No specific restriction was made with respect to the number of hepatic lesions present. The accuracy of findings by CT during arterial portography for predicting resectability was assessed in the 146 patients who had tumors that were considered resectable on the basis of imaging findings and had surgery. RESULTS: Of 404 patients, only 146 (36%) were thought to be candidates for resection on the basis of findings from CT during arterial portography. Of these, 122 (84%) actually had resection. The 24 patients who did not have resection included 22 patients with disease understaged or overstaged by CT during arterial portography, one with true-negative findings by CT during arterial portography, and one who died during surgery. The accuracy of findings by CT during arterial portography for predicting results at surgery was 85% for all patients and 91% for the subset of patients who had primary colorectal tumors with hepatic metastases. CONCLUSION: Our experience shows that CT during arterial portography is a useful procedure for assessing the resectability of hepatic tumors. In our study, 64% of patients were spared unnecessary surgery.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinoma↗