Low-dose nonenhanced head CT protocol for follow-up evaluation of children with ventriculoperitoneal shunt: reduction of radiation and effect on image quality.

BACKGROUND AND PURPOSE: Children with a shunt for hydrocephalus often undergo multiple follow-up head CT scans, increasing the risk for long-term effects of ionizing radiation. The purpose of our study was to evaluate if an unenhanced low-dose head CT could consistently provide acceptable image quality and diagnostic information. MATERIALS AND METHODS: Ninety-two children (mean age, 9 years; range, 8 months to 21 years; 45 boys and 47 girls) with a shunt for hydrocephalus and no clinical evidence of shunt malfunction who were referred for a follow-up nonenhanced head CT were included in the study. All studies were performed on a 4-section multidetector CT. Two CT studies were selected retrospectively for each patient, 1 performed at standard dose (220 mA) and 1 at low dose (80 mAs). Two radiologists independently evaluated and graded both standard-dose and low-dose studies for various image quality parameters. Attenuation and noise levels were measured, and gray-white differentiation and contrast-to-noise ratio (CNR) were calculated. RESULTS: Low-dose CT resulted in 63% mean dose reduction. All low-dose CT scans were diagnostically acceptable. Image quality parameters were significantly lower at low dose (P = .0001) except for the parameters for streak artifacts (P = .46) and need for further imaging (P = .47), which were higher. Mean noise levels were significantly higher (P = .001) in low-dose studies, whereas CNR was significantly higher in standard dose CT (P = .001). A moderate to perfect agreement was noted between the 2 readers with regard to image quality assessment (65%-99%). CONCLUSION: Low-dose nonenhanced head CT consistently provides diagnostically acceptable images with relevant diagnostic information in children with VP shunts resulting in substantial dose savings.

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.

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.

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.

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.

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.

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.

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.

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.

Safety and optimum concentration of a manganese chloride-based oral MR contrast agent.

To determine the safety of a manganese chloride-based oral magnetic resonance (MR) contrast agent and the ideal concentration of the agent for marking in three different anatomic sites (stomach, middle of the small bowel, and ileocecal region), six healthy volunteers were evaluated before and after administration of 900 mL of three different concentrations of the contrast agent. Images were evaluated subjectively and objectively. No adverse events were noted. There was a minimal rise in manganese blood levels at 6 hours after administration, with a return to baseline at 24 hours. The imaging data demonstrated good-to-excellent bowel marking on T1-weighted images at all three concentrations. However, on T2-weighted images, the 40 mg Mn+2/L concentration provided improved hypointense bowel marking relative to the 20 mg/L concentration. Little difference was seen between the 40 and 60 mg/L concentrations. Fast T1- and T2-weighted sequences provided superior image quality to that of conventional spin-echo sequences.

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)

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.

Does CTAP prior to hepatic resection improve patient survival rates?

The purpose of our study was to compare survival rates of colon carcinoma patients who had undergone attempted curative hepatic resection based on liver staging by computed tomographic angiography (CTA) or portography (CTAP) with previously reported survival rates of patients who underwent similar surgery without preoperative CTAP evaluations. A total of 404 CTAP studies performed at three institutions were reviewed. Of this group, 197 had colon carcinoma. Sixty-nine of the colon patients went to surgery. Actuarial adjusted yearly survival rates were calculated for the prior CTAP colon group and compared to historical controls. The control survival data were taken from reports published prior to the CTAP era. Our study demonstrated no difference in the 1-year survival data between the groups. However, the CTAP patients had greater survival in years 2-4. This greater survival may be multifactorial but in part due to better surgical selection caused by CTAP.

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.

Enhancement effects of a hepatocyte receptor-specific MR contrast agent in an animal model.

The enhancement characteristics of the liver and spleen produced by a hepatocyte-specific magnetic resonance imaging agent, an arabinogalactan-coated ultrasmall superparamagnetic iron oxide derivative, BMS 180550, were evaluated. Both heavily T1- and T2-weighted sequences were used. Imaging was performed in the farm pig model, as a function of contrast agent concentration (5, 10, and 20 mumol of iron per kilogram) and delay (immediate, 0.5, 2.5, 5.0, 7.5, and 9.0 hours) after bolus injection of BMS 180550. BMS 180550 provided excellent contrast enhancement characteristics by producing marked positive enhancement with T1-weighted sequences and marked negative enhancement with T2-weighted sequences. The T1-weighted enhancement immediately after contrast agent injection was of greater magnitude in the spleen (329% +/- 83) than in the liver (66% +/- 16). Postcontrast negative enhancement with T2-weighted sequences was largely hepatocyte specific at 5 and 10 mumol/kg but was also seen within the spleen at 20 mumol/kg. The authors discuss the possible mechanisms that produce these changes and conclude that 10 mumol/kg BMS 180550 is near the optimum dose for maximizing the enhancement properties of this agent with all sequences in the farm pig.