Anterior mediastinal solid tumours in adults: characterisation using dynamic contrast-enhanced MRI, diffusion-weighted MRI, and FDG-PET/CT.

AIM: To find significant parameters to characterise anterior mediastinal solid tumours in adults using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), diffusion-weighted MRI (DWI), and combined 2-[(18)F]-fluoro-2-deoxy-d-glucose positron-emission tomography/computed tomography (FDG-PET/CT). MATERIALS AND METHODS: Forty-eight histologically confirmed anterior mediastinal solid tumours in 48 patients (24 men, 24 women; age range 21-83 years, mean 50.7 years) were examined. The parameters analysed were maximal diameter, presence of capsule/septa on T2-weighted images, time-signal intensity curves (TICs), apparent diffusion coefficient (ADC), and maximum standardised uptake value (SUVmax). Also examined was whether any differences between histological types could be seen in these parameters. In a validation study, 42 anterior mediastinal solid tumours in 42 patients were examined consecutively. RESULTS: The washout pattern on TIC was seen only in thymic epithelial tumours (20/32). SUVmax of lymphoma (mean, 17.9), malignant germ cell tumours (14.2), and thymic carcinomas (15.6) were significantly higher than that of thymomas (6.1). The mean maximal diameter of thymic epithelial tumours was significantly smaller than that of lymphomas (p<0.01) and malignant germ cell tumours (p<0.05). The validation study also yielded high accuracy (38/42, 91%) in differentiation among the anterior mediastinal solid tumours. CONCLUSION: The SUVmax, TIC pattern on DCE-MRI, and maximal diameter might be useful to differentiate anterior mediastinal solid tumours in adults.

Changes of the apparent diffusion coefficient in brain diffusion-weighted images due to subject positioning: A simulation study.

BACKGROUND AND PURPOSE: The purpose of this work was to investigate whether the cortical apparent diffusion coefficient (ADC) values derived from brain diffusion-weighted images vary with changes in the position of the subject against a static magnetic field. MATERIALS AND METHODS: To focus on the variations in ADC due to the change of subject positioning, a simulation was performed using a digital brain phantom. The magnetic field inhomogeneities in the digital phantom were calculated for each subject position while changing the angle between the direction of the static field and the head of the digital phantom. The angle was changed from 0 to 40 degrees at 10-degree intervals. For each angle, the diffusion-weighted images were simulated based on magnetic resonance physics in which the magnetic field inhomogeneity was taken into account. The relative differences of average ADC values between the tilt angles were calculated to evaluate the variations in ADC. The Wilcoxon rank-sum test was used for comparisons of ADC values between the tilt angles for each cortical region. RESULTS: In the cortical regions distorted by magnetic field inhomogeneities, the average ADC values differed significantly according to the position of the subject (P < 0.05). The range of the relative differences in average ADC values in relation to the differences in subject positioning was approximately 1% to 12%. CONCLUSION: Our results suggest that subject positioning against a static field is one of the factors affecting the accuracy of cortical ADC measurements derived from brain diffusion-weighted images.

Evaluation of the extent of ground-glass opacity on high-resolution CT in patients with interstitial pneumonia associated with systemic sclerosis: comparison between quantitative and qualitative analysis.

AIM: To verify whether quantitative analysis of the extent of ground-glass opacity (GGO) on high-resolution computed tomography (HRCT) could show a stronger correlation with the therapeutic response of interstitial pneumonia (IP) associated with systemic sclerosis (SSc) compared with qualitative analysis. MATERIALS AND METHODS: Seventeen patients with IP associated with SSc received autologous peripheral blood stem cell transplantation (auto-PBSCT) and were followed up using HRCT and pulmonary function tests. Two thoracic radiologists assessed the extent of GGO on HRCT using a workstation. Therapeutic effect was assessed using the change of vital capacity (VC) and diffusing capacity of the lung for carbon monoxide (DLco) before and 12 months after PBSCT. Interobserver agreement was assessed using Spearman's rank correlation coefficient and the Bland-Altman method. Correlation with the therapeutic response between quantitative and qualitative analysis was assessed with Pearson's correlation coefficients. RESULTS: Spearman's rank correlation coefficient showed good agreement, but Bland-Altman plots showed that proportional error could be suspected. Quantitative analysis showed stronger correlation than the qualitative analysis based on the relationships between the change in extent of GGO and VC, and change in extent of GGO and DLco. CONCLUSION: Quantitative analysis of the change in extent of GGO showed stronger correlation with the therapeutic response of IP with SSc after auto-PBSCT than with the qualitative analysis.

Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter.

Primary systemic carnitine deficiency (SCD; OMIM 212140) is an autosomal recessive disorder characterized by progressive cardiomyopathy, skeletal myopathy, hypoglycaemia and hyperammonaemia. SCD has also been linked to sudden infant death syndrome. Membrane-physiological studies have suggested a defect of the carnitine transport system in the plasma membrane in SCD patients and in the mouse model, juvenile visceral steatosis. Although the responsible loci have been mapped in both human and mouse, the underlying gene has not yet been identified. Recently, we cloned and analysed the function of a novel transporter protein termed OCTN2. Our observation that OCTN2 has the ability to transport carnitine in a sodium-dependent manner prompted us to search for mutations in the gene encoding OCTN2, SLC22A5. Initially, we analysed the mouse gene and found a missense mutation in Slc22a5 in jvs mice. Biochemical analysis revealed that this mutation abrogates carnitine transport. Subsequent analysis of the human gene identified four mutations in three SCD pedigrees. Affected individuals in one family were homozygous for the deletion of a 113-bp region containing the start codon. In the second pedigree, the affected individual was shown to be a compound heterozygote for two mutations that cause a frameshift and a premature stop codon, respectively. In an affected individual belonging to a third family, we found a homozygous splice-site mutation also resulting in a premature stop codon. These mutations provide the first evidence that loss of OCTN2 function causes SCD.

Metabolism of cerebroside sulfate and subcellular distribution of its metabolites in cultured skin fibroblasts from controls, metachromatic leukodystrophy, and globoid cell leukodystrophy.

With pulse-chase study of 1-[14C]stearic acid-labeled cerebroside sulfate (14C-CS) and subsequent subcellular fractionation by Percoll gradient, the metabolism of CS and translocation of its metabolites in human skin fibroblasts from controls, metachromatic leukodystrophy (MLD), and globoid cell leukodystrophy (GLD) were studied. In control skin fibroblasts, CS was transported to lysosome and metabolized there to galactosylceramide (GalCer) and ceramide (Cer) within 1 h. During the chase period, radioactivity was increased at plasma membrane plus Golgi as phospholipids and no accumulation of GalCer or Cer was found in lysosome. In MLD fibroblasts, 95% of 14C-CS taken up was unhydrolyzed at 24 h-chase and accumulated at not only lysosome but also plasma membrane. In GLD fibroblasts, GalCer was accumulated throughout the subcellular fractions and more accumulated mainly at plasma membrane plus Golgi with longer pulse. This translocation of lipid from lysosome seems to have considerable function, even in lipidosis, which may result in an imbalance of the sphingolipid pattern on the cell surface and these changes might be one of causes of neuronal dysfunction in sphingolipidosis.

Kappa-chain gene rearrangement in an apparent T-lineage lymphoma.

We describe a 10-yr-old boy with T-lineage non-Hodgkin's lymphoma. He had a mediastinal mass, swollen supraclavicular lymph nodes, and pleural effusion. A supraclavicular lymph node biopsy under light microscopy showed a malignant lymphoma of diffuse lymphoblastic type. Most of the cells taken from the malignant pleural effusion expressed T cell-associated antigens such as Leu-1 and OKT 8. To confirm these antigens as T-lineage lymphoma, we examined genomic DNA from malignant cells obtained from the pleural effusion. As was expected, T cell receptor beta-chain gene rearrangements were demonstrated. However, when the immunoglobulin gene organization was analyzed, we detected rearrangements in both the heavy- and kappa-chain genes. To our knowledge, this is the first case in which kappa-chain gene rearrangement was detected in apparent T-lineage cells. These findings provide important information relating to determination of the cellular lineage of lymphoid malignancy.

Size and orientation of masticatory muscles in patients with mandibular laterognathism.

Size measurements of jaw muscles reflect their force capabilities and correlate with facial morphology. Using MRI, we examined the size and orientation of jaw muscles in patients with mandibular laterognathism in comparison with a control group. We hypothesized that the muscles of the deviated side would be smaller than those of the non-deviated side, and that the muscles of both sides would be smaller than in controls. In patients, a comparison of deviated and non-deviated sides showed, in orientation, differences for masseter and medial pterygoid muscles, but, in size, differences only for the masseter muscle. Nevertheless, muscle sizes in patients were much smaller than in controls. Lateral displacement of the mandible can explain the orientation differences, but not the smaller muscle size, in patients. It is possible that the laterodeviation initiates an adaptive process in the entire jaw system, resulting in extensive atrophy of the jaw muscles.

Low-dose CT screening using hybrid iterative reconstruction: confidence ratings of diagnoses of simulated lesions other than lung cancer.

OBJECTIVE: To evaluate the confidence ratings of diagnoses of simulated lesions other than lung cancer on low-dose screening CT with hybrid iterative reconstruction (IR). METHODS: Simulated lesions (emphysema, mediastinal masses and interstitial pneumonia) in a chest phantom were scanned by a 320-row area detector CT. The scans were performed by 64-row and 160-row helical scans at various dose levels and were reconstructed by filtered back projection (FBP) and IR. Emphysema, honeycombing and reticular opacity were visually scored on a four-point scale by six thoracic radiologists. The ground-glass opacity as a percentage of total lung volume (%GGO), CT value and contrast-to-noise ratio (CNR) of mediastinal masses were calculated. These scores and values were compared between FBP and IR. Wilcoxon's signed-rank test was used (p < 0.05). Interobserver agreements were evaluated by κ statistics. RESULTS: There were no significant differences in visual assessment. Interobserver agreement was almost perfect. CT values were almost equivalent between FBP and IR, whereas CNR with IR was significantly higher than that with FBP. %GGO significantly increased at low-dose levels with FBP; however, IR suppressed the elevation. CONCLUSION: The confidence ratings of diagnoses of simulated lesions other than lung cancer on low-dose CT screening were not degraded with hybrid IR compared with FBP. ADVANCES IN KNOWLEDGE: Hybrid IR did not degrade the confidence ratings of diagnoses on visual assessment and differential diagnoses based on CT value of mediastinal masses, and it showed the advantage of higher GGO conspicuity at low-dose level. Radiologists can analyse images of hybrid IR alone on low-dose CT screening for lung cancer.

Decreased nuclear uptake of 1,25-dihydroxyvitamin D3 by duodenal mucosal cells in the X-linked hypophosphatemic mouse.

We have shown that there is a significant decrease in the nuclear uptake of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] by duodenal mucosal cells in the X-linked hypophosphatemic (Hyp) mouse. Duodenal mucosal cells prepared from control and Hyp mice were incubated with 1,25(OH)2[26,27-methyl-3H]D3 ([3H]-1,25(OH)2D3) for 30 min. to evaluate the time-course and perform saturation analysis. The results of time-course studies showed that saturation was attained in 30 min., reaching an average nuclear uptake of 10.4 fmol/tube in the control mice and 6.1 fmol/tube in the Hyp mice. The results of Scatchard analyses were as follows: dissociation constant (Kd) 5.71 X 10(-10) M and maximal binding sites 7.31 X 10(4) sites/cell in the control mice, and Kd 2.92 X 10(-10) M and maximal binding sites 4.88 X 10(4) sites/cell in the Hyp mice, the maximal binding sites of the latter showed a significant decrease (P less than 0.05) by Student's t test. In addition, there was no significant difference in the binding of [3H]-1,25(OH)2D3 to its residual cytosol receptors between the control and Hyp mice. On the basis of these data, we speculate that the reported resistance of Hyp mice to vitamin D may be due to decreased nuclear uptake of 1,25(OH)2D3 by their duodenal mucosal cells.

Effect of 1,25-dihydroxyvitamin D3 on insulin secretion: direct or mediated?

In order to clarify the role of vitamin D (D) in regulating insulin secretion, we studied the effect of long term (10 days) and short term (3 days) supplementation with D and/or calcium (Ca) on insulin secretion from the isolated, perfused pancreas of D- and Ca-deficient rats. The influence of the nutritional state induced by D deficiency was also evaluated. The long term supplementation of either D, Ca, or both restored the body weight and improved insulin secretion induced by high glucose concentration to the same extent; thus, no significant difference in insulin secretion was found between the D-only-supplemented group and the Ca-only-supplemented group. When the insulin secretion was compared in D-deplete vs. D-replete rats given the same amount of Ca, insulin secretion was significantly higher in D-replete animals, although plasma Ca levels were also higher. In short term experiments, insulin release was significantly augmented to a similar extent in D- or Ca-replete rats as compared with D- and Ca-deficient rats, despite no significant change in body weight. In a separate experiment, the pancreas from D-deficient rats was perfused with or without 1,25-dihydroxyvitamin D3 [1,25-OH)2D3] to observe its acute effect on insulin release. The perfusion with 1,25-(OH)2D3 did not affect insulin release. This result suggests that impaired insulin secretion in D-deficient rats is caused by a decrease in Ca in the body fluid and possibly by the lack of D effect on the pancreas.

Effects of the administration of phosphate on nuclear 1,25-dihydroxyvitamin D3 uptake by duodenal mucosal cells of Hyp mice.

Effects of the administration of phosphate on nuclear 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] uptake by duodenal mucosal cells of Hyp mice were investigated. In Hyp mice fed a high phosphate diet (1.1% Ca and 2.0% phosphate) for 2 weeks, maximal nuclear 1,25-(OH)2D3 binding by duodenal mucosal cells is significantly increased from 5.01 +/- 0.49 x 10(3) to 8.23 +/- 1.10 x 10(3) sites/cell (P less than 0.05). No significant change was observed in normal mice fed the same diet. The serum phosphate concentration of Hyp mice increased significantly (P less than 0.01), whereas no significant change was found in normal mice. On this regimen, serum calcium, urinary cAMP to creatinine ratio, and cytosolic 1,25-(OH)2D3 receptor number in Hyp mice were not changed significantly. On the basis of these data, we speculate that the recovery of serum phosphate in Hyp mice fed a high phosphate diet affects the recovery of nuclear 1,25-(OH)2D3 uptake by duodenal mucosal cells. The mechanism for this recovery is not related to either the secondary hyperparathyroidism or the change in cytosolic 1,25-(OH)2D3 receptor content but, rather, to increased binding of 1,25-(OH)2D3-receptor complex to nuclei. Hypophosphatemia, therefore, appears to play a role in the vitamin D resistance in Hyp mice.

Effect of dibutyryl adenosine 3',5'-monophosphate administration on plasma concentrations of 1,25-dihydroxyvitamin D in pseudohypoparathyroidism type I.

The effect of dibutyryl cAMP on plasma concentrations of 1,25-dihydroxyvitamin D [1,25-(OH)2D] was studied in two patients with pseudohypoparathyroidism (PHP) type I, five normal adults, and three normal children as controls. In normal adults, plasma 1,25-(OH)2D tended to increase 3 h after the infusion of 2.5 mg/kg dbcAMP and was significantly increased after 6 h. In normal children, plasma 1,25-(OH)2D increased 3 h after the infusion, then gradually decreased; in the patients with PHP type I, it increased greatly from 6.8 and 11.2 pg/ml to 264.6 and 128.2 pg/ml 3 h after the infusion. These results suggest that the renal mechanism for the response to parathyroid hormone is intact distal to the renal adenylate cyclase in patients with PHP type I.

Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1.

cDNA for a novel proton/organic cation transporter, OCTN1, was cloned from human fetal liver and its transport activity was investigated. OCTN1 encodes a 551-amino acid protein with 11 transmembrane domains and one nucleotide binding site motif. It is strongly expressed in kidney, trachea, bone marrow and fetal liver and in several human cancer cell lines, but not in adult liver. When expressed in HEK293 cells, OCTN1 exhibited saturable and pH-dependent [3H]tetraethyl ammonium uptake with higher activity at neutral and alkaline pH than at acidic pH. Furthermore, treatment with metabolic inhibitors reduced the uptake, which is consistent with the presence of the nucleotide binding site sequence motif. Although its subcellular localization and detailed functional characteristics are not clear at present, OCTN1 appears to be a novel proton antiporter that functions for active secretion of cationic compounds across the renal epithelial brush-border membrane. It may play a role in the renal excretion of xenobiotics and their metabolites.

Prognostic value of electrically elicited blink reflex in neonates.

The electrically elicited blink reflex (BR) was evaluated in 80 normal neonates and 12 neonates with neurologic abnormalities. In normal subjects, R1 and bilateral R2 responses were elicited both while awake and in a quiet sleep state. Whereas the R1 response was consistently elicited in the active sleep state, as well as while awake, the ipsilateral R2 response was markedly suppressed and the contralateral R2 response was almost absent. The BR in neonates with neurologic abnormalities showed the following variable results: normal, prolonged latency, or suppressed response at initial recording. Abnormal BRs were detected in most neonates with respiratory or sucking problems. While neonates in whom a suppressed response or prolonged latency persisted for over three months had a poor prognosis, those with normal BRs or early correction of the BR abnormality had almost normal development. The BR appears to be useful not only to evaluate brain-stem function in the neonatal period but also to predict subsequent outcome.

Electronmicroscopy of conjunctival biopsy in mannosidosis.

Electronmicroscopic examination was performed on conjunctival biopsies from two adolescent siblings with mannosidosis. Fibroblasts and endothelial cells contained membrane-bound vacuoles and vesicles that contained homogeneous osmiophilic globules. These vesicles seem to be pathognomonic of mannosidosis. Plasma cells also contained membrane-bound vacuoles, suggesting inhibition of the immunoglobulin production.

Concomitant rearrangements of T-cell beta- and gamma-chain genes in childhood T-lineage leukemia/lymphoma.

Similar to the immunoglobulin (Ig) gene rearrangements in B-lineage cells, identification of T-cell receptor (TCR) gene rearrangements is a novel clonal marker and necessary to establish a T-cell lineage. The function of T-cell gamma-chain (T gamma) gene is still unknown, but because of its shared properties with T-cell alpha-chain (T alpha) and T beta genes, we analysed T gamma gene organization in 10 patients with T-lineage leukemia/lymphoma as well as in non-T lineage leukemias. All 10 cases of T-lineage leukemia/lymphoma, whose phenotypes were different, demonstrated T gamma gene rearrangements as well as T beta gene rearrangements. In contrast, among the non-T-lineage leukemias, the emergence of T beta and/or T gamma gene rearrangements was varied. Based on these findings, concomitant rearrangements of T beta and T gamma genes are characteristic in childhood T-lineage leukemia/lymphoma regardless of their phenotypic differences. Furthermore, no obvious developmental hierarchy was observed between T beta and T gamma gene arrangements in these leukemia/lymphoma cells.

Purification of an 80 kDa Ca2+-dependent actin-modulating protein, which severs actin filaments, from bovine adrenal medulla.

A protein with a molecular weight of 80 kDa, which binds Ca2+-dependently to actin, was purified chromatographically from bovine adrenal medulla by using Sephacryl S-300, DEAE-Sepharose, actin-DNase I Sepharose, and Sephacryl S-200. This protein was retained on an actin-DNase I affinity column only in the presence of Ca2+, and could be eluted from this column by EGTA. The 80 kDa protein is a monomer and binds to G-actin in a Ca2+-dependent manner at an equimolar ratio. It caused fragmentation of actin filaments at more than 4 X 10(-7) M free Ca2+ concentration, as determined by low-shear viscometry and electron microscopy. Saturating amounts of tropomyosin showed a slight protective effect on the fragmentation of actin filaments by the 80 kDa protein. Considering the mode of action on actin filaments, the 80 kDa protein reported here seems to be a gelsolin-like protein. Gel electrophoresis of this protein revealed changes in mobility depending upon the concentration of Ca2+. This result also indicates that the 80 kDa protein itself is a Ca2+-binding protein.

Topographic organization of the projection from the forebrain subcortical areas to the hippocampal formation of the rat.

Using the technique of iontophoretic microinjection of horseradish peroxidase, the present study disclosed the complexity and high degree of the topographic organization in the forebrain subcortical afferents to the different regions of rat hippocampus, e.g. diagonal band, posterior (PH), dorsomedial and rostral lateral hypothalamic nuclei chiefly project to the rostrodorsal part (DRA) and caudal gyrus dentatus including CA3, the supramammillary area predominantly to the rostroventral area (VRA), the area lateral to PH to the DRA and VRA, substantia innominata and some thalamic nuclei (n. reuniens, n. lateralis thalami, n. anterior ventralis and n. lateralis thalami pars posterior) to the dorsal subiculum, respectively.

Study of pathogenesis in twitcher mouse, an enzymatically authentic model of Krabbe's disease.

The twitcher mouse was investigated by examining in vivo synthesis of galactosylceramide (Galcer) and galactosylsphingosine (Galsph) in a sciatic nerve culture, and in vitro enzymic activities for synthesis of Galcer and Galsph in the spinal cord from normal and affected mice. For the in vivo study, the sciatic nerve was incubated for 24 h in medium containing [3H]galactose, or [3H]-sphingosine-labeled Galcer or Galsph. With [3H]galactose, reduced synthesis of Galcer was found as early as 1 week of age and synthesis decreased to about 15% of normal value at 4 weeks. Increased Galsph was detected after 7 days of feeding with galactose. In a study of [3H]sphingosine-labeled Galcer and Galsph feeding, Galcer did not induce Galsph synthesis in either normal or affected mice, and synthesis of Galcer from Galsph was found only in normal mice, suggesting that Galcer was synthesized from sphingosine after hydrolysis of Galsph. In vitro, the activities of UDP-galactose: ceramide galactosyltransferase and UDP-galactose: sphingosine galactosyltransferase were reduced to less than 50% of control after 2 weeks of age in affected mice. We conclude that (1) decreased Galcer was due to impaired synthesis of Galcer, (2) Galsph was synthesized from galactose and not from deacylation of Galcer, and (3) Galsph accumulation was due not to increased synthesis but to decreased hydrolysis.