Identification of an argpyrimidine-modified protein in human red blood cells from schizophrenic patients: A possible biomarker for diseases involving carbonyl stress.

Argpyrimidine (ARP) is an advanced glycation end product thought to be generated from a reaction between methylglyoxal and arginine residues in proteins. In this study, we observed marked accumulation of an approximately 56 kD protein, reactive to anti-ARP antibodies, in the red blood cells (RBCs) of some patients with refractory schizophrenia. This ARP-modified protein was purified from the blood of schizophrenic patients and identified as selenium binding protein 1 (SBP1) by LC-MS/MS. This is the first report of ARP-modified proteins accumulating in RBCs of patients with diseases involving carbonyl stress. We also observed high accumulation of ARP-modified SBP1 in the RBCs of patients with chronic kidney disease. Therefore, this modified protein may be a novel marker of carbonyl stress.

Employment status among non-retired cancer survivors in Japan.

Employed cancer patients confront some challenges as they attempt to return to work after treatment. We aimed to identify correlates of return to work for cancer survivors in Japan, with an emphasis on employment status. Participants were 260 patients (aged <65 years) who had received a cancer diagnosis ≥ 1 year previously and who were employed at the time of diagnosis. Participants completed questionnaires at consultations at any Regional Cancer Center Hospitals in Yamagata, Japan between 28 November 2011 and 9 December 2011. Logistic regression analysis was used to identify correlates of return to work. Data cross-tabulation was used to evaluate relationships to workplace and income-changes by employment status. A high proportion of patients (75.8%) had returned to work. Non-regularly employed survivors were less likely to return to work (odds ratio = 5.03; 95% confidence interval, 1.18-21.35). Individuals with poor health, advanced-stage tumours, of advanced age and women were significantly less likely to return to work. Only 52.8% of non-regular employees continued to be employed, and their income decreased by as much as 61.1%. Social and financial support policies should be organised based on more intensive study of employment circumstances.

Cystatin C as an index of cerebral small vessel disease: results of a cross-sectional study in community-based Japanese elderly.

BACKGROUND AND PURPOSE: Recent studies have shown that kidney dysfunction is associated with cerebral small vessel disease (SVD). Although creatinine-based estimating equations have been used as the standard measure for the evaluation of kidney function, the accuracy of these is limited in the elderly because of muscle mass decrease with aging. Cystatin C is a more useful measurement than creatinine-based estimating equations for evaluating kidney function, however, the relationship amongst cystatin C, cognitive dysfunction, and cerebral SVD has not been fully examined in community-based elderly. METHODS: We performed a cross-sectional study using MRI to determine the relationship amongst cystatin C, cognitive function, and cerebral SVD in a total of 604 community-based Japanese elderly. RESULTS: In this study, subjects with higher cystatin C levels tended to have more lacunas and higher grades of white matter lesions. Although a decline of the Mini-Mental State Examination (MMSE) scores was associated with SVD-related lesions, the relationship between the tertiles of cystatin C and mean MMSE scores was not statistically significant. In the logistic regression analysis, the association between cystatin C and SVD-related lesions was statistically significant, even after adjustment for conventional risk factors and high-sensitivity C-reactive protein. Furthermore, subjects with higher cystatin C levels accompanied with albuminuria had a greater risk for the presence of subclinical cerebral SVD than those with lower cystatin C levels without albuminuria. CONCLUSIONS: The present study suggests that there is a close relationship between cystatin C and subclinical cerebral SVD, independently of conventional risk factors, in community-based elderly.

Loss of heterozygosity at 11p15 in malignant glioma.

Deletions of loci on chromosome 11p have been found frequently in several malignant tumors including gliomas, suggesting the presence of tumor suppressor genes. We analyzed 38 gliomas [26 malignant gliomas (grades III and IV) and 12 less malignant gliomas (grade I and II)] for loss of heterozygosity using microsatellite sequences on 11p as polymorphic markers. Loss of heterozygosity was found in 8 of 26 malignant gliomas (31%) but not in the less malignant gliomas. In the region with loss of heterozygosity, loci on 11p15.5-pter were commonly deleted. Our results suggest that a putative tumor suppressor gene involved in malignant progression of gliomas is located in an approximately 21-cM region on 11p15.5-pter.

IGF2 but not H19 shows loss of imprinting in human glioma.

Genomic imprinting is a gamete-specific modification resulting in the allele-specific expression of genes in somatic cells. A loss of imprinting (LOI) has been found in many embryonal and adult tumors, suggesting that it plays a role in tumor development. The incidence of LOI, however, does not seem to be ubiquitous among tumors because neuroblastoma and colorectal cancer revealed no LOI. We examined the involvement of LOI of IGF2 and H19 genes in human gliomas. The two genes were imprinted in normal brain subcortex tissues. In glioma, 8 of 14 informative cases (57%) revealed LOI in IGF2. The frequency did not depend on the tumor grade. For H19, in contrast, all 13 informative cases maintained imprinting. These results suggest that LOI of IGF2 but not H19 plays a role in the development of human glioma.

Wall Enhancement of the Intracranial Aneurysms Revealed by Magnetic Resonance Vessel Wall Imaging Using Three-Dimensional Turbo Spin-Echo Sequence with Motion-Sensitized Driven-Equilibrium: A Sign of Ruptured Aneurysm?

PURPOSE: Wall enhancement of saccular cerebral aneurysms has not been researched sufficiently. Our purpose of this study was to investigate the incidence of aneurysmal wall enhancement by the three-dimensional turbo spin-echo sequence with motion-sensitized driven equilibrium (MSDE-3D-TSE) imaging after gadolinium injection. METHODS: We retrospectively reviewed the pre- and postcontrast MSDE-3D-TSE images of 117 consecutive patients with intracranial aneurysms from September 2011 to July 2013. A total of 61 ruptured and 83 unruptured aneurysms of 61 patients with subarachnoid hemorrhage (SAH) and 56 non-SAH patients were enrolled in this study. We evaluated the wall enhancement of each aneurysm on postcontrast MSDE-3D-TSE images compared with precontrast images. We classified the aneurysmal wall enhancement into three groups as "Strong enhancement," "Faint enhancement," and "No enhancement." RESULTS: "Strong/Faint enhancement" of the aneurysm was detected in 73.8/24.6 % of the ruptured aneurysms and 4.8/13.3 % of the unruptured aneurysms. "No enhancement" was found in 1.6 % of the ruptured aneurysms and 81.9 % of the unruptured aneurysms. CONCLUSIONS: By magnetic resonance vessel wall imaging using the MSDE-3D-TSE sequence, wall enhancement was frequently observed on ruptured aneurysms. Therefore, aneurysmal wall enhancement may be an indicator of the ruptured condition, which is useful information for managing patients with SAH.

Development of C6⁺ laser ion source and RFQ linac for carbon ion radiotherapy.

A prototype C(6+) injector using a laser ion source has been developed for a compact synchrotron dedicated to carbon ion radiotherapy. The injector consists of a laser ion source and a 4-vane radio-frequency quadrupole (RFQ) linac. Ion beams are extracted from plasma and directly injected into the RFQ. A solenoid guides the low-energy beams into the RFQ. The RFQ is designed to accelerate high-intensity pulsed beams. A structure of monolithic vanes and cavities is adopted to reduce its power consumption. In beam acceleration tests, a solenoidal magnetic field set between the laser ion source and the RFQ helped increase both the peak currents before and after the RFQ by a factor of 4.

Amplification of alpha-platelet-derived growth factor receptor gene lacking an exon coding for a portion of the extracellular region in a primary brain tumor of glial origin.

In a primary brain tumor of glial origin, we found overexpression of the alpha-platelet-derived growth factor (alpha-PDGF) receptor mRNA. Southern blot analysis of the gene revealed amplification of the rearranged alpha-PDGF receptor gene in the glioma. A cDNA coding for an aberrant transcript from the amplified receptor gene was obtained and characterized. Partial nucleotide sequence analysis of the cDNA revealed a deletion of 243 nucleotides coding for 81 amino acids in a portion of the immunoglobulin-like domains of the extracellular region of the receptor. cDNA polymerase chain reaction (PCR) of the total cellular RNA in the glioma indicated that more than 80% of the transcripts have a deletion of 243 nucleotides. Analysis of a PCR-amplified DNA fragment derived from the amplified alpha-PDGF receptor gene in the glioma revealed that an exon coding for the 81 amino acids was removed by a 2.1 kb gene deletion. We also found amplification of the alpha-PDGF receptor gene in macroscopically normal cortex adjacent to the glioma from the same patient. The amplified gene in the macroscopically normal cortex has no major gene deletion, suggesting that gene amplification is not sufficient for the development of malignant gliomas.

Lateral and medial medullary infarction: a comparative analysis of 214 patients.

BACKGROUND AND PURPOSE: No large-scale study has ever compared the clinical and radiological features of lateral medullary infarction (LMI) and medial medullary infarction (MMI). The aim of this study was to investigate them through the use of cooperatively collected cases. METHODS: Medical information on all patients from 1996 to 2000 with medullary infarction (MI) proven by brain MR images at 35 stroke centers in the Tohoku district, Japan, was collected, and their clinical and radiological features were analyzed. RESULTS: A total of 214 cases of MI were registered. They included 167 cases (78%) of LMI, 41 (19%) of MMI, and 6 (3%) of LMI plus MMI. The mean age of onset and the male-to-female ratio were 60.7 years and 2.7:1 in LMI and 65.0 years and 3.6:1 in MMI, respectively. The middle medulla was most frequently affected in LMI, and the upper medulla was most frequently affected in MMI. Dissection of the vertebral artery was observed in 29% of LMI and 21% of MMI. Prognosis, assessed by the Barthel Index, was favorable in both LMI and MMI. Diabetes mellitus was more frequently associated with MMI than with LMI. CONCLUSIONS: The present study surveyed a large number of MI cases and revealed that (1) the mean age of onset of MMI is higher than that of LMI, (2) the dissection of the vertebral artery is an important cause not only of LMI but also of MMI, and (3) diabetes mellitus is frequently associated with MMI.

Thyroxine 5-deiodinase in human brain tumors.

To determine whether human brains contain deiodinating pathways, we studied the activity of T4 5-monodeiodinase (5-D) in 20 human brain tumors obtained intraoperatively, including astrocytoma (10), meningioma (4), oligodendroglioma (2), glioblastoma (2), medulloblastoma (1), and malignant lymphoma (1). Mitochondrial-microsomal fractions prepared from these tumor tissues were used as the source of T4 5-D. Each sample was incubated with 32.2 nmol/L T4 and 30 mmol/L dithiothreitol at 37 C for 90 min. T4 5-D activity was measured by the production of rT3 from T4 with a RIA. T4 5-D activity was found in 6 of 10 astrocytomas, 2 oligodendrogliomas, 1 of 2 glioblastomas, and 1 malignant lymphoma. This activity depended on protein concentration, incubation time, incubation temperature, and pH of the incubation mixture. It was also heat labile. T4 5-D was not inhibited by 1 mmol/L propylthiouracil, but was inhibited by iopanoic acid and aurothioglucose in a dose-dependent manner. The apparent Km and maximum velocity for T4 5-D at 30 mmol/L dithiothreitol were 106.6 nmol/L and 22.7 pmol/mg protein.h, respectively. These data suggest that human gliomas (and probably malignant lymphomas) contain T4 5-D activity, which is similar to type III enzyme activity in the rat. T4 5-D may regulate the intracellular concentration of thyroid hormone in gliomas.

Methylated cytosine level in human liver DNA does not decline in aging process.

In order to ascertain a generality of the age-dependent decrease in DNA methylation level among different mammalian species, methylated cytosine contents in human liver and spleen DNA at different ages have been determined using high performance liquid chromatography (HPLC). Unexpectedly, the liver DNA revealed no appreciable decline with age while the spleen DNA showed a slight reduction. It indicates that a decrease of methylation level in genomic DNA is not a common denominator of age-related changes in mammals.

Production and secretion of adrenomedullin from glial cell tumors and its effects on cAMP production.

The expression of adrenomedullin (ADM) and its mRNA was studied in human glial cell tumors and cultured glioblastoma cell lines, T98G and A172. Northern blot analysis showed that ADM mRNA was expressed in all brain tumors examined (three anaplastic astrocytomas and two glioblastomas multiforme) and in the glioblastoma cell lines. Immunoreactive (IR-) ADM was detectable in these brain tumors by radioimmunoassay (0.31-2.0 pmol/g wet weight), except for one anaplastic astrocytoma. Reverse phase high performance liquid chromatography of the tumor extracts showed a single peak eluting in the position of ADM-(1-52). IR-ADM concentrations in the cultured media of T98G cells were 205.5 +/- 8.4 fmol/10(5) cells/24 h (mean +/- SEM, n = 5). Treatment of T98G cells with interferon gamma or interleukin 1 beta increased the expression levels of ADM mRNA and the IR-ADM concentrations in the cultured media, whereas tumor necrosis factor alpha decreased them in a dose-dependent manner. Treatment with synthetic ADM-(1-52) (10(-8) or 10(-7) mol/l) increased the cAMP concentrations in the cultured media of T98G cells. These findings suggest that ADM is secreted from glial cell tumors and is related to the pathophysiology of these tumors.

Three-dimensional and ultrastructural ICAM-1 distribution in the choroid plexus, arachnoid membrane and dural sinus of inflammatory rats induced by LPS injection in the lateral ventricles.

To investigate immunological environment in the cerebrospinal fluid (CSF) system, ultrastructural and three-dimensional localization of intercellular adhesion molecule-1 (ICAM-1) was studied in the choroid plexus, arachnoid membrane and dural sinus of LPS-stimulated rats with immuno-SEM and TEM. The choroid plexus epithelial cells expressed rich ICAM-1 along the microvilli. The arachnoid trabeculae fibroblast-like cells demonstrated ICAM-1 expression on both sides facing the subarachnoid space moderately. The dural sinus endothelial cells, however, showed only few ICAM-1 expression and no specific localization. These results suggest that the choroid plexus and arachnoid membrane may play an important mutual role for leukocyte migration in the CSF system, and that the CSF system may function in immunoreaction independently of the vascular system with the aid of up-regulated ICAM-1 expression.

Spin trapping agent, phenyl N-tert-butylnitrone, reduces nitric oxide production in the rat brain during experimental meningitis.

Phenyl N-tert-butylnitrone (PBN) is a spin trapping agent previously shown to exert a neuroprotective effect in infant rat brain during bacterial meningitis. In the present study, we investigated the effect of systemic PBN administration on nitric oxide (NO) production in a rat model of experimental meningitis induced by lipopolysaccharide (LPS). We assessed the NO concentration in rat brain tissues with an electron paramagnetic resonance (EPR) NO trapping technique. In this model, rats receiving intracisternal LPS administration showed symptoms of meningitis and cerebrospinal fluid (CSF) pleocytosis. The time course study indicated that the concentration of NO in the brain reached the maximum level 8.5 h after injection of LPS, and returned to the control level 24 h after the injection. When various doses of PBN (125-400 mg/kg) were injected intraperitoneally 30 min prior to LPS, NO production in the brain was reduced with increasing PBN dose (250 mg/kg suppressed 80% at 8.5 h after LPS injection), and white blood cells (WBC) in CSF were significantly decreased. We concluded that reduction of NO generation during bacterial meningitis contributes to the neuroprotective effect of PBN in addition to its possible direct scavenging of reactive oxygen intermediate (ROI).

Edema along the optic tract: a useful MR finding for the diagnosis of craniopharyngiomas.

BACKGROUND AND PURPOSE: The pattern of edema caused by craniopharyngiomas and other common suprasellar masses could be useful for determining the differential diagnosis of lesions in this region. The purpose of this study was to ascertain whether the pattern of edema spread on MR images can be used in the diagnosis of craniopharyngiomas. METHODS: The preoperative MR images in eight consecutive patients with craniopharyngiomas, 15 patients with large pituitary adenomas compressing the optic chiasm, and six patients with tuberculum sellae meningiomas were evaluated. All the patients were treated surgically at our hospital and a pathologic diagnosis was obtained. We analyzed the spread of edema surrounding the tumor on the coronal dual-echo fast spin-echo images and compared this finding with tumor location and size as seen on contrast-enhanced T1-weighted images. RESULTS: Not only peritumoral edema but also edema spreading along the optic tracts was observed in five patients with craniopharyngiomas, one of whom also had edema within one optic nerve. The location of edema in the visual pathway was not always associated with the degree of visual disturbance. None of the patients with large pituitary adenomas or with tuberculum sellae meningiomas had such edema along the visual pathway. CONCLUSION: Edema caused by craniopharyngiomas tends to spread along the optic tracts. It is a useful MR finding for distinguishing craniopharyngiomas from other common parasellar tumors.

Noninvasive evaluation of malignancy of brain tumors with proton MR spectroscopy.

PURPOSE: To test clinical proton MR spectroscopy as a noninvasive method for predicting tumor malignancy. METHODS: Water-suppressed single-voxel point resolved spectroscopy in the frontal white matter of 17 healthy volunteers and 25 patients with brain tumors yielded spectra with peaks of N-acetyl aspartate (NAA), choline-containing compounds (Cho), creatine/phosphocreatine (Cre), and lactate. These peak intensities were semiquantitated as a ratio to that of the external reference. The validity of the semiquantitation was first evaluated through phantom and volunteer experiments. RESULTS: The variation in measurements of the designated region in the volunteers was less than 10%. Normal ranges of NAA/reference, Cho/reference, and Cre/reference were 3.59 +/- 0.68, 1.96 +/- 0.66, and 1.53 +/- 0.64 (mean +/- SD), respectively. In 17 gliomas, the Cho/reference value in high-grade gliomas was significantly higher than in low-grade gliomas. Levels of NAA/reference were also significantly different in low-grade and high-grade malignancy. In eight meningiomas (four newly diagnosed and four recurrent), the level of Cho/reference was significantly higher in recurrent meningiomas than in normal white matter or in newly diagnosed meningiomas. CONCLUSIONS: Higher grades of brain tumors in this study were associated with higher Cho/reference and lower NAA/reference values. These results suggest that clinical proton MR spectroscopy may help predict tumor malignancy.

Multilobulated cystic formation in the brain stem with Benedikt's syndrome: case report.

A 26-year-old man presented with an unusual multilobulated cystic formation in the brain stem with normal pressure hydrocephalus, followed by fluctuating cyst volume and Benedikt's syndrome. Ventriculoperitoneal shunting to relieve the hydrocephalus caused an increased cystic size, resulting in worsened neurological deficits. Cystectomy and an additional shunt resolved the symptoms. Immunohistochemical and electron microscopic examinations of the surgical specimen revealed no epithelial lining but numerous astrocytic processes on the luminal surface, probably resulting from expansion of the cyst. This case suggests that cystectomy before shunt emplacement is recommended in similar cases.

Huge multilobular cavernous angioma in an infant: case report.

The authors encountered a rare case of multilobular cavernous angioma arising from the paraventricular region in an infant. Total resection of the angioma, which was 8 cm in diameter, was performed. The patient showed no neurological deficit. Although 22 cases in infants have previously been reported, this is the largest cavernous angioma and it is especially rare because of its multilobular configuration.

Subarachnoid hemorrhage of unknown cause.

After the institution of computed tomography (CT), 814 cases of spontaneous subarachnoid hemorrhage (SAH) were treated during a period of 6 years and 9 months (April 1978 through December 1984). In 9 (22.0%) of 41 patients whose cause of SAH was not determined by the first four-vessel study (cerebral panangiography), ruptured aneurysms were found by repeated four-vessel study. Thus, of 814 cases, only 32 (3.9%) were diagnosed as cases of unknown etiology at discharge. The 32 cases were monitored by follow-up examination for 5 to 67 months (median, 27.1 months) after onset. No recurrence of SAH was reported, and all patients were rehabilitated except 2 who suffered terminal carcinoma. A third follow-up four-vessel study was performed 8 to 44 months (median, 22.0 months) after the second study in 14 of the 16 patients with SAH initially demonstrated by CT. In 1 of these cases, an aneurysm found 9 months after the initial SAH was treated surgically. Ultimately, 31 cases (3.8%) were diagnosed as cases of SAH of unknown cause. This incidence is low when compared with those in previous reports. Because of the strict examination schedule including repeated angiography, the incidence is lower and the prognosis is relatively favorable.

Magnetic resonance imaging of titanium anterior cervical spine plating systems.

Magnetic resonance imaging (MRI) of titanium anterior cervical plating systems and their effect on postoperative images were evaluated ex vivo and in vivo. The Synthes and Caspar plating systems were examined by 0.5- or 1.5-T MRI scanners. A phantom study of these implants showed that in spin-echo modes, the plates and screws were seen as areas of signal loss accompanying a marginal hyperintense band, which was more obvious in higher tesla magnetic fields. Distortion of the magnetic field was more prominent in T2-weighted images. In gradient echo mode, the plate and screws were seen as areas of signal loss larger than the size of the metal because of the magnetic susceptibility effect. Postoperative MRI produced images of the implants similar to those observed ex vivo. The Synthes plating system did not interfere with the evaluation of the spinal cord, and the Caspar screw (which penetrated the posterior cortex of the vertebral body) caused a small artifact to be present at the anterior aspect of the spinal cord. In addition to being able to provide fixation of the cervical spine, titanium anterior cervical plates allow superior MRI of the postoperative spine.