Differentiation between Treatment-Induced Necrosis and Recurrent Tumors in Patients with Metastatic Brain Tumors: Comparison among 11C-Methionine-PET, FDG-PET, MR Permeability Imaging, and MRI-ADC-Preliminary Results.

BACKGROUND AND PURPOSE: In patients with metastatic brain tumors after gamma knife radiosurgery, the superiority of PET using 11C-methionine for differentiating radiation necrosis and recurrent tumors has been accepted. To evaluate the feasibility of MR permeability imaging, it was compared with PET using 11C-methionine, FDG-PET, and DWI for differentiating radiation necrosis from recurrent tumors. MATERIALS AND METHODS: The study analyzed 18 lesions from 15 patients with metastatic brain tumors who underwent gamma knife radiosurgery. Ten lesions were identified as recurrent tumors by an operation. In MR permeability imaging, the transfer constant between intra- and extravascular extracellular spaces (/minute), extravascular extracellular space, the transfer constant from the extravascular extracellular space to plasma (/minute), the initial area under the signal intensity-time curve, contrast-enhancement ratio, bolus arrival time (seconds), maximum slope of increase (millimole/second), and fractional plasma volume were calculated. ADC was also acquired. On both PET using 11C-methionine and FDG-PET, the ratio of the maximum standard uptake value of the lesion divided by the maximum standard uptake value of the symmetric site in the contralateral cerebral hemisphere was measured (11C-methionine ratio and FDG ratio, respectively). The receiver operating characteristic curve was used for analysis. RESULTS: The area under the receiver operating characteristic curve for differentiating radiation necrosis from recurrent tumors was the best for the 11C-methionine ratio (0.90) followed by the contrast-enhancement ratio (0.81), maximum slope of increase (millimole/second) (0.80), the initial area under the signal intensity-time curve (0.78), fractional plasma volume (0.76), bolus arrival time (seconds) (0.76), the transfer constant between intra- and extravascular extracellular spaces (/minute) (0.74), extravascular extracellular space (0.68), minimum ADC (0.60), the transfer constant from the extravascular extracellular space to plasma (/minute) (0.55), and the FDG-ratio (0.53). A significant difference in the 11C-methionine ratio (P < .01), contrast-enhancement ratio (P < .01), maximum slope of increase (millimole/second) (P < .05), and the initial area under the signal intensity-time curve (P < .05) was evident between radiation necrosis and recurrent tumor. CONCLUSIONS: The present study suggests that PET using 11C-methionine may be superior to MR permeability imaging, ADC, and FDG-PET for differentiating radiation necrosis from recurrent tumors after gamma knife radiosurgery for metastatic brain tumors.

On-ground detection of an electron-positron annihilation line from thunderclouds.

Thunderclouds can produce bremsstrahlung gamma-ray emission, and sometimes even positrons. At 00:27:00 (UT) on 13 January 2012, an intense burst of gamma rays from a thundercloud was detected by the GROWTH experiment, located in Japan, facing the Sea of Japan. The event started with a sharp gamma-ray flash with a duration of <300 ms coincident with an intracloud discharge, followed by a decaying longer gamma-ray emission lasting for ∼60 s. The spectrum of this prolonged emission reached ∼10 MeV, and contained a distinct line emission at 508±3(stat.)±5(sys.) keV, to be identified with an electron-positron annihilation line. The line was narrow within the instrumental energy resolution (∼80keV), and contained 520±50 photons which amounted to ∼10% of the total signal photons of 5340±190 detected over 0.1-10 MeV. As a result, the line equivalent width reached 280±40 keV, which implies a nontrivial result. The result suggests that a downward positron beam produced both the continuum and the line photons.

Hardening and termination of long-duration γ rays detected prior to lightning.

We report the first observation of 3-30 MeV prolonged gamma-ray emission that was abruptly terminated by lightning. The gamma-ray detection was made during winter thunderstorms on December 30, 2010, by the Gamma-Ray Observation of Winter Thunderclouds experiment carried out in a coastal area along the Sea of Japan. The gamma-ray flux lasted for less than 3 min, continuously hardening closer to the lightning occurrence. The hardening at energies of 3-10 MeV energies was most prominent. The gamma-ray flux abruptly ceased less than 800 ms before the lightning flash that occurred over 5 km away from the experimental site. In addition, we observed a clear difference in the duration of the 3-10 MeV gamma rays and those >10 MeV, suggesting that the area of >10 MeV gamma-ray emission is considerably smaller than that of the lower-energy gamma rays. This work may give a manifestation that a local region emitting prolonged gamma rays connects with a distant region to initiate lightning.

Detection of high-energy gamma rays from winter thunderclouds.

A report is made on a comprehensive observation of a burstlike gamma-ray emission from thunderclouds on the Sea of Japan, during strong thunderstorms on 6 January 2007. The detected emission, lasting for approximately 40 sec, preceded cloud-to-ground lightning discharges. The burst spectrum, extending to 10 MeV, can be interpreted as consisting of bremsstrahlung photons originating from relativistic electrons. This ground-based observation provides the first clear evidence that strong electric fields in thunderclouds can continuously accelerate electrons beyond 10 MeV prior to lightning discharges.

Interpersonal and intrapersonal variance of exponent of power function observed in grip strength task.

For grip strength there is a power function with an exponent of 1.7 between the subjective magnitude and the actual force exerted by a subject, but large variabilities among and within individuals were found. We focused on these variabilities and investigated the relationship between them by conducting a ratio production procedure requiring trials of maximum effort and half of maximum effort. For 30 adults we conducted four measurement trials, two on the same day, and the remaining two trials on a day or two later. The mean value of the exponent, the standard deviation, and the coefficient of variation of the four trials for each subject were calculated. The mean value of the exponent of the power function for all subjects was 1.6. This value approximated the value of 1.7 reported by Stevens and Mack. The values ranged from .50 to 5.39. The correlation between subjects' mean exponent value and standard deviation was .90, and the correlation between the mean value of the exponent and the coefficient of variation was .50. There was a close relationship between interpersonal and intrapersonal variance.

Protein-losing enteropathy exacerbated with the appearance of symptoms of systemic lupus erythematosus.

A 38-year-old woman visited our hospital with edema on her face and conjunctivae. The underlying disease was not clarified, and she did not visit the hospital afterwards. She suffered from diarrhea, polyarthralgia, Raynaud's phenomenon, malar rash and hair loss in the subsequent two years, and was hospitalized because of hypoproteinemia. Her urine, liver and heart test results did not account for her hypoproteinemia. She was diagnosed as having protein-losing enteropathy (PLE) associated with SLE based on the 99mtechnetium-labeled human serum albumin scintigraphy findings, clinical findings and laboratory results of antinuclear and anti-Sm antibodies. This case report demonstrates a strong association between PLE and SLE because PLE was aggravated along with the appearance of SLE symptoms and PLE subsided with prednisolone treatment along with improvement of SLE.

Sjögren's syndrome with primary biliary cirrhosis, complicated by transverse myelitis and malignant lymphoma.

A 53-year-old woman with Sjögren's syndrome (SS) and primary biliary cirrhosis (PBC) complicated by transverse myelitis (TM) and malignant lymphoma (ML) is reported. TM has been described only in seven cases of primary SS, including three with PBC and four without PBC. The features of SS associated with PBC and complicated by TM were less typical compared with those seen in SS without PBC complicated by TM. This case is the first report of a case with SS, PBC, TM and ML. SS in association with PBC is, in general, overlooked, but such cases must be investigated with great caution for extraglandular complications.

Are children with Down syndrome less careful in performing a tray-carrying task than children with other types of mental retardation?

To investigate whether children with Down syndrome are less careful in performing motor tasks than children with other types of mental retardation, a tray-carrying task was devised in which subjects carried a tray bearing a glass filled with water which they tried not to spill. This task was given to children with Down syndrome (6 boys and 4 girls, n = 10) and those with other types of mental retardation (9 boys and 9 girls, n = 18; most of them diagnosed as undifferentiated). Mean chronological ages in the groups were 15.4 yr. for the Down group, and 16.3 yr. for the Mental retardation group. Mental ages were the same in both groups: 4.8 yr. The performance of children with Down syndrome was not significantly different from that of other children as measured by the amount of water spilled. Children with Down syndrome required more time and took more steps than the other children, although the time taken for each step was the same in both groups. The strategy of children with Down syndrome appeared to be to make each unit of movement smaller to carry out the given motor task.

The relationship between the effect of setting a goal on standing broad jump performance and behaviour regulation ability in children with intellectual disability.

The objectives of the present study were to investigate the differences in standing broad jump performance between two task conditions (with and without goal) and to clarify the relation of verbal behaviour regulation to this difference in children with intellectual disability. The subjects were 30 children with intellectual disability with an average age of 16.2 years. In the without-goal condition, subjects were instructed to jump as far as possible. In the with-goal condition, on the other hand, subjects were given a goal set 20 cm away from the distance of the first trial in the without-goal condition and instructed to jump for the goal. Verbal behaviour regulation ability was measured by three tasks on Garfield's motor impersistence test keeping eyes closed, protruding tongue with eyes open and keeping mouth open. The mean performance of the with-goal condition was 108 cm, while that of the without-goal condition was 102 cm. The difference between these results was significant, thus indicating the effectiveness of setting a goal to improve jumping performance. Among three independent variables (chronological age, IQ and behaviour regulation score), only the behaviour regulation score was found to be significantly related to the condition difference. It was more effective to demonstrate the goal when the behaviour regulation abilities of the children were lower, but giving the children a goal was not effective for subjects with Down's syndrome. Children with Down's syndrome were considered to have a deficiency in the motor ability itself, not in the system for expressing the motor ability.

Apoptosis-mediated regulation of recombinant human granulocyte colony-stimulating factor production by genetically engineered fibroblasts.

We investigated the feasibility of an inducible apoptosis system to regulate cells genetically engineered for ectopic cytokine production. In a previous study, cDNA encoding the ligand-binding domain of the rat estrogen receptor was fused to the sequence for murine Fas transmembrane and cytoplasmic regions, and expression of the fusion protein (MfasER) in L929 fibroblasts resulted in estrogen-dependent apoptosis. We applied this MfasER/estrogen strategy to apoptosis-mediated regulation of cytokine production, using the human granulocyte colony-stimulating factor (G-CSF) as a model. Upon estrogen treatment, the G-CSF producers expressing MfasER showed an apoptotic phenotype and died in several hours, with termination of G-CSF production. This estrogen-induced apoptosis was not influenced by whether the target cells were proliferating or resting, unlike a conventional suicide system involving the herpes simplex virus 1 thymidine kinase (HSVtk). That is, estrogen induced prompt and extensive apoptosis in the resting cells which expressed MfasER, while ganciclovir treatment induced only partial reduction of the resting cells which expressed HSVtk. These results imply the feasibility of apoptosis-mediated regulation of cytokine production by genetically modified cells for supplement gene therapy.

Primary Sjögren's syndrome complicated by sarcoidosis.

Sjögren's syndrome and sarcoidosis share several common features, such as keratoconjunctivitis sicca, swelling of parotid glands, lung involvement, cutaneous anergy, T cell-mediated immunodeficiency, an increased CD4+/CD8+ lymphocyte ratio, and association with the human leucocyte antigen (HLA)-B 8 and DR 3 haplotypes. However, only five patients with primary Sjögren's syndrome and sarcoidosis have been previously reported in the English language literature. The rare case of a 49-year-old Japanese woman with primary Sjögren's syndrome complicated by sarcoidosis is described. The serum angiotensin-converting enzyme level was increased, and histological examination of lung and skin biopsies revealed noncaseating granulomas, indicating that her primary Sjögren's syndrome was complicated by sarcoidosis.

Development of a novel selective amplifier gene for controllable expansion of transduced hematopoietic cells.

To overcome the low efficiency of gene transfer into hematopoietic cells, we developed a novel system for selective expansion of transduced cells. To this end, we constructed a chimeric cDNA (GCRER) encoding the fusion protein between the granulocyte colony-stimulating factor receptor (G-CSFR) and the hormone-binding domain (HBD) of the estrogen receptor (ER) as a selective amplifier gene. Use of the intracellular signaling pathway of G-CSFR was considered to be appropriate, because G-CSF has the ability not only to stimulate the neutrophil production, but also to expand the hematopoietic stem/progenitor cell pool in vivo. To activate the exogenous G-CSFR signal domain selectively, the estrogen/ER-HBD system was used as a molecular switch in this study. When the GCRER gene was expressed in the interleukin-3 (IL-3)-dependent murine cell line, Ba/F3, the cells showed IL-3-independent growth in response to G-CSF or estrogen. Moreover, the Ba/F3 cells transfected with the Delta(5-195)GCRER, whose product lacks the extracellular G-CSF-binding domain, did not respond to G-CSF, but retained the ability for estrogen-dependent growth. Further, murine bone marrow cells transduced with the GCRER or Delta(5-195)GCRER gene with retroviral vectors formed a significant number of colonies in response to estrogen, as well as G-CSF, whereas estrogen did not stimulate colony formation by untransduced murine bone marrow cells. It is noteworthy that erythroid colonies were apparently formed by the bone marrow cells transduced with the GCRER gene in the presence of estrogen without the addition of erythropoietin, suggesting that the signals from the G-CSFR portion of the chimeric molecules do not preferentially induce neutrophilic differentiation, but just promote the differentiation depending on the nature of the target cells. We speculate that when the selective amplifier genes are expressed in the primitive hematopoietic stem cells, the growth signal predominates and that the population of transduced stem cells expands upon estrogen treatment, even if some of the cells enter the differentiation pathway. The present study suggests that this strategy is applicable to the in vivo selective expansion of transduced hematopoietic stem cells.

Synoviocyte proliferation in joints of SCID mice induced by toxic shock syndrome toxin-1 stimulated T cells from patient with rheumatoid arthritis.

OBJECTIVE: To investigate the histopathological arthropathy in severe combined immunodeficient (SCID) mice given intraarticular injection of toxic shock syndrome toxin-1 (TSST-1) stimulated T cells from patients with rheumatoid arthritis (RA). METHODS: Unstimulated or TSST-1 stimulated T cell blasts (TB-TSST) of synovial fluid mononuclear cells from patients with RA (RASFMC) were intraarticularly injected into the knee joint of SCID mice. Four weeks later, the knee joints were histopathologically examined and the numbers of fibroblasts in the synovial tissues were compared with those of controls. Total RNA of the SCID mouse knee joints was isolated and Southern analysis for human T cell receptor (TCR) V beta 2 and human tumor necrosis factor-alpha (TNF-alpha) was carried out. RESULTS: Hyperplasia and increased numbers of the fibroblasts as well as neovascularization of the synovial tissues were observed in the SCID mouse knee joint tissues injected with TB-TSST of RASFMC compared with those injected with unstimulated T cells from RASFMC or with TB-TSST from peripheral blood of healthy controls. Messenger RNA for human TCR V beta 2 and TNF-alpha were detected in the SCID mouse knee joint tissues injected with TB-TSST from RASFMC. CONCLUSION: Superantigen TSST-1 stimulated T cells from RASFMC have the ability to induce chronic arthropathy with fibroblast proliferation and neovascularization in the SCID mouse.

Comparison of postural control of children with Down syndrome and those with other forms of mental retardation.

To confirm the 1994 findings of Okuzumi, Haishi, and Kokubun, the displacement of the center of foot pressure, one-foot balance and head sway were measured in children with Down syndrome (n = 11) compared to those with other types of mental retardation (n = 17). The magnitudes of the displacement of the center of foot pressure and head sway were not significantly different between the Down group and other forms of mental retardation, whereas the performance of one-foot balance was significantly lower in the Down group. The mean frequencies of sway waves were generally higher in the Down group, and the differences between the two groups were significant except for sagittal head sway. The results generally supported the prior findings. We proposed that it was not the magnitude of the displacement of the center of foot pressure but rather the manner of the whole body's sway which might be related to postural control.

Enhanced interleukin-8 production by cultured Chang liver cells subjected to ethanol exposure and subsequent stimulation with tumor necrosis factor-alpha.

We investigated the production of interleukin-8 (IL-8) and chemotactic activity released from Chang liver cells subjected to long-term treatment with ethanol (Et) and subsequent stimulation with tumor necrosis factor-alpha (TNF-alpha). Chang liver cells were cultured in the presence of 5, 50 or 100 mmol/l Et for 4 weeks and then treated with recombinant TNF-alpha (1, 10, 100 U/ml). The culture supernatants were assayed for IL-8 using a sandwich ELISA and chemotactic activity was measured using a chemotactic chamber. Total RNA was also extracted from these cells and IL-8 mRNA was assayed by RT-PCR. In addition, TNF-receptor expression on the Et-treated cells was analyzed by flow cytometry. IL-8 levels in supernatants of cells stimulated with 100 U/ml of TNF-alpha for 48 h rose significantly with increasing concentrations of Et and values obtained were as follows: 4,918 +/- 244.4 pg/ml at 0 mmol/l Et, 5,335 +/- 266.2 pg/ml at 5 mmol/l Et, 8,726 +/- 873.4 pg/ml at 50 mmol/l Et and 9,134 +/- 866.0 pg/ml at 100 mmol/l Et. The chemotactic activity also increased with increasing concentrations of Et and was almost completely suppressed by anti-IL-8 antibody. Using semiquantitative analysis of radioactivity of IL-8 mRNA using a 32P gamma ATP-labeled primer for IL-8 mRNA, Et-treated cells were shown to have markedly higher levels of radioactivity than untreated cells. In addition, TNF-receptor expression was significantly higher in cells treated with 100 mmol/l Et. These data suggest that long-term Et treatment of Chang liver cells stimulated with TNF-alpha may enhance transcription of the IL-8 gene with up-regulation of the TNF receptor.

Antibodies to E1 and E2/Protein X components of pyruvate dehydrogenase complex in sera of patients with primary biliary cirrhosis.

AIMS/METHODS: Using purified E1 component of pyruvate dehydrogenase complex (PDC) from bovine heart, we measured the levels of anti-E1 antibodies in PBC sera using ELISA and determined the degree of inhibition that these antibodies exerted on E1 enzyme activity. We also estimated levels of anti-E2/Protein X (Pro-X) antibodies in PBC sera using purified E2 and Pro-X of PDC which were copurified with E1. RESULTS/CONCLUSIONS: Anti-E1 antibodies were detected in 87.5% (35/40) of PBC sera. Some of these sera inhibited E1 enzyme activity but inhibition did not correlate with levels of anti-E1 antibodies. A high positive correlation (r = 0.918) was found between levels of anti-E1 and anti-E2/Pro-X antibodies, suggesting that anti-PDC antibody production was stimulated by PDC itself. Levels of IgG class anti-E2/Pro-X antibodies were significantly higher in sera of symptomatic PBC patients than in those of asymptomatic PBC patients. It was also found that patients who were positive for only IgM class anti-E2/Pro-X antibodies had early-stage PBC.

Interleukin-6 induces proliferation of rat hepatocytes in vivo.

BACKGROUND/AIMS: The aim of this study was to assess the effect of interleukin-6 (IL-6) on the proliferation of hepatocytes and to study the interaction between IL-6 and hepatocyte growth factor (HGF) in vivo. METHODS: IL-6 was injected at a dose of 200 micrograms/mg subcutaneously into rats every day for 14 days. Liver and blood samples were obtained at 1, 3, 7 and 14 days during IL-6 administration. Hepatocyte proliferative activity of sera was measured using 3H-thymidine incorporation into cultured rat hepatocytes. To evaluate the proliferative activity of the hepatocytes in tissue sections, hepatic DNA content and immunostaining of the liver tissue sections for proliferating cell nuclear antigen (PCNA) were performed. Plasma HGF levels were measured using specific EIA. In addition, total RNA was extracted from the liver and expression of HGF mRNA was detected by RT-PCR. RESULTS: The DNA contents of liver taken from IL-6-treated rats were increased during IL-6 administration compared with untreated rats. Sera taken from IL-6-treated rats at various intervals during administration also significantly increased 3H-thymidine incorporation by cultured rat hepatocytes compared with sera from untreated rats, suppressing 3H-thymidine incorporation at day 1 and 3 by anti-HGF antibody. IL-6 itself did not increase 3H-thymidine incorporation. Increased expression of PCNA in these hepatocytes was noted from 1 day after IL-6 administration, and at 14 days, the number of PCNA-positive cells was sevenfold greater than in the livers of untreated rats. However, plasma HGF levels showed a peak at day 1, decreased gradually from day 3, and became undetectable by day 14. HGF mRNA expression in livers of IL-6-treated rats was suppressed from day 3 to day 14 of IL-6 administration. CONCLUSIONS: These data show that IL-6 induces an early phase of liver cell growth in vivo and suggest that an increase level of HGF mediates this effect.

Predictive value of age of walking for later motor performance in children with mental retardation.

The purpose of the present study was to clarify the predictive value of age of walking for later motor performance in children with mental retardation. While paying due attention to other factors, our investigation focused on the relationship between a subject's age of walking, and his or her subsequent beam-walking performance. The subjects were 85 children with mental retardation with an average age of 13 years and 3 months. Beam-walking performance was measured by a procedure developed by the authors. Five low beams (5 cm) which varied in width (12.5, 10, 7.5, 5 and 2.5 cm) were employed. The performance of subjects was scored from zero to five points according to the width of the beam that they were able to walk without falling off. From the results of multiple regression analysis, three independent variables were found to be significantly related to beam-walking performance. The age of walking was the most basic variable: partial correlation coefficient (PCC) = -45; standardized partial regression coefficient (SPRC) = -0.41. The next variable in importance was walking duration (PCC = 0.38; SPRC = 0.31). The autism variable also contributed significantly (PCC = 0.28; SPRC = 0.22). Therefore, within the age range used in the present study, the age of walking in children with mental retardation was thought to have sufficient predictive value, even when the variables which might have possibly affected their subsequent performance were taken into consideration; the earlier the age of walking, the better the beam-walking performance.

A case of idiopathic portal hypertension complicated with narrowing of intrahepatic bile ducts.

A 37-year-old woman who had portal hypertension followed by splenomegaly, developed collateral blood flow of spleno-renal shunt and paraesophageal veins, esophageal varices and further with narrowing of intrahepatic bile ducts shown by endoscopic retrograde cholangiography was described. Liver function was almost normal except the slight elevation of serum alkaline phosphatase and gamma-glutamyl transpeptidase levels. However, endoscopic retrograde cholangiography revealed the narrowing of the intrahepatic bile ducts. The histological examination of biopsied specimen showed no prominent change in portal tracts and bile ducts without cell infiltration or fibrosis in the portal area. This case will be considered as idiopathic portal hypertension complicated by narrowing of the intrahepatic bile ducts.