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Noise suppression effect of Co-Pd-Al-O nanogranular thin films, which have considerably high permeability up to gigahertz range, was investigated. The films with large variety of electrical resistivity (/spl rho/) from 10/sup 2/ to 10/sup 7/ /spl mu//spl Omega//spl middot/cm were prepared by reactive sputtering method and by changing both target compositions and deposition conditions. The films with /spl rho/ less than 10/sup 3/ /spl mu//spl Omega//spl middot/cm are ferromagnetic, and the films with /spl rho/ more than 10/sup 6/ /spl mu//spl Omega//spl middot/cm are superparamagnetic. A microstrip line with granular films placed on its top was used to evaluate conduction noise suppression. The result of transmission and reflection measurements reveals that these nanogranular soft magnetic Co-Pd-Al-O thin films have high potential for noise suppressors in the gigahertz range. In particular, the broad maximum of power loss (P/sub loss//P/sub in/) about 0.6 at 6 GHz has been obtained in Co-Pd-Al-O films with /spl rho/ around 10/sup 4/ /spl mu//spl Omega//spl middot/cm.

The influence of the addition of third elements into permalloy films on anisotropic magnetoresistance (AMR) has been investigated for a large number of third elements. AMR decreases rapidly for the addition of Sc, Ti, V, Cr, Ge, Zr, Nb, Mo, Ru, Ta and W. On the other hand, the decreases in AMR are relatively slow for the addition of Co, Cu, Pd, Ag, Pt and Au. We have found the tendency that the influence of the elements which are situated near Ni in the periodic table is smaller than that of the elements which are situated far from Ni.

Although CT studies have addressed symptomatic and asymptomatic cerebral infarctions in nonrheumatic atrial fibrillation (NRAF), pathologic verification of the results is lacking. The purpose of this study was to assess the frequency, location, and extent of symptomatic and asymptomatic brain infarction in autopsy specimens from elderly patients with NRAF. We examined autopsy specimens from 136 consecutive NRAF patients 70 years of age or older who received no anticoagulant therapy during their lifetime and compared them with 231 age-matched control subjects with similar health histories except for the absence of NRAF. Symptomatic cerebral infarctions were present in 82 (60.3%) NRAF patients and in 55 (23.8%) control subjects (p < 0.0001). Of symptomatic cerebral infarctions, cardioembolic infarction was present in 53 (64.6%) NRAF patients and in two (3.6%) of the control subjects (p < 0.0001), atherothrombotic infarction in 13 (15.9%) NRAF patients versus 36 (65.5%) control subjects (p < 0.0001), and lacunar infarction in four (4.9%) NRAF patients versus 12 (21.8%) control subjects (p < 0.01). Stroke-related death occurred in 34 (25.0%) NRAF patients and in 18 (7.8%) control subjects (p < 0.0002). Symptomatic cerebral infarction was generally accompanied by asymptomatic infarctions in both NRAF patients and control subjects. Asymptomatic cortical infarctions were more common in NRAF patients, but asymptomatic infarctions in the white matter or deep structures were more common in control subjects. In this autopsy series of individuals over 70 years of age, symptomatic brain infarction was 2.5 times more common in NRAF patients than in NRAF-free control subjects; two-thirds of the infarctions in the NRAF cases were judged to be cardioembolic in origin. Most asymptomatic cerebral infarctions in the NRAF patients were located in the cortices.

Current-perpendicular-to-plane magnetoresistance was measured for ferrimagnetic Co/Gd multilayers which have twisted spin structure accompanied with spin-flop transition. The influence of twisted spin structure on the electronic transport was exclusively obtained, eliminating the effect of anisotropic magnetoresistance. MR curves showed a downturn around the spin-flop field, suggesting that the formation of twisted spin structure leads to a negative resistance change.

There was an epidemic of non-A non-B hepatitis in a small area of a town in the central part of Japan, which began with an outbreak of several patients in 1981 and then spread extensively with the result that about one third of the inhabitants showed abnormality in serum liver function tests at the health check performed in 1985. We determined histological diagnoses on that occasion for 167 individuals of the abnormal population and recently assayed antibodies against hepatitis C virus (HCV) for most of their sera left available. Histologically, chronic active hepatitis (CAH) was the major pattern, accounting for 59.3% (99 cases) of the total. Others were chronic persistent hepatitis (CPH) (13.2%), chronic lobular hepatitis (CLH) (16.2%), liver cirrhosis (LC) (6.6%) and fatty liver (4.8%). In the serological studies, the newly developed system to detect antibodies against the viral core protein p 22 was found to be much more sensitive than the conventional system to detect anti C 100-3 antibodies. By using these two methods in combination, we found that 82% were antibody-positive, indicating strong implication of HCV in this epidemic. This was further supported by direct detection of the viral genome in patients' sera by polymerase chain reaction following reverse transcription. We further found a strong correlation between the histological inflammatory activity and the antibody prevalence, since nearly all (97.6%) of the CAH cases were antibody-positive by at least either of the antibody assays, while only about 50% were positive in the less active cases such as CPH and CLH.

There have been several reports that double negative (DN) CD4-8- T alpha beta-cells might be responsible for the onset of autoimmune diseases in humans and mice. We previously revealed that such DN T alpha beta-cells are generated in the liver of autoimmune MRL-lpr/lpr mice. In the present study, we further characterize the histology of the liver in these mice by light and electron microscopic studies. An intensive accumulation of mononuclear cells in the liver was demonstrated and a significant proportion of these mononuclear lymphocytes was found to intimately interact with Kupffer cells or endothelial cells of the hepatic sinusoids. The majority of such lymphocytes were TcR+CD4-8-Pgp-1+ alpha beta-cells. Identification of DN T alpha beta-cells was then performed in various autoimmune model mice. Interestingly, all autoimmune mice tested (i.e., MRL-lpr/lpr, C3H/HeJ-gld/gld, BXSB, NOD, MRL(-)+/+ and NZB/W F1 mice), showed an increased proportion of DN T alpha beta-cells (greater than 11% among all MNC) in the liver when they became old and diseased. On the other hand, young and old normal mice and young autoimmune mice before the onset of disease did not have such a high proportion of DN T alpha beta-cells (less than 10%) in the liver. Among autoimmune mice, MRL-lpr/lpr and C3H/HeJ-gld/gld mice had lymphadenopathy, which consisted of DN T alpha beta-cells (greater than 25%), after the onset of disease. Autoimmune mice of the other strains had neither lymphadenopathy nor DN T alpha beta-cells in the periphery, even when they were diseased. These results suggest that the expansion of the DN T alpha beta-cell population in the liver is a common feature of autoimmune mice, irrespective of the information of lymphadenopathy.

Immunohistochemical localization of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) was performed in 55 cases of morphologically normal human ovaries by using a specific polyclonal antibody against purified human placental 3 beta-HSD. In small developing follicles, immunoreactivity was observed only in the theca interna but also became recognizable in the membrana granulosa with development of the follicle. At a late stage of folliculogenesis, the intensity of the 3 beta-HSD activity in the membrana granulosa was nearly equal to that of theca interna in 2 or 3 large follicles examined. One to several layers of theca interna cells just beneath membrana granulosa did not demonstrate any immunoreactivity of 3 beta-HSD or that of cytochrome P-450 17 alpha-hydroxylase. These unstained theca interna cells did not appear to be directly involved in ovarian steroidogenesis and might be designated as 'enzymically inactive theca interna cells.' Marked immunoreactivity was observed in luteinized theca and granulosa cells of the corpus luteum.

The authors describe a control scheme incorporated in the voltage-fed full-bridge series resonant high-frequency inverter using static induction high power transistors (SITs), which is based on a load-adaptive variable frequency modulated phase-shift PWM (pulse-width modulation) control strategy. The operating principle of the load-adaptive variable frequency PWM series resonant inverter system with a new control scheme is described along with its operating characteristics in steady state. The 20 kW-200 kHz prototype inverter system suitable for induction heating in industry is demonstrated, including a specially designed power transformer. SIT stacks with a water cooling system, and a building-block assembly for high-power use. Experimental results and simulation results are presented. Finally, an improved variable frequency PWM series resonant inverter topology incorporating partially inserted capacitive lossless snubbers is proposed for soft switching and compared with the inverter mentioned above. >

The single chip power meter is a programmable mixed signal IC for three phase power line measurement. The DSP block includes two programmable 32 bit processors which executes metering functions and calibration algorithm for six AD converter inputs. In the calibration algorithm correction methods for two major errors have been attempted: for a non-linearity error of input transformers and AD converters, for a phase leading error of the current transformers against the voltage transformers. 30 correction coefficients including frequency dependency are computed by an automatic calibration system. The experimental results demonstrate the efficiency of the corrections: the non-linearity of RMS current measurement has been reduced from /spl plusmn/0.17%FS to /spl plusmn/0.07%FS by the nonlinearity correction, the measurement offset error of three phase power has been reduced from /spl plusmn/3%FS to /spl plusmn/0.25%FS by the phase error correction. These correction techniques bring a breakthrough for cutting the production cost, by permitting use with inexpensive transformers which have less linearity and large characteristic deviation. >

The effect of the rapid immunostaining of gastrointestinal cancer-associated antigens, CA19-9, CEA, DUPAN2, and CA50 was discussed for intraoperative pathological diagnosis of pancreatic cancer. The method can be completed in only 13 minutes with microwave irradiation to accelerate the incubation of the primary antibody. Only 3 seconds of irradiation at 500 W for fresh-frozen sections produced specific antigen staining of greater intensity than that obtained with longer incubation by the conventional method. Preservation of the tissue structure was satisfactory with minimal nonspecific background staining enabling us to diagnose the intrapancreatic spread of cancer. This method was also applied to intraoperative peritoneal washing cytology. As with frozen section biopsy, the sensitivity of intraoperative cytology is greater than by the conventional staining method, which is able to achieve more precise staging of pancreatic cancers. Our rapid immunoperoxidase staining method on the cryostat section of pancreatic biopsy specimens and on cytology samples provides important information to determine an appropriate operative approach for pancreatic cancer.

Matrix metalloproteinases (MMPs) are involved in tissue remodelling, which is one of the important aspects of inflammatory disease. To assess the balance between the matrix degradation and production, we analysed the in situ expression of MMP-1, -3, -8 and -9, tissue inhibitor of metalloproteinases (TIMP)-1 and -2, and type I procollagen (PC-I) in inflammatory bowel disease.Immunohistochemistry using frozen sections was performed in 17 patients with ulcerative colitis (UC) and 16 with Crohn's disease (CD). In both UC and CD, MMPs and TIMPs were expressed by inflammatory cells as well as by fibroblastic cells most prominently in actively inflamed areas in ulcer bases, but sparsely in intact inflamed mucosa in both UC and CD. In UC, inflamed mucosa with erosions expressed these substances focally. Fibroblasts also expressed PC-I. We identified that vascular smooth muscle cells of venules in ulcer bases expressed MMP-1 and -9, TIMP-1 and PC-I. These venules also expressed E-selectin, a cell adhesion molecule to facilitate the leucocyte extravasation, and vascular endothelial growth factor (VEGF) receptor 2, consistent with their property of newly formed vessels.Our results suggest that MMPs are involved in the tissue remodelling, angiogenesis and promotion of leucocyte extravasation in the actively inflamed area in the ulcer base in both UC and CD. MMP-1 expression in the mucosa may be related to the initial step of ulceration in UC. Therapeutic manipulation of extracellular matrix turnover would be an effective therapy to alleviate active inflammation and accelerate ulcer healing.

Tumor-infiltrating lymphocytes, particularly CD8(+) T cells, could be a manifestation of antitumor immunity. We clinicopathologically analyzed the biological significance of tumor-infiltrating lymphocytes in 221 patients with renal cell carcinoma without preoperative treatments. More abundant infiltration of tumor tissue not only by CD8(+) but also CD4(+) T cells was associated with shorter survival of the patients, because of the positive correlation between the number of lymphocytes and representative tumor grade factors. This suggests that immune cell reactions are more pronounced as the tumor grade/biological malignancy progresses, probably because of increased antigenicity of tumor cells. We next analyzed the proliferative activity of CD8(+) T cells that infiltrated in tumor cell nests, which could also reflect antitumor immunity. Higher labeling index of Ki-67, a proliferation-associated antigen, among CD8(+) T cells in contact to tumor cells was associated with a longer survival by both uni- and multivariate analyses. Our data in human renal cell carcinoma suggest that infiltration of tumor tissue by T cells itself does not denote the efficacy of antitumor immunity because of its dependence on the biological malignancy of tumor cells, but infiltration of tumor tissue by CD8(+) T cells bearing more pronounced proliferative activity could reflect effective antitumor immunity. This concept would be important for future immunotherapy of human cancer.

The incidence of human esophageal squamous cell carcinoma in males is well-known to be higher than in females and its biological action in male patients is generally much more aggressive than that of the female. Recently, aberrations and/or other abnormalities of the sex chromosomes, especially the Y chromosome, have been postulated to be involved in some of the differences in the incidence and/or biological action of human malignancies between male and female patients. Therefore, in this study, we examined abnormalities of the sex chromosomes in cell smears obtained from 30 male patients diagnosed with esophageal squamous cell carcinoma. In addition, TE series cell lines, derived from esophageal squamous cell carcinomas, were studied for sex chromosome abnormalities by utilizing a simultaneous double color fluorescent in situ hybridization (FISH) and these findings were correlated with various clinicopathological parameters in order to examine its likely biological significance. In esophageal squamous cell carcinoma, Y chromosome loss was detected in all cases studied (1.6-86.9%, mean 22.98 +/- 22.04%), but the loss of the X chromosome was encountered in only 6 of the cases (7.1-40.6%, mean 15.90 +/- 12.46%). There was no significant association between the rate of Y chromosome loss in carcinoma cells and any of the clinicopathological parameters examined including age and stage of the cancer. Loss of the Y chromosome was observed in only two cases of adjacent non-pathological esophageal squamous cell epithelium. Among the TE series examined, the cell lines derived from male patients demonstrated loss of the Y chromosome in all cell lines (1.4-92.9%, mean 44.92 +/- 42.55%), but the great majority of cell lines derived from female patients were associated with the karyotype of XX. These results indicated that the loss of the Y chromosome is associated with the malignant phenotype in human esophageal squamous epithelium, but possibly not with biological behavior. These results also suggested that at least one X chromosome is indispensable for the survival of esophageal squamous cell carcinoma.

Estrogens exert various biological effects by acting through their native receptors, two of which have been identified to date: estrogen receptors alpha (ERalpha) and beta (ERbeta). In this study we examined the expression and cellular localization of ERalpha and ERbeta in various human fetal tissues by semiquantitative RT-PCR (13 and 20 gestational weeks) and immunohistochemistry (13, 20, and 38 gestational weeks), respectively, to study the possible effects of estrogens on human fetal tissues during development. Relatively high levels of ERbeta expression were detected in various human fetal tissues, whereas those tissues expressing ERbeta had markedly lower levels of ERalpha expression. ERbeta messenger ribonucleic acid expression was especially high in the adrenal gland. ERbeta-immunoreactive protein was localized to the definitive zone, but not in the fetal zone, of the adrenal cortex. Although low levels of ERbeta messenger ribonucleic acid were present in the brain, heart, lung, and kidney, ERbeta immunoreactivity was not detected in these tissues. These results suggest that the effects of estrogens in these tissues are predominantly mediated through ERbeta. ERbeta immunoreactivity was detected in Sertoli cells and spermatogonia in the male reproductive tract and in germ cells in the fetal testis and epididymis. In the female reproductive tract, both ERalpha and ERbeta were immunopositive in epithelium of the oviduct. The results of the present study have demonstrated the possible sites for estrogenic action in the human fetus and suggest that the effects of estrogen via ERbeta may play important roles in human fetal development, especially in the definitive zone of the adrenal cortex, and in the reproductive tissues of the developing fetus.

We report a case of genetically confirmed spinocerebellar ataxia type 1 (SCA1) in which magnetic resonance imaging (MRI) demonstrated a high signal intensity on T2-weighted images in the white matter of the frontal lobes. The patient was a 60-year-old Japanese man who complained of gait instability and speech difficulties. He was diagnosed as having spinocerebellar ataxia at the age of 46. A CAG repeat number of the patient was 48/26. Brain MRI showed marked atrophy of the cerebellum and brain stem. The high-signal intensity lesions on T2-weighted MRI in the white matter of the frontal lobes were evident in the periventricular regions. Such MRI abnormalities have not been described in SCA1 previously.

The gastrointestinal mucosa is exposed to myriads of infectious and food antigens, and a unique barrier mechanism handles them on the mucosal surface, and specific immune responses to these antigens call on the mucosal immune system in the mucosal tissues to maintain homeostasis of gastrointestinal functions and structure. Abrogation of these mucosal defense mechanisms may lead to alter immunologic homeostasis in the gastrointestinal tract and to induce pathological features of inflammatory bowel disease (IBD) and Helicobacter pylori-infected chronic active gastritis, including chronic active inflammation, mucosal atrophy and tissue injuries. Regardless of the initiating cause of these long-standing chronic active mucosal inflammations, characteristic immuno-inflammatory mechanisms are involved in their pathogenesis, that is, similar and/or different specific prolonged impaired and excessive immuno-inflammatory responses following the abrogation of the mucosal barrier system are present in the diseased mucosa with IBD and H. pylori infection, respectively.

Helicobacter pylori (HP)-infected gastric mucosa displays a conspicuous infiltration of mononuclear cells as well as neutrophils. RANTES is a potent chemoattractant peptide for memory T lymphocytes and eosinophils. RANTES protein concentration and the numbers of RANTES-, CD45RO-, and major basic protein (MBP)-positive cells were therefore evaluated in the gastric mucosa from 51 patients with HP-positive chronic gastritis before and after HP eradication and from 22 HP-negative healthy volunteers. RANTES protein concentration was significantly elevated in HP-positive cases and remained high after HP eradication. The numbers of RANTES-, CD45RO-, and MBP-positive cells were significantly increased in HP-positive cases and were well correlated with RANTES protein levels. All tended to decrease after HP eradication, but did not reach the level of HP-negative cases, even at 24 months after HP eradication. It was concluded that persistent expression and secretion of RANTES were closely related to residual infiltration of memory T lymphocytes and eosinophils, for a prolonged period after HP eradication. This seems to be an important mechanism of prolonged gastric mucosal immune response against HP infection, even after HP eradication, and of persistent mucosal damage and atrophy.

Article abstract The authors report a patient of pure apraxic agraphia with normal praxis due to left thalamic infarction. 15O-gas-PET showed reduced oxygen metabolism in the left thalamus and the left dorsolateral premotor area, while MRI and 11C-fulumazenil-PET showed no remarkable lesions in the frontal cortex. The patient’s word imaging remained normal. The authors hypothesize that thalamic destruction causes pure apraxic agraphia by exerting a remote effect on left dorsolateral premotor area and blocking somewhere between graphemic area and motor programming.

Serrated adenoma (SA) is a relatively newly defined entity of colorectal neoplasm. In this study, we examined the cell proliferation, DNA ploidy, and clinicopathological features of SA in order to investigate its biological features.We reviewed 10,532 polypectomy specimens of the colorectum obtained from Japanese cases between 1974 and 1998 at Tohoku University Hospital. In total, 193 cases of SA were detected. We first examined clinical features of these cases by reviewing the charts, and then studied cell proliferation using immunohistochemistry of Ki-67 and topoisomeraseIIa, p53 immunoreactivity and DNA ploidy. Results were subsequently compared with those of tubular adenoma (TA) and hyperplastic polyp (HP). Mean size of SA (8.6 +/- 4.6 mm) was significantly larger than those of TA (7.3 +/- 4.6 mm) and HP (5.6 +/- 3.0 mm). More than 80% of SA were protuberant in macroscopic appearance. SA was located predominantly in the sigmoid colon and rectum. Incidences of concomitant carcinoma in HP, SA and TA were 0.4% (1 out of 263), 4.1% (8 out of 193) and 10.3% (809 out of 7838), respectively. Labeling indices for Ki-67 and topoisomeraseIIa in HP, SA and TA were as follows: Ki-67--24.2%, 30.8%, 39.5% and topoisomeraseIIa--15.3%, 16.1%, 23.9%, respectively. In SA, p53 immunoreactivity was detected in the intramucosal carcinoma co-existing with the serrated component. Two out of the ten SA cases examined demonstrated non-diploid patterns of DNA ploidy.SA is a distinct colorectal neoplastic lesion with the potential of malignant transformation similar to that of tubular adenoma.

Our previous clinicopathologic study revealed an inverse association of liver metastasis of colorectal cancer and stromal expression of matrix metalloproteinase-9 (MMP-9) or urokinase receptor (uPAR). This suggests that host cells, particularly macrophages, expressing matrix-degrading enzymes/factors could be protective for the host against hematogenous metastasis. However, our previous study was unable to differentiate whether our results were causes or effects of widely spread cancer. To solve this point, we designed the present study on colorectal cancers that developed hematogenous metastasis after operation, ie., metachronous hematogenous metastasis. These cancers, being solely micrometastasized at the time of operation, allowed us to eliminate possible systemic effects by widely spread cancer. Sixty-two primary tumors with metachronous metastasis showed a decreased number of MMP-9+ stromal cells and CD68+ macrophages along the invasive margin with unchanged uPAR+ stromal area as compared with those in 72 control cases, which were free from tumor metastasis or recurrence for more than 5 years. Therefore, we judged the decrease of MMP-9+ host cells or macrophages in the primary site is irrelevant of effects of widely spread metastasis but probably related to causes of metastasis. Our data also characterized the metachronous metastasis group by uPAR expression in fibroblasts. The number of uPAR+ cancer cells, although small in number, were also larger in the metachronous metastasis group. Our data revealed that macrophages, a major source of uPAR and one of the sources of MMP-9, could be inhibitory to hematogenous metastasis, while uPAR+ fibroblasts and cancer cells, in turn, facilitate hematogenous metastasis. This suggests the functional multiplicity of matrix degradation processes in cancer tissue.

In mineralocorticoid target organs, 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) confers specificity on the mineralocorticoid receptor (MR) by converting biologically active glucocorticoids to inactive metabolites. Placental 11beta-HSD2 is also thought to protect the fetus from high levels of circulating maternal glucocorticoid. In this study, we examined the immunoreactivity of 11beta-HSD2 and MR in human placenta from 5 weeks gestation to full term using immunohistochemistry, 11beta-HSD2 messenger RNA (mRNA) expression using Northern blot analysis, and MR mRNA expression using RT-PCR analysis. Marked 11beta-HSD2 immunoreactivity was detected in placental syncytiotrophoblasts at all gestational stages. MR immunoreactivity was moderately detected in syncytiotrophoblasts, some cytotrophoblasts, and interstitial cells of the villous core. Marked mRNA expression of 11beta-HSD2 was detected in placenta by Northern analysis. RT-PCR analysis of MR in placental tissues showed an amplified product consistent in length with the primers selected. These results suggest that placental 11beta-HSD2 is involved in not only regulating the passage of maternal active glucocorticoids into the fetal circulation but also in regulation of maternal-fetal electrolyte and water transport in the placenta, as in other mineralocorticoid target organs.

The present study investigates the expression patterns of 17beta-hydroxysteroid dehydrogenase (17betaHSD) isozymes in human fetal tissues to understand how estrogenic activity is regulated in the human fetus. Using enzyme assay, high 17betaHSD activity was detected in the placenta and liver, and low levels of 17betaHSD activity were also present in the gastrointestinal tract and kidney. After Northern blot analysis, we detected the messenger ribonucleic acid for 17betaHSD type 1 (17betaHSD1) only in the placenta, whereas that for 17betaHSD type 2 (17betaHSD2) was detected in the placenta, liver, gastrointestinal tract, and urinary tract at 20 gestational weeks. In RT-PCR analysis of the messenger ribonucleic acid transcripts, 17betaHSD 1 was predominantly expressed in the placenta, brain, heart, lung, and adrenal, whereas 17betaHSD2 expression was predominantly detected in the liver, gastrointestinal tract, and kidney. In addition, we detected 17betaHSD2 immunoreactive protein in surface epithelial cells of the stomach, absorptive epithelial cells of the small intestine and colon, hepatocytes of the liver, and interstitial cells surrounding the urinary tubules of the renal medulla. 17betaHSD2 in these tissues may be functioning in the prevention of in utero exposure of the fetus to excessive estradiol from the maternal circulation and amniotic fluids.

Type IIbeta-hydroxysteroid dehydrogenase endows specificity on the mineralocorticoid receptor by metabolizing cortisol and regulates sodium absorption in renal and colonic epithelium. Altered expression of this enzyme may be associated with impaired sodium absorption often seen in colonic mucosa of inflammatory bowel disease. The aim of this study was to investigate possible abnormality of 11beta-hydroxysteroid dehydrogenase protein and mRNA expression in inflammatory bowel disease. In Crohn's disease, the colonic epithelium showed comparable levels of immunoreactivity and mRNA expression to those of control, except for the decreased immunoreactivity in severe inflamed lesions with deep ulcer. In contrary, a lack or decrease of immunoreactivity was relevant in ulcerative colitis regardless of the histological degree of inflammation. The mRNA expression was also significantly decreased in ulcerative colitis. This study demonstrates that abnormality of epithelial cells in ulcerative colitis includes the enzyme that regulates water and sodium absorption, which are physiologically essential.

An 80-year-old man who had was administered antihypertensive medication showed repeated transient unresponsiveness during standing and/or walking. Neurological examination showed no focal neurological signs except mild dementia. Head-up tilting examination induced unresponsiveness and a decrease of systolic blood pressure from 111 mmHg to 86 mmHg. This unresponsiveness disappeared 3 minutes later when the blood pressure recovered to 102/64 mmHg. Cerebral angiography demonstrated occlusion in the right internal carotid artery and the right vertebral artery. Severe stenosis was observed at the left internal carotid artery and the left vertebral artery. Discontinuance of the antihypertensive medication reduced the frequency of orthostatic transient unresponsiveness. Elastic stockings in the lower extremities completely prevented the attack; head-up tilting did not induce hypotension with elastic stockings. The transient unresponsiveness in the present case was probably correlated to hemodynamic failure under the condition of severe cerebral arteriosclerosis.

DNA topoisomerase II alpha (topo II alpha) is associated with active cell proliferation of mammalian cells. Topo II alpha overexpression has been reported in a number of human malignancies and is considered to be related to their biological behaviors.We examined the expression of topo II alpha immunohistochemically in 136 cases of human esophageal squamous cell carcinoma, 10 foci of squamous dysplasia and 10 non-pathologic squamous epithelium. We calculated the labeling index (LI) or the percentage of immunopositive cells for Topo II alpha and Ki67, and Topo II alpha LI/Ki67 LI (T/K ratio). These findings were then correlated with clinicopathological features of the patients including their clinical outcome.Both topo II alpha and Ki67 immunoreactivity were detected in the nuclei. A significant positive correlation was obtained between Topo II alpha and Ki67 LIs in all the specimens examined. Topo II alpha LI and T/K ratio were 24.5 +/- 8.0% and 1.04 +/- 0.64 for carcinoma, 19.1 +/- 15.2% and 0.68 +/- 0.29 for dysplasia and 14.0 +/- 14.1% and 0.55 +/- 0.17 for non-pathologic epithelium, respectively. Topo II alpha LI and T/K ratio in carcinoma cases were significantly higher than those of normal epithelium. Topo II alpha LI alone did not correlate with any of clinicopathological parameters examined but among carcinoma cases, cases with lymph nodes metastasis or higher histological stages had significantly higher T/K ratio than those without lymph node metastasis or lower histological stages. In addition, carcinoma cases with T/K ratio of greater than 0.8 demonstrated significantly worse prognosis than those with T/K ratio of smaller than 0.8.The relative overexpression of topo II alpha as compared with Ki67, i.e., increased T/K ratio was detected in esophageal squamous cell carcinoma and is considered to represent a dysregulation or qualitative alteration in topo II alpha, possibly associated with malignances, as reported in other human cancers. In addition, topo II alpha overexpression may also be correlated with the aggressive biological behavior of the patients with esophageal squamous cell carcinoma.

p27 protein is one of the cdk inhibitors which regulates the progression from G1 to S phase of the cell cycle. Reduced expression of p27 protein has been reported to be correlated with poor clinical outcome in patients with various cancers.We performed immunohistochemistry of both p27 and Ki67 in 136 cases of resected human esophageal squamous cell carcinoma, and evaluated the association between p27 immunoreactivity and clinicopathological features including clinical outcome in these patients. We also examined the correlation between labeling index or the percentage of positive tumor cells for p27 and Ki67 in serial tissue sections in these cases.Cases with invasion of the muscularis propria or adventitia had significantly (p0.05) higher p27 LI (65.0 +/- 23.7) than those with invasion limited to mucosa or submucosa and those with carcinoma in situ (58.9 +/- 18.3). There were no significant correlations between p27 and other clinicopathological factors such as sex, age, tumor size, differentiation type, nodal status and histological stage. The cases with p27 LI below 40% tended to have a worse prognosis than those with p27 LI above 40%. There was no significant correlation between Ki67 and p27 LIs.Reduced expression of p27 may be correlated with the biological behavior of esophageal squamous cell carcinoma and may play an important role in the early stages of cancer.

Urocortin is a recently identified neuropeptide of the corticotrophin-releasing factor (CRF) family in the mammalian brain and has been demonstrated to stimulate ACTH secretion from pituitary cells, but its expression in human brain tissue including the hypothalamus has not been examined. In this study, we first examined urocortin expression in the hypothalamus (20 cases) and pituitary stalks (17 cases) of human brain obtained from autopsy using immunohistochemistry and mRNA in situ hybridization.Neither urocortin immunoreactivity nor mRNA hybridization signals were detected in the hypothalami and pituitary stalks while CRF immunoreactivity was detected in the paraventricular nuclei of the hypothalami in 10/20 cases and in nerve fibres of the stalks in 17/17 cases. These results indicate that urocortin does not act on the hypothalamo-pituitary-adrenal axis, at least not in the same manner as CRF in humans. We then examined urocortin expression in various portions of the brain in 7 cases. Both urocortin immunoreactivity and mRNA hybridization were detected in Purkinje cells of the cerebellum and anterior horn cells of the spinal cord in specimens examined. Urocortin expression was, however, variably seen in superior olivary nuclei (two out of six cases examined) and in the Edingar-Westphal nuclei (one out of three cases examined).The distribution of urocortin in the human central nervous system suggests that urocortin may work as a neurotransmitter like other neuropeptides in the human.

The spleen has two main functions. The first is to provide a proper microenvironment to lymphoid and myeloid cells, whereas the second involves clearance of abnormal erythrocytes. Ad4BP/SF-1, a product of the mammalian FTZ-F1 gene (mFTZ-F1), was originally identified as a steroidogenic, tissue-specific transcription factor. Immunohistochemical examination of the mammalian spleens confirmed the expression of Ad4BP/SF-1 in endothelial cells of the splenic venous sinuses and pulp vein. In mFtz-F1 gene-disrupted (KO) mice, several structural abnormalities were detected in the spleen, including underdevelopment and nonuniform distribution of erythrocytes. Examination of the spleen of KO fetuses showed failure of development of certain tubular structures during embryogenesis. These structures are normally assembled by Ad4BP/SF-1 immunoreactive cells, and most likely form the vascular system during later stages of development. Other structural abnormalities in the spleen of the KO mice included defects in the tissue distribution of type-IV collagen, laminin, c-kit, and vimentin. These morphologic defects in the vascular system were associated with a decrease in the proportion of hematopoietic cells, although differentiation of these cells was not affected significantly. A high number of abnormal red blood cells containing Howell-Jolly bodies were noted in the KO mice, indicating impaired clearance by the splenic vascular system. We also detected the presence of an mRNA-encoding cholesterol side-chain cleavage P450 in the spleen, resembling the findings in steroidogenic tissues such as the gonads and adrenal cortex. The mRNA transcript was not involved in splenic structural defects as it was detected in the spleens of both normal and KO mice, indicating that the regulatory mechanism of the P450 gene in the spleen is different from that in steroidogenic tissues. Our results indicate that a lack of the mFtz-F1 gene in mice is associated with structural and functional abnormalities of the splenic vascular system.

We examined the expression of a recently characterized novel estrogen receptor (ER) beta in 25 cases of invasive ductal carcinoma of the breast, using messenger RNA (mRNA) in situ hybridization, and compared the findings with those of ERalpha, to study its localization and its possible biological significance in human breast cancer. ERalpha and ERbeta hybridization signals were both detected, predominantly in carcinoma cells and in some stromal cells, in 18 of 25 (72%) and 11 of 25 (44%) cases, respectively. The cases in which more than 25% of carcinoma cells demonstrated mRNA hybridization signals were 13 of 25 (52%) and 2 of 25 (8%) cases for ERalpha and ERbeta, respectively. Among the cases expressing ERbeta, 10 of 11 (91%) also expressed ERalpha mRNA; and in these 10 cases, coexpressing both ERalpha and beta, the number of carcinoma cells expressing ERalpha was greater than that expressing ERbeta in 9 cases. Eight cases demonstrated only ERalpha mRNA hybridization signals in carcinoma cells. These results indicate that ERbeta is coexpressed with ERalpha in most ERbeta-positive breast carcinoma cells, which suggests that the expression of ERbeta depends on the presence of ERalpha in the great majority of human breast cancer. In addition, the number of carcinoma cases and/or the ratio of carcinoma cells expressing ERalpha was much greater than those expressing ERbeta. The relative ratio of ERalpha and ERbeta expression in carcinoma cells may be related to various estrogen-dependent biological features of human breast cancer.

Caspase3/CPP32 is a member of the interleukin-1 beta-converting enzyme (ICE) or cell death effector (CED)-3 family, which is involved in the induction of apoptosis and has been considered to be correlated with apoptosis because of the most downstream enzyme in their apoptosis inducing pathway. We immunolocalized Caspase3/CPP32 in both normal and neoplastic human gastric mucosa. We then correlated the findings with cell proliferation studied by Ki67 immunostaining and apoptosis, which was tested for by DNA fragmentation in situ using TdT-mediated dUTP biotin nick end labeling (TUNEL) method in order to examine possible biological significance in cell turnover of normal and pathological human gastric tissues. Caspase3/CPP32 immunoreactivity was detected in both the cytoplasm and nuclei of glandular epithelial cells, predominantly in the Ki67 positive proliferative zone and TUNEL positive foveolar epithelium of normal non-neoplastic gastric mucosa (n = 10) and tumor cells of both adenoma (n = 17) and carcinoma (n = 33). We determined the labeling index (LI) of Ki67, Caspase3/CPP32 and TUNEL positive cells by evaluating the number of positive cells in the same areas of serial tissue sections using computer-assisted image analysis. Ki67 LI in adenocarcinoma (78.6 +/- 12.6%) was significantly [p0.0001] higher than that of adenoma (43.8 +/- 8.9%) and non-neoplastic gastric mucosa (24.2 +/- 9.0%). Caspase3/CPP32 LI in adenocarcinoma (17.1 +/- 10.3%) was significantly lower [p0.0001] than that of gastric adenoma (33.1 +/- 19.8%) and non-neoplastic gastric mucosa (42.4 +/- 15.8%). TUNEL LI in adenocarcinoma (1.9 +/- 2.1%) was significantly [p0.0001] lower than that of non-neoplastic gastric mucosa (6.0 +/- 3.5%), but not significantly different from that of adenoma (3.0 +/- 2.9%). These results indicate that gastric adenocarcinoma is associated with an inhibition of apoptosis and the augmentation of proliferative activity of tumor cells compared to non-neoplastic gastric mucosa. There was a tendency to a positive correlation between the Caspase3/CPP32 and TUNEL LI and an inverse correlation between the Caspase3/CPP32 and Ki67 LI, when evaluating all the specimens, although the correlation did not reach statistical significance. These results also suggest that Caspase3/CPP32 is involved in the development or regulation of apoptotic cell death in cell turnover of normal and neoplastic mucosa of the human stomach.

The colon plays an important role in water and electrolyte homeostasis and is a major target tissue for aldosterone. 11 beta-Hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) confers specificity to the non-selective mineralocorticoid receptor by inactivating glucocorticoids, thus allowing binding by mineralocorticoids. Using immunohisto/cytochemistry and Northern blot analysis, we examined 11 beta-HSD2 expression in human fetal colon (23 cases ranging in age from 15 to 40 weeks gestation), neonatal colon (2 cases, 6 and 12 months old), normal adult colon (15), adenoma (35), adenocarcinoma (34) and the human colonic epithelial cell line T84, in the presence or absence of sodium butyrate, to study the correlation between enzyme expression and cellular or neoplastic differentiation. In fetal colon, weak 11 beta-HSD2 immunoreactivity was detectable in superficial epithelium from 25 weeks gestation, but normal adult levels were apparent only after 40 weeks gestation, suggesting that fully developed aldosterone induced electrolyte transport can occur only at late gestational stages. In adult normal colon, superficial absorptive cells at the top of crypts were strongly positive for 11 beta-HSD2, whereas immunoreactivity was weak in adenomas and carcinomas, and the pattern of localization varied among patients. Northern blot analysis performed on 4 cases of adenocarcinoma also demonstrated lower levels of mRNA than autologous non-neoplastic colonic mucosa. In carcinomas, 11 beta-HSD2 immunoreactivity was more frequently detected in differentiated structures, such as those forming glandular or tubular structures. Studies with T84 cells showed that expression of 11 beta-HSD2 was markedly enhanced with the addition of sodium butyrate, a well known inducer of cell differentiation in colonic epithelia. These results suggest that the expression of 11 beta-HSD2 is associated with differentiation or maturation in human colonic epithelia and that the enzyme may serve as a useful marker in development and disease.

In estrogen metabolism, the enzymatic properties of the 17beta-hydroxysteroid dehydrogenase (17betaHSD) isozymes play very important roles in steroid hormone metabolism in various tissues, including the placenta. 17betaHSD type 1 catalyzes primarily the reduction of estrone (E1) to estradiol (E2), whereas 17betaHSD type 2 catalyzes primarily the oxidation of E2 to E1. In this study, we examined immunohistochemical localization of 17betaHSD types 1 and 2 in human placenta (31 cases) ranging from 4-40 weeks gestation. The immunoreactivity of 17betaHSD type 1 was exclusively detected in syncytiotrophoblast from 4 weeks gestation to term placenta. Immunoreactivity of 17betaHSD type 2 first appeared in endothelial cells of intravillous vessels at 12 weeks gestation, and the number of 17betaHSD type 2-positive endothelial cells markedly increased up to 19 weeks, then reached a plateau. We quantitatively evaluated the 17betaHSD type 2-positive endothelial cells in chorionic villi and determined the ratio of 17betaHSD type 2-positive endothelial cells using immunohistochemistry of CD34, an endothelial antigen, in serial mirror tissue sections and subsequent image analysis using CAS 200. CD34 was detected from 4 weeks gestation, and its positive areas continued to increase toward term. The 17betaHSD type 2-positive area per CD34-positive area markedly increased from 13 weeks gestation and reached a plateau at 19 weeks gestation, in which almost all endothelial cells were positive for 17betaHSD type 2. 17BetaHSD type 2, therefore, is considered to prevent the passage of excessive estrogens into the fetal circulation at endothelial cells of the intravillous fetal capillaries by catalyzing the inactivation ofE2 to E1.

The pathophysiological significance of tumor infiltrating lymphocytes remains controversial. To clarify their role, we performed clinicopathological analysis of CD8+ T cells in 131 cases of human colorectal cancer. CD8+ T cells were classified into three groups by their localization: (a) those infiltrated within cancer cell nests; (b) those distributed in the cancer stroma; and (c) those present along the invasive margin (tumor-host interface). Of these, CD8+ T cells within cancer cell nests were most significantly associated with a better survival of patients by both mono- and multivariate analyses. The impact on survival was similar to that of Dukes' staging. Granzyme B+ cytoplasmic granules were detected in lymphocytes within cancer cell nests, confirming their activated, cytotoxic phenotype. CD8 and Ki-67 double immunohistochemistry confirmed higher proliferative activity of CD8+ T cells within cancer cell nests. Our data suggested that human colorectal cancer tissue was infiltrated by various numbers of T cells that had cytotoxic phenotype, contributing to a better survival of patients. This infiltration of colorectal cancer cell nests by CD8+ T cells could be a novel prognostic factor.

Oestrogen produced locally by aromatase is thought to participate in numerous biological functions in the adult central nervous system (CNS). However, little is known about aromatase expression in the human CNS.We examined aromatase expression in human brain regions, (4 men, 2 women) obtained from autopsy, by reverse transcriptase (RT)-polymerase chain reaction (PCR) and also studied alternative use of multiple exons 1 of its gene, which is involved in tissue specific expression of aromatase in human.The amount of aromatase mRNA determine by RT-PCR assay in 6 cases tended to be highest in pons, thalamus, hypothalamus and hippocampus. Analysis of multiple exons 1 revealed that 1f, considered specific for brain, as well as 1b (fibrolast type) and 1d (gonadal type), were expressed. 1d and 1f tended to be utilized in hypothalamus, thalamus and amygdala. The amount of overall mRNA expression was also higher in hypothalamus, thalamus and amygdala than in other regions of the brain. There were no differences of utilization of exons 1 and mRNA expression of aromatase between female and male brain.These results demonstrate that aromatase is expressed widely in various regions of human brain tissues in both men and women.

It has long been postulated that angiogenesis plays important roles in tumor cell proliferation and hormonal secretion of endocrine tumors, including adrenocortical neoplasms. Detailed examination of vascularity, however, has not been reported in adrenocortical tumors. In this study, we quantitatively examined vascularity in normal adrenal, adrenocortical adenoma, and carcinoma using an image analysis system to evaluate vascularity or angiogenesis in these lesions. Vascular density (VD: vessel number/mm2), endothelial area of each vessel (EA: microm2/vessel) and vascular area (VA: the percentage of EA per field) were examined using immunohistochemical analysis of CD34 and the CAS 200 image analysis system. EA and VA of adrenocortical carcinomas (EA, 113.4 +/- 33.1; VA, 6.34 +/- 2.03) were significantly higher than those of adenoma (EA, 66.1 +/- 43.0; VA, 3.11 +/- 1.56) and normal adrenal tissue (EA, 65.4 +/- 26.0; VA, 4.26 +/- 1.19). There were no significant differences in VD among normal cases (702.2 +/- 173.2), adenomas (488.9 +/- 153.2), and carcinomas (573.2 +/- 185.2). These results suggest that adrenocortical carcinoma might be associated with increased endothelial cell proliferation but not with an increased number of intratumoral microvessels. There were no significant differences in these parameters of vascularity examined in the zona glomerulosa, zona fasciculata, and zona reticularis of aldosteronomas, Cushing's adenomas, and nonfunctioning hormonally inactive adenomas nor between specimens from patients who died of the disease and those from patients who did not.

We studied the immunolocalization of cyclins D1 and E and their corresponding partner cyclin dependent kinases (cdk), cdk4 and cdk2 in 41 cases of human breast malignancy (21 invasive ductal carcinomas and 19 invasive lobular carcinomas) and examined the correlation of the labeling indexes among these cyclins, cdks, Ki67, estrogen receptor (ER) and progesterone receptor (PR). Cyclin D1 immunoreactivity was observed exclusively in the nuclei of tumor cells in 27/41 (65%) of the cases examined. Immunoreactivity for cyclin E and cdk2 was detected in all the cases and observed in the nuclei of both carcinoma and non-carcinoma cells. cdk4 immunoreactivity was detected in 39/41 (95%) cases and found in carcinoma and non-carcinoma cells. In all carcinomas examined, a significant correlation was observed only between Ki67 and cyclin D1 (p = 0.0037). However, when examining only invasive ductal carcinomas, a significant correlation was detected between Ki67 and cyclin D1 (p = 0.0069), Ki67 and cdk2 (p = 0.0043) and cyclin D1 and cdk4 (P = 0.0024). Only cyclin D1 correlated with the pathologic stages of the disease and histological grades of invasive ductal carcinoma. Among these cyclins and cdk, overexpression of cyclin D1 is considered to play an important role in the development of human breast malignancy through abnormal proliferation. No significant correlation was observed between steroid receptor status and any of cyclins and cdks examined. Cyclin D1 and cdk2 expression correlated with cell proliferation (Ki67) and cyclin D1 expression with expression of cdk4 in invasive ductal carcinoma but not invasive lobular carcinoma. Cyclin E expression did not correlate with cell proliferation, cyclin D1 or cdks possibly due to deregulation of its expression. These results also indicate different patterns of cyclin D1, cyclin E, cdk2 and cdk4 expression between invasive ductal and lobular carcinoma of human breast.

Localization of growth factors such as transforming growth factor alpha (TGF-alpha) and beta1 (TGF-beta1), insulin-like growth factor 1 (IGF-1), and epidermal growth factor receptor (EGFR) in breast cancer tissue is controversial. We immunohistochemically investigated expression patterns of these growth factors and EGFR along with estrogen receptor (ER) status in 36 breast carcinomas (21 invasive ductal, 11 invasive lobular, 4 noninvasive ductal) and compared the results with those found in 10 fibroadenomas. Twenty-four of 36 carcinomas and all of the 10 fibroadenomas showed positivity for ER. TGF-alpha was immunoreactive in all of the carcinomas and fibroadenomas. TGF-beta1 was negative in all of the invasive ductal carcinomas and positive in all of the fibroadenomas and in five lobular carcinomas. EGFR was regularly expressed preferentially in the myoepithelial cells of mammary ducts in the fibroadenomas and in nontumorous glands. Six of the 36 carcinomas were positive for EGFR. Those tumors were negative for ER (P.001). There was IGF-1 expression in all of the cases of carcinoma and fibroadenoma. We conclude that TGF-alpha is expressed abundantly in invasive and intraductal breast carcinomas and in fibroadenomas. EGFR expression significantly correlates with negative ER status in breast carcinoma. In breast carcinoma, IGF-1 is broadly expressed by the tumor as well as by stromal cells and might act as a growth stimulator in endocrine, paracrine, and autocrine manners.

Costimulatory molecules B7-1 (CD80) and B7-2 (CD86) are indispensable for T-cell activation. Recently, a paucity of these costimulatory molecules was reported in inflammatory cells in colon cancer, which may permit the immune evasion of the cancer. The present study uses immunohistochemistry to reveal the expression of these molecules in 43 cases of colorectal cancer tissue. B7-2 was expressed in mononuclear calls distributed along the invasive margin in 37 of 43 cases. B7-1 was positive in the same area in 22 cases. In contrast, the expression of B7-1/B7-2 was usually inconspicuous in the stroma within cancer. Most B7-1+ and B7-2+ cells were identified as macrophages because of the coexpression of CD68 antigen or acid phosphatase activity. CD4+ or CD8+ T cells were distributed in the same area and were in close contact to B7-1/B7-2+ cells. Both CD4+ and CD8+ T cells had a proliferative activity with a labeling index of Ki-67 of 1.5% and 2.5%, respectively. Conventional electron microscopy confirmed both the accumulation of macrophages along the invasive margin and the attachment of lymphocytes to them. Immunoelectron microscopy confirmed: (a) localization of B7-2/B7-1 along the cell membrane; (b) abundance of vacuoles and heterophagosomes (a finding indicative of phagocytosis of other cells) in the cytoplasm of these cells; and (c) direct cell-to-cell contact between these macrophages and lymphocytes. The present data, which suggest that an immune reaction occurs along the invasive margin of colorectal cancer, are in accordance with previous clinicopathologic studies suggesting that peritumoral lymphocytic infiltration is one of the favorable prognostic factors in this disease.

Tuberous sclerosis (TSC) is an autosomal dominant condition characterized by various hamartomas. To assess whether these hamartomas have common features, we immunohistochemically analyzed an autopsy case of TSC with subependymal giant cell astrocytoma, hamartomatous lymphangioleiomyomatosis in the lungs and uterus, and angiomyolipomas in the liver, bilateral kidneys, parametrium, and a lymph node, using the specific antibodies for tuberin (the gene product of TSC2) and HMB-45 (a monoclonal antibody specific for human melanoma). Tuberin was ubiquitously expressed in the normal organs. It was negative or very weakly expressed in the hamartomas. In contrast, HMB-45 was commonly observed in the hamartomas except for the lesions in the brain. The subependymal giant cell astrocytoma was composed of cells immunoreactive for synaptophysin, neurofilament protein, glial fibrillary acidic protein, and S-100 protein but negative for HMB-45 and tuberin. The suppression of tuberin in the brain tumor and visceral hamartomas and an abnormal expression of HMB-45 in the visceral hamartomas were observed. We conclude that the hamartomas associated with TSC have common phenotypic and etiologic expressions and that the genes responsible for both tuberin and the antigen recognized by HMB-45 have important roles in the pathogenesis of these hamartomas.

FDG-PET activation study was performed in two pure akinesia (PA) patients with silent pattern in surface electromyography (EMG) frozen gait analysis. Three patients (2 PA and 1 PD with reciprocal co-contraction pattern) and 7 normal subjects underwent FDG-PET study in two different condition of "rest" and "walk", in order to evaluate the change in regional cerebral activity during gait. In a PD patient, the activated pattern was no different from that of normal individuals; the cerebellar vermis was solely activated significantly. In contrast, 2 PA patients showed characteristic activation in the dorsolateral frontal area in addition to the areas found in normals. These results suggest that the dorsolateral frontal cortex may play an inhibiting role to the motor cortex resulting in the silent pattern of frozen gait in PA. Combined study of surface EMG and FDG-PET during gait may be useful for analyzing the pathophysiological mechanism of gait disturbance.

The pathogenesis of Crohn's disease, an intractable inflammatory disease, involves impaired and/or excessive activation of mucosal macrophages and T lymphocytes. B7-1 (CD80) and B7-2 (CD86) molecules are costimulatory molecules that are indispensable to T-cell activation by antigen-presenting cells. To elucidate the roles and characteristics of these antigen-presenting cells in Crohn's disease, in situ localization of B7-1 and B7-2 (in relation to the distribution of T cells) was clarified by light and electron microscopic immunohistochemistry. The results were compared with those from a study of ulcerative colitis. Normal colonic tissue expressed B7-1 or B7-2 only sporadically. In active Crohn's disease, however, an increase in the number of B7-1/B7-2+ cells correlated with an increase in expression of HLA-DR and intercellular adhesion molecule-1. Most B7-1/B7-2+ cells were identified as noncaseating granulomas or as macrophages, which tended to form an aggregate especially in ulcer bases. In active ulcerative colitis, the increase of B7-1/B7-2+ cells was not as prominent as that in Crohn's disease. Double immunohistochemistry revealed a close cellular distribution between noncaseating granulomas and T cells. Immunoelectron microscopy confirmed the expression of B7-1/B7-2 along the plasma membranes of cytoplasmic processes of granuloma cells, where lymphocytes were closely attached. The present study suggested that granuloma formation in Crohn's disease is coupled with antigen presentation via a B7-1/B7-2-CD28 pathway, which may contribute to the pathogenesis of the disease.

Among 100 patients with cervical myelopathy, we found 7 patients with gait disturbance in which motor or sensory involvements were absent (group A). In these patients, the gait was unsteady, but not ataxic nor spastic. Some of them showed mild hyperreflexia, but no one had Romberg's sign. We compared the effect of neck traction and radiological findings in group A with these in 25 patients who had gait disorders as well as other symptoms associated with cervical myelopathy (group B). Mean age in group A (mean 83.9 +/- 7.9 ys) was older than that in group B (mean 76.6 +/- 5.7 ys). Gait disorders improved in 6 cases of group A (86%), and 5 cases in group B (20%) by conservative therapy of Glisson's traction. On plain X-ray examination, the physiologic lordosis of cervical spine was preserved, the cervical canal diameters from C2 to C7 were more wide, and the number of intervertebral excessive mobility had tendency to be less in group A than in group B. Cervical MRI indicated that the number of intervertebral spinal compression was less in group A than in group B. In the cervical myelopathy, there was a type showing only gait disturbance which was characterized by the good response to Glisson's neck traction, and by the preserved physiological lordosis, relatively wide spinal canal, and slight intervertebral compression.

A rare case of leiomyoma of the mandible is reported together with the conventional histologic, immunohistochemical, and electron microscopic findings. On immunohistochemical evaluation the tumor cells were positive for vimentin, desmin, and alpha-smooth muscle actin but negative for neurogenic antigens and markers for vascular endothelial cells. Ultrastructural examination revealed smooth muscle cell differentiation. The Ki-67 labeling index was 4.7%. The tumor showed rapid increase in size and clinical features suggestive of malignancy. However, on histopathologic evaluation it was diagnosed as a benign neoplasm, and this diagnosis was supported by the results for mitotic rate, Ki-67 labeling index, and p53 immunostaining.

Expression of members of the epidermal growth factor family, including epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), amphiregulin (AR), and Cripto, as well as their putative receptor, epidermal growth factor receptor (EGFR), was studied immunohistochemically in human gastric mucosa to evaluate their possible roles in cell proliferation of normal and regenerative gastric mucosa. We also examined the correlation betwen cell proliferation and EGFR by double immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and EGFR. In normal gastric mucosa, TGF-alpha, Cripto, and AR immunoreactivities were observed in the surface epithelial and parietal cells of gastric fundic glands, respectively. EGF immunoreactivity was not observed in any of normal mucosa examined. EGFR immunoreactivity was detected on foveolar cells in proliferative zones and in parietal cells. Double immunostaining revealed that EGFR immunoreactivity was distributed much more widely than PCNA immunoreactivity. PCNA positive epithelial cells adjacent to gastric ulcer margin expressed relatively intense EGFR but did not express any of the growth factors examined. On the other hand, relatively intense immunoreactivity of both TGF-alpha and Cripto was detected in PCNA-negative regenerative epithelium located distant from gastric ulcer margin. Relative immunoreactivity of AR in regenerative gastric epithelium associated with ulcer was not different from that in normal gastric mucosa. TGF-alpha, AR, and Cripto are considered to play important roles in normal gastric mucosal proliferation, and TGF-alpha and Cripto may be involved in ulcer healing, possibly via a paracrine mechanism.

It remains controversial whether agraphia can coexist in a case with apraxia of speech, and whether an apraxia of speech can be classified into a category of aphasia. We examined the presence of agraphia in 2 right-handed patients of apraxia of speech. Case 1 of mild agraphia showed an infarcted lesion in the left precentral gyrus extending to the neighboring white matter, which involving the arcuate fasciculus on MRI. Positron emission tomography (PET) indicated decrease of cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) in the infarcted lesion, but no decrease of CBF and CMRO2 in the Broca's area. In this case, agraphia was more conspicuous in "kanji" than in "kana" and severity of the agraphia was not correlated to that of speech disturbance on naming test. Case 2 without agraphia showed a small infarcted lesion in the left precentral gyrus, which did not extend to the deep white matter on MRI. Agraphia can coexist with apraxia of speech in a case with the lesion in the left precentral gyrus, in which the cortical lesion is relatively widespread or extends to the deep white matter. However, lack of etiological connection between the agraphia and the apraxia of speech was suggested. We could not confirm the location in the left precentral gyrus which is responsible for the agraphia.