Infrequent genetic alterations of the PTEN gene in Japanese patients with sporadic prostate cancer

Prostate cancer is a major cause of cancer death among elderly men in America, Europe, and Japan. However, the molecular mechanism of carcinogenesis is not yet well characterized. Frequent loss of heterozygosity (LOH) on chromosome 10q was reported in prostate cancer, and a candidate tumor suppressor gene, PTEN, was isolated on chromosome band 10q23.3. To investigate the genetic alterations of PTEN, we examined 45 primary prostate cancer specimens. LOH at the PTEN locus was observed in two (11.1%) of 18 tumors. However, no mutations were observed in any of the primary prostate cancers. These data suggest that mutation of the PTEN gene does not play a major role in prostate carcinogenesis of Japanese patients. Received: February 6, 1998 / Accepted: July, 3, 1998     

Ultrastructural, cytochemical, and biophysical aspects of mechanisms of bone matrix calcification

Primary calcification in embryonic ossification occurs as follows: crystallization within matrix vesicles, formation of calcified nodules, and finally the establishment of expansive calcified matrix. However, the participation of the matrix vesicles in other types of bone calcification, such as bone formation during bone remodeling in adults has not been examined sufficiently. We introduce our recent observations on the presence of matrix vesicles in aged bones. In addition, although it is well known that the extracellular fluid supersaturates the calcification crystal, hydroxyapatite, the specific mechanisms by which bone matrix calcify remain unclear. In order to further approach the mechanisms of bone matrix calcification, we also review ultrastructural and localizational alterations of the matrix organics according to the progression of calcification, and an evaluation of mineral micro-environment in the calcifying sites by energy-filter transmission electron microscopy.     

h-Caldesmon in leiomyosarcoma and tumors with smooth muscle cell-like differentiation: its specific expression in the smooth muscle cell tumor

h-Caldesmon (h-CD) is a protein combined with actin and tropomyosin that regulates cellular contraction. h-CD has been thought to be expressed exclusively in vascular and visceral smooth muscle cells (SMC). We examined h-CD expression immunohistochemically in tumors with SMC and SMC-like differentiation to clarify whether h-CD is specifically expressed in SMC tumors. The tumors examined in this study were six leiomyomas (LM), two angioleiomyomas (ALM), six leiomyosarcomas (LMS), eight rhabdomyosarcomas (RMS), eight malignant fibrous histiocytomas (MFH), four desmoids, three glomus tumors (GT), and two inflammatory myofibroblastic pseudotumors (IMP) of urinary bladder. We found that LM, ALM, LMS, and GT showed intense and extensive immunoreactivity for h-CD, whereas other tumors were completely negative for h-CD. In addition, h-CD was not present in the vascular pericytes and myofibroblasts, in contrast to actin. Although myoepithelial cells were immunopositive for h-CD, neoplastic myoepithelial cells of myoepithelial tumors and mixed tumors of the salivary gland and skin were all negative. These findings indicate that h-CD is a specific marker of both SMC and its neoplasms and that immunohistochemical detection of h-CD may facilitate the differential diagnosis between LMS and other tumors with SMC-like differentiation, including myofibroblastic tumors.     

Simultaneous activation of natural killer T cells and autoantibody production in mice injected with denatured syngeneic liver tissue

Denatured syngeneic liver tissue prepared by mechanical procedures was intraperitoneally injected into adult C57BL/6 mice. In parallel with a decrease in the total number of lymphocytes in the liver, spleen, and thymus from days 1-7 after the injection, the proportion of the CD4+NK1.1+CD3(int) subset of these cells (i.e. natural killer T or NKT cells) increased in the liver. Even the absolute number of these NKT cells increased in the liver on days 14 and 21. In response to the injection of denatured liver tissue, tissue damage was induced in the liver, as shown by elevated levels of serum transaminases and hepatocyte degeneration observed by electron microscopy. Sera obtained on days 7 and 14 contained autoantibodies including anti-DNA antibodies. The proportion of CD1d(high)B cells in the liver was found to decrease on days 1-7. In other words, denatured liver tissue stimulated both NKT cells and certain B cells in the liver. These results suggest that liver lymphocytes might contain not only autoreactive T cells (e.g. CD3(int) or NKT cells) but also some B cells (e.g. B-1 cells) which produce autoantibodies and that the denatured tissue had the potential to stimulate these lymphocytes and to evoke an autoimmune-like state.     

Three-dimensional eye position and slow phase velocity in humans with downbeat nystagmus

Downbeat nystagmus (DN), a fixation nystagmus with the fast phases directed downward, is usually caused by cerebellar lesions, but the precise etiology is not known. A disorder of the smooth-pursuit system or of central vestibular pathways has been proposed. However, both hypotheses fail to explain why DN is usually accompanied by gaze-holding nystagmus, which implies a leaky neural velocity-to-position integrator. Because three-dimensional (3-D) analysis of nystagmus slow phases provides an excellent means for testing both hypotheses, we examined 19 patients with DN during a fixation task and compared them with healthy subjects. We show that the presentation of DN patients is not uniform; they can be grouped according to their deficits: DN with vertical integrator leakage, DN with vertical and horizontal integrator leakage, and DN without integrator leakage. The 3-D analysis of the slow phases of DN patients revealed that DN is most likely neither caused by damage to central vestibular pathways carrying semicircular canal information nor by a smooth pursuit imbalance. We propose that the observed effects can be explained by partial damage of a brain stem-cerebellar loop that augments the time constant of the neural velocity to position integrators in the brain stem and neurally adjusts the orientation of Listing's plane.     

Multiple epithelial cysts of the spleen and on the splenic capsule, and high serum levels of CA19-9, CA125 and soluble IL-2 receptor

An 18-year-old woman with abdominal pain was diagnosed as having splenic cysts by computed tomography scan. She had high serum levels of CA19-9 (2886.8 U/mL; normal value, <35 U/mL), CA125 (131.1 U/mL; normal value, <35 U/mL) and soluble IL-2 receptor (1490 U/mL; normal range, 220-530 U/mL). The resected spleen weighed 1050 g, was 14 x 28 cm, and had more than 10 macroscopic cysts up to 10.3 x 9.5 cm. There were numerous microscopic cysts in the spleen and several on the splenic capsule. The levels of CA19-9 and CA125 in the cyst fluid were 2165550 U/mL and 160400 U/mL, respectively. After the surgery, the serum levels of the tumor markers decreased gradually. The inside of the largest cyst was mainly covered by granulation tissue with a focal lining of epithelial cells, and the other macroscopic cysts had stratified squamous epithelium. The microscopic splenic cysts and cysts on the splenic capsule were lined by either attenuated single-layered or multilayered epithelial cells. The lining epithelial cells of these cysts were positive for epithelial membrane antigen and cytokeratins. CA19-9 and CA125 were detected in the lining cells of the splenic cysts. In the present case, it is suspected that the splenic cysts were derived from the capsular lining cells that showed migration from the capsule or formed microcysts on the splenic capsule, as in the case of ovarian inclusion cysts.     

Embryonic development of the pituitary gland in the chick

Pituitary glands of chicken, from stages 20 (70 approximately 72 h of incubation) to 46 (20 days) of Hamburger and Hamilton (1951), were studied by immunocytochemical and histological stainings and India ink injection into blood vessels. Using the distribution pattern of 6 types of immunoreactive adenohypophyseal cells and the location of pituitary stalk as guideposts, we found how specific areas in the epithelium of Rathke's pouch differentiate into specific regions of the adenohypophysis at 20 days. In the sagittal plane, the walls of Rathke's pouch were tentatively divided into the upper part (A(1) + A(2)) and lower part (A(3)) of the anterior wall, and the posterior wall (P(1) + P(2) + P(3)). The cephalic lobe was mainly assembled by the proliferation of parenchymal cells in the areas A(2) + A(3) + P(2) of Rathke's pouch epithelia at 3 days of incubation. The caudal lobe was derived from A(1) + P(1) + P(3). The pars tuberalis was derived from A(1) + A(2). Thus, the avian adenohypophysis is established at 13 days, though the blood supply to the pars distalis is established at 20 days. Therefore, the cephalic lobe and caudal lobe of the pars distalis and the pars tuberalis of the chicken adenohypophysis are derived from specific areas of the cell cords of Rathke's pouch at 3 days of incubation.     

M pathway and areas 44 and 45 are involved in stereoscopic recognition based on binocular disparity

We characterized the visual pathways involved in the stereoscopic recognition of the random dot stereogram based on the binocular disparity employing a functional magnetic resonance imaging (fMRI). The V2, V3, V4, V5, intraparietal sulcus (IPS) and the superior temporal sulcus (STS) were significantly activated during the binocular stereopsis, but the inferotemporal gyrus (ITG) was not activated. Thus a human M pathway may be part of a network involved in the stereoscopic processing based on the binocular disparity. It is intriguing that areas 44 (Broca's area) and 45 in the left hemisphere were also active during the binocular stereopsis. However, it was reported that these regions were inactive during the monocular stereopsis. To separate the specific responses directly caused by the stereoscopic recognition process from the nonspecific ones caused by the memory load or the intention, we designed a novel frequency labeled tasks (FLT) sequence. The functional MRI using the FLT indicated that the activation of areas 44 and 45 is correlated with the stereoscopic recognition based on the binocular disparity but not with the intention artifacts, suggesting that areas 44 and 45 play an essential role in the binocular disparity.