Cholinergic neurons contain Calbindin-D28k in the monkey medial septal nucleus and nucleus of the diagonal band: an immunocytochemical study

The distribution patterns of choline acetyltransferase (CAT), as a marker for cholinergic neurons, and Calbindin-D_28k (CaBP) immunoreactivities in the forebrain basal ganglia of the Japanese monkeyMacaca fuscata were compared. Similar distribution patterns of CAT and CaBP immunoreactivities were found in the medial septal nucleus (MS) and the nucleus of the diagonal band of Broca (DBB). Double-labeling fluorescence immunocytochemistry revealed that most, but not all, cholinergic neurons were CaBP-immunoreactive in the MS and DBB. The results suggest that CaBP may play a role in the septohippocampal cholinergic neuron system of the monkey.     

When is total thyroidectomy indicated as a treatment of “follicular carcinoma”?

Clinicopathologic studies were performed to establish rational criteria for total thyroidectomy as a treatment of follicular carcinoma. During the 4-year period from 1981 to 1984, total thyroidectomy was carried out on 23 patients in whom unequivocal vascular invasion and/or obvious extracapsular extension were disclosed on pathological study of the primary thyroid lesion. Although occult metastatic lesions were detected postoperatively in 5 patients, no distant metastases have been found in 12. Distant metastasis was clinically manifest on admission in the other 6 patients. The degree of vascular invasion at the primary lesion was not correlated with the occurrence of distant metastasis. However, 10 of the 15 patients with tumors characterized by a thick fibrous capsule had distant metastases, while all but 1 of 8 patients with a thin capsule showed no metastasis. Apparent capsular invasion seemed to increase the relative risk of distant metastasis. On the other hand, solid clusters of tumor cells containing a variable number of small follicles, which characterize Langhans' wuchernde Struma, were found in 6 patients, and 5 of them showed distant metastases. Thus, total thyroidectomy should be considered when (a) distant metastases are clinically apparent, (b) the primary lesion has a thick fibrous capsule with or without obvious capsular invasion, or (c) solid clusters of tumor cells are demonstrated microscopically.

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Resumen Se realizaron estudios clinicopatológicos con el propósito de establecer criterios racionales para la tiroidectomía total en el tratamiento del carcinoma folicular. En el curso de un perfodo de 4 anos entre 1981 y 1984, se realizó tiroidectomía total en 23 pacientes en quienes se halló inequívoca invasión vascular y/o obvia extension extracapsular en el examen histopatológico de la lesión tiroidea primaria. Aunque postoperatoriamente se detectaron lesiones metastáticas ocultas en 5 pacientes, no se encontraron metástasis distantes en 12. Metástasis distantes eran clínicamente manifiestas en el momenta de la admisión en los otros 6 pacientes. El grado de invasión vascular en la lesión primaria no apareció correlacionado con la ocurrencia de metástasis distantes. Sin embargo, 10 de los 15 pacientes con tumores caracterizados por una cápsula gruesa y fibrosa tenían metástasis distantes, mientras solo 1 de 8 pacientes con tumores de cápsula fina mostró metástasis. La invasión capsular aparente parece incrementar el riesgo relativo de metástasis distantes. Por otra parte, agrupaciones sólidas de células tumorales con presencia de números variables de folículos pequeños, que caracterizan al wuchernde Struma de Langhans, fueron encontrados en 6 pacientes, 5 de los cuales mostraron metastasis distantes. Por lo tanto, se debe considerar la tiroidectomía total cuando: (a) haya metástasis distantes clínicamente aparentes, (b) la lesión primaria tenga una gruesa cápsula fibrosa con o sin invasión capsular obvia, y (c) se demuestren microscópicamente agrupaciones sólidas de células tumorales.

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Résumé Une étude clinicopathologique a été menée pour déterminer les critères de thyroïdectomie totale comme traitement dans le cancer folliculaire de la thyroïde. Pendant 4 ans, de 1981 à 1984, 23 patients ont subi une thyroïdectomie totale pour envahissement vasculaire non équivoque et/ou extension extracapsulaire évidente découverte sur la pièce d'exérèse initiale. Cinq patients avaient des métastases occultes découvertes dans la période postopératoire, 6 avaient des métastases cliniquement évidentes, alors que 12 ne présentaient aucun signe de métastase à distance. Le degré d'envahissement vasculaire de la lésion primitive n'était pas corrélé avec la survenue de métastases à distance. Cependant, 10 des 15 patients à tumeurs caractérisées par un épaississement de la capsule fibreuse avaient des métastases à distance, alors que 7 des 8 patients avec une capsule mince n'avaient pas de métastases. L'envahissement capsulaire était associé à un plus grand risque de métastases à distance. Des amas solides de cellules tumorales contenant de petits follicules, le wuckernde struma de Langhans, étaient retrouvés dans 6 cas, dont 5 avaient des métastases à distance. Ainsi, la thyroïdectomie totale est préconisée lorsque (a) des métastases à distance sont cliniquement évidentes, (b) la lésion primitive possède une capsule fibreuse épaisse avec ou sans envahissement évident, et (c) on met en évidence des cellules tumorales en amas microscopiquement.

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Presented at the International Association of Endocrine Surgeons in Sydney, Australia, September, 1987.     

Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease

Collapsin response mediating protein-2 (CRMP2) has been identified as an intracellular protein mediating Semaphorin3A (Sema3A), a repulsive guidance molecule. In this study, we demonstrate that cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3beta (GSK3beta) plays a critical role in Sema3A signalling. In In vitro kinase assay, Cdk5 phosphorylated CRMP2 at Ser522, while GSK3beta did not induce any phosphorylation of CRMP2. Phosphorylation by GSK3beta was exclusively observed in Cdk5-phosphorylated CRMP2, but barely in CRMP2T509A. These results indicate that Cdk5 primarily phosphorylates CRMP2 at Ser522 and GSK3beta secondarily phosphorylates at Thr509. The dual-phosphorylated CRMP2, but not non-phosphorylated or single-phosphorylated CRMP2, is recognized with the antibody 3F4, which is highly reactive with the neurofibrillary tangles of Alzheimer's disease. 3F4 recognized the CRMP2 in the wild-type but not cdk5-/- mouse embryonic brain lysates. The phosphorylation of CRMP2 at Ser522 caused reduction of its affinity to tubulin. In dorsal root ganglion neurones, Sema3A stimulation enhanced the levels of the phosphorylated form of CRMP2 detected by 3F4. Over-expression of CRMP2 mutant substituting either Ser522 or Thr509 to Ala attenuates Sema3A-induced growth cone collapse response. These results suggest that the sequential phosphorylation of CRMP is an important process of Sema3A signalling and the same mechanism may have some relevance to the pathological aggregation of the microtubule-associated proteins.     

Amino acid residues conferring the nucleotide binding properties of N-acetyl-D-glucosamine 2-epimerase (renin binding protein)

Our recent studies have demonstrated that the middle domain of N-acetyl-D-glucosamine (GlcNAc) 2-epimerase participates in the specificity for and binding of nucleotides. To identify the residue conferring nucleotide binding, amino acid substitutions were introduced in the human and rat GlcNAc 2-epimerases. The mutational analyses indicate that residue 171 of GlcNAc 2-epimerase is critical for the nucleotide binding of GlcNAc 2-epimerase.     

Lipopolysaccharide Induces CD25-Positive, IL-10-Producing Lymphocytes Without Secretion of Proinflammatory Cytokines in the Human Colon: Low MD-2 mRNA Expression in Colonic Macrophages

Despite the huge number of colonized Gram-negative bacteria in the colon, the normal colon maintains its homeostasis without any excessive immune response. To investigate the potential mechanisms involved, human colonic lamina propria mononuclear cells (LPMCs) obtained from uninflamed mucosa were cultured with lipopolysaccharide (LPS) prepared from Bacteroides vulgatus (BV-LPS) or Bacteroides fragilis (BF-LPS), as representatives of indigenous flora, or pathogenic Salmonella minnesota (SM-LPS). Colonic LPMCs failed to produce inflammatory cytokines in response to any type of LPS. Colonic macrophages barely expressed mRNA for MD-2, an essential association molecule for LPS signaling via Toll-like receptor 4. Further, BV-LPS induced CD25 and Foxp3 expression in lymphocytes and CD4(+)CD25(+) cells expressed IL-10 mRNA. Thus, the low expression of functioning LPS receptor molecules and induction of IL-10-producing CD4(+)CD25(+) lymphocytes by indigenous LPS may play a central role in the maintenance of colonic immunological homeostasis.     

Bcl11b is required for differentiation and survival of alphabeta T lymphocytes

The gene Bcl11b, which encodes zinc finger proteins, and its paralog, Bcl11a, are associated with immune-system malignancies. We have generated Bcl11b-deficient mice that show a block at the CD4-CD8- double-negative stage of thymocyte development without any impairment in cells of B- or gammadelta T cell lineages. The Bcl11b-/- thymocytes showed unsuccessful recombination of V(beta) to D(beta) and lacked the pre-T cell receptor (TCR) complex on the cell surface, owing to the absence of Tcrb mRNA expression. In addition, we saw profound apoptosis in the thymus of neonatal Bcl11b-/- mice. These results suggest that Bcl11b is a key regulator of both differentiation and survival during thymocyte development.     

Chromophobe renal cell carcinoma

Chromophobe renal cell carcinoma (RCC) is a recently established subtype of RCC, which has rarely been reported in Japan. In this communication, the authors report two Japanese cases of chromophobe RCC together with the immunohistochemical findings. The tumors were composed of sheets and cribriform glands formed by tumor cells with cloudy and reticular cytoplasm. Ultrastructurally, the cytoplasm was filled with numerous microvesicles. The tumor cells were positive for cytokeratin, epithelial membrane antigen, and Tamm-Horsfall protein. Occasionally, LeuM1-positive cells were also noted. Vimentin was negative, unlike the usual RCC. Reactivity for peanut agglutinin was more frequent than that to Lotus tetragonolobus agglutinin. The results of this study suggest that the tumor cellq possessed phenotypes similar to the distal nephron rather than to the proximal tubular cells.     

HEPATITIS-ASSOCIATED APLASTIC ANEMIA WITH SYSTEMIC PLASMACYTOSIS

An autopsy case of hepatitis associated aplastic anemia was presented. A 58-year-old Japanese female with non-A, non-B hepatitis was admitted on August 2, 1983. Moderate grade of fever and hemorrhagic diathesis appeared on September 16, when hepatitis was evaluated as being under resolving. The peripheral blood and bone marrow findings were consistent with aplastic anemia. Since infection was suggested by increased levels of serum gamma-globulin and CRP, treatment with antibiotics as well as prednisolone and blood transfusion was initiated. Since September 21, gradual tenderness and edema on the right lower abdominal wall appeared. She died on October 3.
On postmortem examination, systemic plasmacytosis with lymphadenopathy and septic monilial infection was revealed. Numerous plasma cells were atypical, but were immunohistochemically proved to be polyclonal. The bone marrow showed a massive and diffuse plasma cell proliferation with extremely scarce myeloid cells and megakaryocytes. There was a large granulomatous lesion with monilial infection in the wall of the ileocecum. By these findings, systemic plasmacytosis was suspected to be due to chronic monilial infection.
The pathogenesis of systemic plasmacytosis in aplastic anemias and in other diseases were discussed with relation to the present case.     

Effects of suramin on metastatic ability,proliferation, and production of urokinase-type plasminogen activator and plasminogen activator inhibitor type 2 in human renal cell carcinoma cell line SN12C-PM6

Effects of suramin, a polysulfonated naphthylurea compound, on metastatic ability, proliferation, and production of plasminogen activators and plasminogen activator inhibitors were studied using the highly metastatic human renal cell carcinoma cell line, SN12C-PM6. After renal subscapular implantation of tumor cells in nude mice, suramin significantly inhibited metastasis of tumor cells to the lungs and liver. In vitro growth of tumour cells was inhibited by suramin in a dose-dependent manner, at relatively low doses (ID₅₀ = 105 µg/ml). Plasminogen activator inhibitor type 2 (PAI-2) production by tumor cells was enhanced by suramin (100 µg/ml), whereas urokinase-type plasminogen activator (uPA) production was suppressed. Thus, the increase in PAI-2 and the decrease in uPA production correlated with the inhibitory effects on tumour growth and metastasis by suramin. Therefore suramin may be beneficial for the treatment of patients with an early stage of renal cancer with potential risk of metastasis.     

Dna ploidy of pheochromocytoma on cytology specimen by image analysis

Pheochromocytoma usually shows prominent nuclear atypia, but the presence of such atypical cells is known to be an unreliable predictor of malignancy. DNA ploidy of pheochromocytomas has been analyzed by flow cytometry or photospectrometry on paraffinem-bedded tissue, but the results were controversial. We performed DNA analysis on cytology specimens of 11 pheochromocytomas using an image analysis system. All tumors had a mixed pattern of a large population of diploid cells and a small population of polyploid cells. DNA content correlated with nuclear size, and larger cells had more DNA content. Such larger tumor cells had polyploid nuclei, such as 4 C, 8 C, 16 C, and 32 C, in both malignant and benign pheochromocytomas. The larger polyploid nuclei may result from difficulty of duplication at the mitotic phase of the cell cycle.