Construction of a generalized simulator for multi-cellular organisms and its application to SMAD signal transduction.

In this paper, we report development of a generalized simulation system based on ordinary differential equations for multi-cellular organisms, and results of the analysis on a Smad signal transduction cascade. The simulator implements intra-cellular and extra-cellular molecular processes, such as protein diffusion, ligand-receptor reaction, biochemical reaction, and gene expression. It simulates the spatio-temporal patterning in various biological phenomena for the single and multi-cellular organisms. In order to demonstrate the usefulness of the simulator, we constructed a model of Drosophila's Smad signal transduction, which includes protein diffusion, biochemical reaction and gene expression. The results suggest that the presence of negative feedback mechanism in the Smad pathway functions to improve the frequency response of the cascade against changes in the signaling.

A gene network inference method from continuous-value gene expression data of wild-type and mutants.

In this paper we introduce a new inference method of a gene regulatory network from steady-state gene expression data. Our method determines a regulatory structure consistent with an observed set of steady-state expression profiles, each generated from wild-type and single deletion mutant of the target network. Our method derives the regulatory relationships in the network using a graph theoretic approach. The advantage of our method is to be able to deal with continuous values of steady-state data, while most of the methods proposed in past use a Boolean network model with binary data. Performance of our method is evaluated on simulated networks with varying the size of networks, indegree of each gene, and the data characteristics (continuous-value/binary), and is compared with that of predictor method proposed by Ideker et al. As a result, we show the superiority of using continuous values to binary values, and the performance of our method is much better than that of the predictor method.

Clinical analysis and TPO levels in three patients with refractory thrombocytopenia.

Refractory thrombocytopenia (RTC) is a counter-concept to refractory anemia, which is characterized by isolated thrombocytopenia associated with clonal chromosomal abnormality. The diagnosis of RTC is difficult to establish based on morphologic features alone. And steroid therapy for RTC is often ineffective. We examined 3 patients with RTC to identify its characteristics and measured serum thrombopoietin levels. The mean platelet count was 5.1 x 10(4)/microl and the mean age was 64 years. None of our patients had clinical nor laboratory evidence of liver dysfunction, renal disease or disseminated intravascular coagulation. All patients were negative for antiplatelet antibody, PA-IgG and anticardiolipin-beta2GPI antibody. Leukocyte alkaline phosphatase level was low in two patients. Clonal chromosomal abnormalities of different types were detected in all patients. Bone marrow smears showed micromegakaryocytes. But there were no apparent morphological abnormalities of erythroid and granuloid series. Thrombopoietin levels, as determined by enzyme-linked immunosorbent assay, varied from <0.2 to 1.40 fmol/ml. We could not find the screening tool of RTC. In conclusion, there is a need to identify RTC from isolated thrombocytopenia because the patients with RTC don't have good prognosis as patients with isolated thrombocytopenia. Cytogenetic analysis is necessary to establish the diagnosis of RTC. We recommend that a patient above 50 years of age presenting with isolated thrombocytopenia and a low leukocyte alkaline phosphatase score should be suspected of having RTC.

[Primary pleural non-Hodgkin's lymphoma without chronic pyothorax].

Most cases of primary pleural malignant lymphoma develop following chronic pyothorax. We report a case of primary pleural non-Hodgkin's lymphoma without chronic pyothorax. A 63-year-old woman was referred and admitted to our hospital with a right pleural effusion that was detected during a routine physical checkup. Her liver, spleen, and superficial lymph nodes were not palpable on physical examination. The massive right pleural effusion and a pleural mass were demonstrated on chest X-ray films and thoracic computed tomograms. Diffuse large B-cell non-Hodgkin's lymphoma was diagnosed by needle biopsy from the pleura, and the clinical stage was IE. Pleural effusion specimens contained no identifiable lymphoma cells, and examinations for Mycobacterium species were also negative. Human herpes virus 8 (HIV-8) DNA was detected in lymphocytes from the peripheral blood and pleural effusion. Epstein-Barr virus-encoded small RNAs and HHV-8 DNA were both negative in biopsied tissue from the pleural mass. Although a complete remission was achieved, the lymphoma relapsed about 8 months later. The patient is currently receiving salvage chemotherapy. Cases of primary pleural non-Hodgkin's lymphoma with massive pleural effusion that are not preceded by chronic pyothorax or Kaposi's sarcoma are very rare.

Monomorphic agranular natural killer cell lymphoma/leukemia with no Epstein-Barr virus association.

The conceptual view of natural killer (NK) cell malignancies has recently undergone a significant evolution. The majority of such diseases are associated with Epstein-Barr virus (EBV), while only a limited number of EBV-negative cases has been reported. We report an unusual case of NK cell lymphoma/leukemia showing a monomorphic histology, absence of intracytoplasmic azurophilic granules, and no EBV association. The patient was a 57-year-old woman who died 26 months after the diagnosis. Autopsy revealed tumor infiltration in the liver, spleen, lymph node, blood, and bone marrow. There was no involvement of the skin or nasal cavity throughout the clinical course. The tumor showed the monotonous proliferation of medium-sized cells without intracytoplasmic azurophilic granules. Phenotypic analysis showed CD2+, CD3/Leu4-, cytoplasmic CD3epsilon+, CD4-, CD5-, CD7+, CD8-, CD16-, CD38+, CD56+, CD57-, TdT-, granzyme B-, and TIA1+ phenotype. There were no detectable rearrangements of T cell receptor genes or immunoglobulin heavy chain genes. Furthermore, there were no EBV-encoded small RNAs. These findings provide information to improve the understanding of poorly defined entities, i.e. aggressive NK cell lymphoma/leukemia and blastic NK cell lymphoma/leukemia.

Simulation of genetic interaction for Drosophila leg formation.

The formation of Drosophila wings and legs are major research topics in Drosophila development, and several hypotheses, such as the polar-coordinate model and the boundary model, has been proposed to explain mechanisms behind these phenomena. A series of recent studies have revealed complex interaction among genes involved in establishing three principal axes (A-P, D-V, and P-D) of leg formation. In this paper, we present a simulation system for leg formation, simulating the genes interactions involved. We use this simulator to investigate a mathematical framework of leg formation which is otherwise well-founded from a molecular perspective. Particularly, we focus on the formation of the expression patterns of dpp, wg, dll, dac, al, en, hh and ci genes, which are involved in the development of the third instar Drosophila leg disc. The most interesting part of this research is showing how the coaxial gene expression patterns behind the P-D axis can be formed, and how positional information, as postulated in the polar-coordinate model, can be conveyed to each cell. Our results suggest that P-D axis can be formed by a set of genes with different activation thresholds; the process involves different chemical gradients of dpp and wg products, forming a bi-polar contour. Interestingly, this combination of chemical gradients can specify unique positions of cells for the hemisphere, leaving the A-P axis determiner to decide only whether the cells are anterior or posterior. All in all, our so-called Bi-Polar Model describes axial formation of the leg disc well.

Cavernous sinus syndrome associated with nonsecretory myeloma.

The case of a 53-year-old man who developed cavernous sinus syndrome (CSS) four years after being diagnosed as having nonsecretory myeloma is described. He was admitted with diplopia and dull pain over the right infraorbital and zygomatic region in June 1997. The cause of CSS was the intracranial involvement of myeloma, which was diagnosed by fiberscopic biopsy. The results of endocrinologic evaluation were almost normal. The response to radiotherapy and chemotherapy was mild. CSS caused by nonsecretory myeloma is rare and its prognosis is poor. More aggressive chemotherapy with stem cell support may be indicated.

Primary hepatic lymphoma in a patient with chronic hepatitis B.

Primary hepatic lymphoma is a rare disorder and the clinical behavior remains unknown. We report a patient with primary hepatic lymphoma who had chronic hepatitis B. She was asymptomatic; however, a solitary tumor in the left lobe was incidentally detected. After left hepatic lobectomy was performed, a diagnosis of non-Hodgkin's lymphoma was made. No tumor was found except in the liver. Immunohistochemical stains for hepatitis B surface and core antigens were positive in hepatocytes; however, both were negative in the tumor tissue. The patient received no chemotherapy and the tumor relapsed. After chemotherapy, the tumor disappeared. However, exacerbation of hepatitis occurred after the fourth chemotherapy. The patient was followed up without chemotherapy, and she remains in apparent remission. Chemotherapy is effective against primary hepatic lymphoma and, if possible, patients with this disorder should be treated with chemotherapy postoperatively.

Prognostic significance of immunoglobulin heavy chain gene rearrangement in patients with acute myelogenous leukemia.

Recently the immunoglobulin heavy chain (IgH) gene rearrangement in B cell malignancies has been analyzed. Clonality can be determined using the polymerase chain reaction (PCR). Little attention, however, has been given to the relationship between prognosis and IgH gene rearrangement in patients with acute myelogenous leukemia (AML). In this study, we examined IgH gene rearrangement in 35 untreated AML patients by PCR. PCR was performed using consensus heavy chain complimentarity-determining region (CDR)-3 primers. Clonal IgH gene rearrangement was detected in 14 patients (40%). Four of five patients (80%) who were positive for B cell markers had clonal IgH gene rearrangement. Ten of 30 B cell antigen-negative patients (33%) also showed IgH rearrangement. All patients were treated with a daunorubicin-based regimen, resulting in complete remission for 29 patients (83%). Sixty-four percent of those with IgH rearrangement and 95% of those without rearrangement had complete remission. Overall survival of IgH-PCR positive and negative patients at 25 months was 29 and 88%, respectively. IgH-PCR positivity may be a poor prognostic factor in AML.

Nerve terminals associated with the central lacteal lymphatics in the duodenal and ileal villi of the monkey.

An intimate association of nerve fibers with the central lacteal endothelium was demonstrated in the duodenum and ileum of the monkey by immunohistochemistry and transmission electron microscopy. In the basal portion of the central lacteal, nerve fibers containing large cored vesicles and small clear vesicles were located closely beneath the lacteal endothelium. Identification of nerves was performed by immunohistochemistry using antisera against substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide, gastrin-releasing peptide and neuropeptide Y. These nerves contained immunoreactivities for SP and CGRP only. Some of the nerves, either singly or in a dense bundle, indented the endothelial cells to form a conspicuous cushion protruding into the lumen. The attenuated endothelium covering the cushion occasionally was failing, and the nerves were exposed to the lumen. Tight of occasionally subendothelial nerve terminals bundles formed a synapse-like association between themselves: a swollen axonal profile was invaginated by a finger-like projection of another axon, the latter being filled with synaptic vesicles. These results suggest that the central lacteal lymphatics might be afferently monitored, presumably with regard to the luminal pressure, and, at the same time, efferently modulated by these nerves.