Effects of oral theophylline on sick sinus syndrome.

OBJECTIVES: We sought to determine the effect of theophylline on cardiac pauses in sick sinus syndrome. BACKGROUND: Sick sinus syndrome, a relatively benign condition, is usually treated with pacemaker implantation without any proved effectiveness. Thus, an appropriate pharmacologic therapy would be useful. METHODS: Theophylline (200 to 400 mg/day for 1 month) was initially administered orally to 17 patients with sick sinus syndrome, which is manifested by sinus pauses of > 2.5 s. Eleven of the 17 patients subsequently received theophylline for an additional 8 to 37 months. Twenty-four-hour Holter recordings were obtained before treatment, at the end of 1 month of treatment and then at 6-month intervals. RESULTS: Theophylline decreased the frequency of sinus pauses from 256 +/- 230 to 23 +/- 62 pauses per 24 h and decreased the duration of the longest pauses from 4.7 +/- 1.8 to 2.2 +/- 0.97 s after 1 month of treatment. Subjective symptoms associated with cardiac pauses disappeared in 16 of 17 patients. Ventricular premature beats increased in frequency but did not last longer than two beats. Three patients experienced adverse effects. Nine of the 11 patients receiving long-term treatment had a good outcome, but 2 patients required a pacemaker because of the reappearance of long sinus pauses. CONCLUSIONS: The results suggest that oral theophylline may be beneficial for the treatment of patients with sick sinus syndrome.

Forskolin potentiates myocardial reactive hyperaemia in the open chest dog: the contribution of adenylate cyclase.

Forskolin, a diterpene, directly stimulates adenylate cyclase and also potentiates receptor mediated stimulation of this enzyme by many stimulatory agonists. We exploited the potentiating effect of forskolin to test the hypothesis that activation of adenylate cyclase contributes to myocardial reactive hyperaemia, especially by release of adenosine at the time of brief coronary occlusions. In 10 open chest dogs, intracoronary forskolin infusions which produced plasma concentrations between 0.22 and 0.34 mumol.litre-1 slightly increased coronary blood flow and had no effect on haemodynamics or myocardial metabolism. Under these conditions, though peak reactive hyperaemic flow rates were not affected, forskolin infusions reversibly potentiated repayments of flow debt by 28, 25 and 27% following coronary occlusions of 15 s, 20 s and 30 s, respectively (p less than 0.05). In another seven dogs, after observations of the effects of forskolin (0.16-0.26 mumol), 10 mumol of 8-phenyltheophylline, a potent adenosine antagonist, was infused simultaneously with forskolin into the coronary arteries. Forskolin increased debt repayments by about 23-27% following 15 s, 20 s and 30 s occlusions, but with simultaneous 8-phenyltheophylline, forskolin induced increments in the debt repayments were reduced significantly (p less than 0.05). These results indicate that adenylate cyclase contributes to myocardial reactive hyperaemia, and adenosine has a significant role as metabolic regulator of reactive hyperaemia through activation of adenylate cyclase.

Oxygen metabolism of the hypertrophic right ventricle in open chest dogs.

STUDY OBJECTIVE: The aim was to investigate oxygen metabolism of the hypertrophic right ventricle in anaesthetised open chest dogs. DESIGN: Right ventricular hypertrophy was induced by right ventricular pressure overload with banding the pulmonary artery for six months. Coronary blood flow and myocardial oxygen metabolism of the hypertrophic right ventricle were determined during control and after increasing right ventricular oxygen consumption, and compared with those of the normal right and left ventricles. SUBJECTS: Seven mongrel dogs with right ventricular hypertrophy and 21 normal dogs were used. All were anaesthetised with pentobarbitone sodium. MEASUREMENTS AND MAIN RESULTS: Oxygen extraction [(A-V)O2] of the hypertrophic right ventricular myocardium was greater than that of normal right ventricle in controls and almost identical to the (A-V)O2 of the normal left ventricle. It showed no increase when coronary blood flow and right ventricular oxygen consumption were raised in response to a further elevation of the right ventricular pressure and isoprenaline infusion. However, the right ventricular interventions which increased right ventricular oxygen consumption produced an elevation of (A-V)O2 of the right ventricle with an increase in right coronary blood flow. CONCLUSIONS: Higher oxygen extraction during control and no response of oxygen extraction of the hypertrophied right ventricle in response to stimuli which increase right ventricular oxygen consumption indicate that oxygen supply to the hypertrophic right ventricle is different from that of the normal right ventricle, and is more like that of the left ventricle.

Amplification and expression of a decoy receptor for fas ligand (DcR3) in virus (EBV or HTLV-I) associated lymphomas.

The recently identified decoy receptor 3 (DcR3) binds to FasL and inhibits FasL-induced apoptosis, and is considered to play a role in the immune escape system of neoplastic cells. To examine the involvement of DcR3 in the immune evasions of virus-associated lymphoma, we analyzed the amplification and expression of DcR3, using dot blot and in situ hybridization (ISH), in 45 cases, which included 17 cases with Epstein-Barr virus (EBV)-associated lymphoma (seven pyothorax-associated B-cell lymphomas (PAL); ten natural killer lymphoma (NKL)), seven cases with adult T-cell leukemia lymphoma (ATLL), 13 Hodgkin's disease (eight EBV-associated cases; five non-EBV-associated cases), and eight control cases (three reactive lymphadenopathy; five non-EBV-associated-B-cell lymphoma). EBV-associated PAL and NKL exhibited DcR3 amplification and expression in lymphoma cells. ATLL also showed DcR3 expression and amplification. The cases with DcR3 amplification showed DcR3 expression; however, the expression was confined in the neoplastic cells, but not in the reactive cells. In Hodgkin's disease (HD), DcR3 was expressed only in Hodgkin and Reed-Sternberg giant (H-RS) cells. However, DcR3 was not expressed or amplified in reactive lymphadenopathy. Non-EBV-associated B-cell lymphoma also rarely expressed DcR3, and showed no amplification except in two cases, in which rare expression was present. Our results suggest that EBV and HTLV-I probably use DcR3 to escape from the immune system during lymphomagenesis, or virus-infected lymphoma cells with DcR3 expression might be selected in the multistep tumorigenesis.

B-cell lymphoma of 708 cases in Japan: incidence rates and clinical prognosis according to the REAL classification.

New insights into the pathogenesis of lymphoid malignancies have been gained through novel techniques such as genetic, molecular and immunologic methods. Recently, based on those findings, a new classification system for lymphoid malignancies, known as the REAL classification, has been proposed. To clarify the relation between the histological classification and prognosis of B-cell lymphoid malignancies, we re-classified 708 cases. In all cases, the B-cell phenotype and/or genotype was confirmed by immunohistochemical staining and/or receptor gene analysis. The most common B-cell lymphoma types were diffuse large B-cell lymphoma (58.8%), follicular lymphoma (12.1%), marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) (9.0%) and mantle cell lymphoma (5.9%). Minor types were lymphoblastic lymphoma (3.4%), Burkitt's lymphoma (2.4%), nodal marginal zone lymphoma (2.1%), lymphoplasmacytic lymphoma (2.0%) and plasmacytoma (1.4%). Rare types were prolymphocytic lymphoma and splenic marginal zone lymphoma. Using overall survival rates, the various B-cell lymphoma types could be divided into three broad groups for prognostic purposes: (1) the low risk group consisted of follicular lymphoma, marginal zone lymphoma of MALT, nodal marginal zone lymphoma, plasmacytoma and lymphoplasmacytic lymphoma; (2) the intermediate risk group consisted of diffuse large B-cell lymphoma, Burkitt's lymphoma and mantle cell lymphoma; and (3) the high risk group consisted of lymphoblastic lymphoma. In MALT, the low grade type had a better prognosis than the high grade type. In diffuse large B-cell lymphoma, the common type had a better prognosis than the variant type, which mainly consisted of the immunoblastic lymphoma. The histological classification will have a benefit for the clinical approach.

Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of T-lymphocytes, and human T-cell lymphotropic virus type-I (HTLV-I) is etiologically considered as the causative virus of ATLL. The karyotypes of ATLL are very complex in both number and structure, although no specific karyotype abnormalities have been identified. HTLV-I is thought to integrate its provirus into random sites in host chromosomal DNA and induces chromosomal instability. The BUB gene is a component of the mitotic checkpoint in budding yeast. Recently, human homologues of the BUB were identified and mutant alleles of hBUB1 and hBUBR1 were detected in two colorectal tumor cell lines, which showed microsatellite instability (MIN). In vitro, BUB proteins form a complex of monomers. These proteins interact with the human MAD1 gene product, a target of the HTLV-1 tax oncogene. We examined the role of checkpoint gene in the chromosomal abnormalities of ATLL by investigating mutations of hBUB1 and hBUBR1, and MIN of replication errors of BAX, insulin-like growth factor, and transforming growth factor beta type II. We analyzed ten cases with ATLL and eight B-cell lymphomas (five diffuse large cell lymphomas, three follicular lymphomas). Complex chromosomal abnormalities were detected in ATLL, while B-cell lymphomas showed only simple or minimal chromosomal abnormalities. Significant mutations/deletion of hBUB1 or hBUBR1 were detected in four of ten cases with ATLL, including two heterozygous point mutations, one homozygous point mutation, and one with a 47 bp deletion. In contrast, only one of eight B-cell lymphomas showed nonsense mutation of hBUBR1. None of the ATLL and B-cell lymphomas showed MIN. In the multistage process of leukemogenesis of ATLL, our findings indicate that mutations of mitotic checkpoint genes may play an important role in the induction of complex chromosomal abnormalities.

Decreased expression of telomerase-associated RNAs in the proliferation of stem cells in comparison with continuous expression in malignant tumors.

Telomerase, an enzyme associated with cellular immortality, is expressed by malignant tumor and stem cells, especially germ cells. Normal somatic cells, however, usually do not express telomerase. In the malignant tumor, deregulation of telomerase is thought to facilitate tumorigenesis and cellular immortality by providing cancer cells unlimited proliferation capacity. We investigated the relationship between proliferation activity and in situ expression of the telomerase RNA component (human telomerase RNA component, hTERC). In addition, in situ hybridization of the telomerase-associated proteins (telomerase-associated protein 1, TEP1; human telomerase reverse transcriptase, TERT), and MIB-1 immunohistochemistry for proliferation activity were performed, using the malignant tumors of adenocarcinoma, squamous cell carcinoma, and malignant lymphoma, and somatic tissues of testis, endometrium, stomach, skin, and lymph nodes. In the somatic tissues, the stem cells expressed telomerase-associated RNA, but no proliferation activity. When the proliferation activity of the stem cells increased, however, the telomerase-associated expressions decreased. In the malignant tumors, both proliferation activity and expression of the telomerase-associated RNA significantly increased. Deregulation of telomerase, in addition to proliferation activity, is associated with tumorigenesis.

Participation of T lymphocytes in atherogenesis: sequential and quantitative observation of aortic lesions of rats with diet-induced hypercholesterolaemia using en face double immunostaining.

Using en face double immunostaining coupled with electron microscopy, we studied the temporal and spatial distribution of T lymphocytes and macrophages during the development of atherosclerosis in a diet-induced rat model fed an atherogenic diet for 2-40 weeks. T lymphocytes and macrophages adhered to the aortic surface by 2 weeks on the diet, with subsequent migration under the endothelium, and formed a fatty streak-like lesion. Analysis of the cellular components revealed that infiltration of T lymphocytes was most prominent in the incipient phase of lesion formation accounting for 60%, 29% and 34% of mononuclear cells appearing in 2-week lesions of the superior thoracic, inferior thoracic and abdominal segments of the aorta, respectively. After the incipient phase, the relative number of T lymphocytes in the three segments of the aorta showed a slow decline; the proportion of T lymphocytes to macrophages was approximately 1:3 to 1:4 in 10- to 20-week lesions. An overall view of the lesional cells often demonstrated direct cellular contact between T lymphocytes and macrophages. Further, OX6/ED1 double immunostaining demonstrated that Ia antigen was expressed on most macrophages. In later stages, breakdown of foamy macrophages occurred, and the extracellular accumulation of lipids and cell debris became prominent. The results demonstrated that in the diet-induced rat model, together with macrophages, large numbers of T lymphocytes participated in all stages of aortic lesions, initially adhering to the surface at prelesional stages and later as the principal component of the atherosclerotic lesion. It is possible that the method described here will provide a good tool for examining the role of T lymphocytes in atherogenesis.

Endothelial cell heterogeneity in experimentally-induced rabbit atherosclerosis. Demonstration of multinucleated giant endothelial cells by scanning electron microscopy and cell culture.

We investigated the aortic endothelial cells of cholesterol-fed rabbits, using scanning electron microscopy and a cell culture technique. Rabbits were given a 1% cholesterol diet intermittently for up to 40 weeks. In these animals, the area of endothelial cells was increased and the cells showed polymorphism in relation to the progression of atherosclerosis. In animals fed the cholesterol diet for 12, 28 and 40 weeks, the average area of the endothelial cells was 436 +/- 15, 762 +/- 153, and 836 +/- 165 microns2, respectively. In the cholesterol-fed 40-week group, in particular, giant endothelial cells, measuring more than 1200 microns2, accounted for 14% of the population. In animals fed a standard diet there was no significant difference in endothelial cell morphology between control 0-week and control 40-week groups; in both, the luminal surface of the thoracic aorta formed a homogeneous sheet covered by small rhomboidal endothelial cells, the area of most being less than 400 microns2. Primary cultured endothelial cells harvested from those control groups were mononuclear typical small cells with a centrally located nucleus; the proportion of binucleated cells was less than 2% and no multinucleated giant cells with three or more nuclei were detected. Endothelial cells from the cholesterol-fed groups, however, contained larger numbers of binucleated cells, with the number increasing in proportion to the duration of cholesterol feeding. The major distinguishing feature of the endothelial cells in the cholesterol-fed groups was the presence of multinucleated giant cells with three or more nuclei; these accounted for 2.3% and 3.3% of the total cell population in the cholesterol-fed 28- and 40-week groups, respectively. No bromodeoxyuridine uptake was found in the nuclei of the cultured multinucleated giant cells. Heterogeneity of endothelial cells, with the concomitant appearance of multinucleated giant cells, emerges with the progression of diet-induced atherosclerosis. The morphological alterations of endothelial cells observed in the present study intimately reflect changes in their function associated with the progression of atherosclerotic lesions.

Analysis of the immunoglobulin heavy chain gene variable region of intravascular large B-cell lymphoma.

Intravascular large B-cell lymphoma (IVLBL) is a rare neoplasm characterized by proliferation of lymphoma cells within the blood vessels. The cell origin of IVLBL has not yet been determined. We examined cell lineage, with immunohistochemical staining and molecular analysis, using polymerase chain reaction (PCR) of the variable region of the immunoglobulin heavy chain (Ig-VH) gene. We also investigated the cell origin using direct sequence analysis of the complementary-determining region 2 (CDR2) and framework region 3 (FR3) in six cases, consisting of two male and four female patients. The sequences in five cases showed frequent mutations. The percent homology to their closest germline genes ranged from 74.7 to 91.8%. However, one case showed a percent homology of 99.4% in CDR2 and FR3 of Ig-VH. All cases showed rearrangements of VH3 family genes. Interestingly, three of the IVLBL cases with hypermutated IgH genes showed the expression of CD5. Therefore, expression of CD5 in lymphoma cells does not indicate that the origin of IVLBL is the same as mantle cell lymphoma having the character of CD5 expression, which develops in pre-germinal center cells. Our results indicate that most IVLBLs may originate in the post-germinal center cells, based on the presence of somatic mutation in VH genes, although some heterogeneous cases are intermingled within IVLBL.

The Tsukuba hypertensive mouse (transgenic mouse carrying human genes for both renin and angiotensinogen) as a model of human malignant hypertension: development of lesions and morphometric analysis.

The renin-angiotensin system has a pivotal role in hypertension. The Tsukuba hypertensive mouse (THM; a transgenic mouse carrying human genes for both renin and angiotensinogen) was generated to allow further examination of the renin-angiotensin system in a variety of pathologic conditions. We evaluated the development of renal lesions in these mice and in controls by morphometric, immunohistochemical and ultrastructural methods. Blood pressure was significantly higher in THM than in control mice; 1 year after birth, it was approximately 40 mmHg higher. The kidney-to-body weight ratio was also higher in THM than in control. Morphometrical analysis revealed that the glomerular sclerosis index was significantly elevated in THM with 10% of the glomeruli sclerotic at 18 months. The grade of vascular lesion and the frequency of fibronoid arteritis of the kidney exhibited the same tendency as the glomerular sclerosis index. Murine renin was located exclusively in the juxtaglomerular apparatus, whereas human renin was expressed not only in the juxtaglomerular apparatus, but also in periarteriolar smooth muscle cells and in mesangial and epithelial cells of the glomeruli. Light and electron microscopy revealed significant fibrinoid arteritis of the kidney in THM and also "onion skinning", both pathognomonic for malignant nephrosclerosis. THM may be an excellent model of human malignant hypertension.

Clinical, immunohistochemical and phenotypic features of aggressive nodal cytotoxic lymphomas, including alpha/beta, gamma/delta T-cell and natural killer cell types.

Cytotoxic cells include natural killer (NK) cells and cytotoxic alpha beta and gamma delta T lymphocytes (CTLs). These cells express cytotoxic molecules of T-cell restricted intracellular antigen (TIA-1), and activated cytotoxic molecules of perforin, granzyme B, and FasL. Recent studies suggest that most extranodal T-cell lymphomas are derived from CTLs, and that NK cell lymphomas are extranodal. However, only a few nodal NK and cytotoxic lymphomas have been described so far. We present here the clinicopathological features of seven cases of nodal cytotoxic T and NK cell lymphomas. The study excluded anaplastic large-cell lymphomas expressing cytotoxic molecules. The neoplastic cells of all cases contained activated cytotoxic molecules of TIA-1, granzyme B, Fas ligand, and/or perforin. Phenotypically and genotypically, four cases showed alpha beta T cell type [CD2+, CD3+, T-cell receptor (TCR)-delta-1-, beta F1+, and TCR gene rearrangement], two cases showed gamma delta cell type [CD2+, CD3+, T-cell receptor (TCR) delta-1+, beta F1-, and TCR gene rearrangement], and one case showed NK cell type [CD2+, CD3-, CD56+, T-cell receptor (TCR) delta-1-, beta F1-, and TCR gene germline]. Using Southern blot analysis, Epstein-Barr virus (EBV) sequences were detected in six cases, and monoclonal terminal repeat proliferation was confirmed. In addition, in situ hybridization (ISH) studies for EBV showed EBV infection in almost all neoplastic cells. Clinically, all patients presented with peripheral lymphadenopathy in high clinical stages and showed an aggressive course. Hepatosplenomegaly was detected in six cases. During the course of the disease, bone marrow and extranodal invasion were noted in five cases. The nodal type showed an aggressive clinical course in all cases but one, as did the extranodal type. The nodal type varied in phenotype, but was closely associated with EBV infection.

Absence of cytotoxic molecules in CD8- and/or CD56-positive adult T-cell leukaemia/lymphoma.

Adult T-cell leukaemia/lymphoma (ATLL) cells usually exhibit a CD4+ (helper/inducer) phenotype (CD4+/8-/56-), and only a minority of tumours express the CD8 (cytotoxic/suppressor) or CD56 (natural killer [NK]-associated) antigens. TIA-1 is a cytotoxic granule-associated protein expressed in NK cells and cytotoxic T lymphocytes (CTLs). Granzyme B, perforin and Fas ligand (FasL) are also expressed in activated CTLs and NK cells. To clarify the cytotoxic potential of ATLL cells, immunohistochemistry was performed in CD8+ and/or CD56+ ATLL cells, using anti-TIA-1, anti-granzyme B, anti-perforin and anti-FasL antibodies. We studied nine cases of CD8+ and/or CD56+ ATLL, all of which exhibited monoclonal integration of human T-cell leukaemia virus type 1 (HTLV-1) proviral DNA. Four cases exhibited a CD8+/CD56- phenotype, four others had a CD8-/CD56+ phenotype, and one was CD8+/CD56+. All but one case also expressed the surface antigens CD3, TCR alpha beta, and CD4. Expression of granzyme B and TIA-1 were demonstrated in three and two cases, respectively, but none expressed perforin or FasL. In the control study, 10 cases with typical CD3+/4+/8-/56- ATLL demonstrated no expression of those cytotoxic-associated proteins. Our findings suggest that CD8 and/or CD56 positivity probably confer(s) no cytotoxic function on ATLL cells, and it is possible that CD8 and CD56 may be simply aberrant surface markers in ATLL.

Possible immortalization of Hodgkin and Reed-Sternberg cells: telomerase expression, lengthening of telomere, and inhibition of apoptosis by NF-kappaB expression.

Telomerase, an enzyme associated with cellular immortality, is expressed on malignant tumor cells. Deregulation of telomerase is thought to facilitate tumorigenesis and cellular immortality by providing cancer cells with unlimited proliferation capacity. Hodgkin and Reed-Sternberg (H&RS) cells are generally considered as neoplastic cells in Hodgkin's disease (HD), however, such cells are only found in a minority of HD lesions. In addition, H&RS cells with mitotic features are rare and mummified forms are occasionally encountered. There are no available data on the relationship between telomerase activity and apoptosis in HD. We studied 14 cases with Hodgkin's disease (mixed cellularity type, nine cases; nodular sclerosis type, five cases) to clarify the relationship between telomerase activity and apoptosis using in situ hybridization of human telomerase reverse transcriptase (hTERT), reverse transcriptase-polymerase chain reaction (RT-PCR) of hTERT, using extracted RNA and immunohistochemistry of nuclear factor-?B (NF-?B), and TdT-mediated dUTP-digoxigenin nick end-labeling (TUNEL) technique for apoptosis. We also analyzed the telomere length, using sorted H&RS cells. TUNEL showed a few apoptotic H&RS cells, but the cells frequently expressed hTERT, as confirmed by ISH and RT-PCR. Lengthening of the telomere of H&RS cells was noted in ten cases. In addition, H&RS cells frequently expressed NF-?B, which is known as an inducible transcription factor and inhibitor of apoptosis. Our findings of telomerase activity in H&RS cells indicate that these cells are neoplastic and are potentially immortal. In addition, NF-?B expression on H&RS cells suggests its possibility in inhibition of apoptosis of these cells.

Gastrointestinal T cell lymphoma: predominant cytotoxic phenotypes, including alpha/beta, gamma/delta T cell and natural killer cells.

Gastrointestinal T cell lymphoma (TCL) is a rare subset of peripheral TCL, presenting with or without cytotoxic phenotype, a history of coeliac disease (CD) and enteropathy. However, CD is rare in Japan. Here, we describe the clinicopathological features of 18 Japanese cases. Lesions were found in the small intestine (n=13), stomach (n=3) and colon (n=2). Seven patients presented with enteropathy but none had a history of CD. Lymphomas appeared as ulceration (n=11), tumour formation (n=6), or polypoid growth (n=1). Histologically (REAL classification), neoplastic lesions were composed of intestinal type T cell lymphoma (ITCL, n=13, including one case with NK type), anaplastic large cell (ALCL, n=2), adult T cell leukaemia/lymphoma (ATLL, n=2), and lymphoblastic type (n=1). Epstein Barr virus infection was detected by EBER-1 in situ hybridization in 6 of 11 cases with ITCL but not in the other types. ALCL expressed CD30. CD56 was expressed in 3 of 11 cases of ITCL but not in other types. Among the 10 examined cases, 8 were alphabeta T cell type [CD2+, CD3+, T cell receptor (TCR)delta-1-, betaF1+], one was gammadelta T cell type [CD2+, CD3+, TCRdelta-1+, betaF1-], and the remaining case expressed natural killer (NK) cell type [CD2+, CD3-, CD56+, TCRdelta-1-, betaF1-]. Among the 8 examined cases, 3 expressed CD103 molecule, which was associated with extrathymic T cells of intraepithelial lymphocytes. All cases except ATLL expressed the cytotoxicity-associated molecule of TIA-1, and 11 of 14 TIA-1 positive cases expressed activated cytotoxic molecules of perforin, granzyme B, and/or Fas ligand. Despite the morphological, genetic and phenotypic heterogeneity, prognosis was poor, and 11 of 13 patients with small intestinal lesions died albeit appropriate treatment, but 3 of 4 patients with gastric or colonic lesions were still alive. The main cause of death was intestinal perforation. The latter might be due to the site specificity of small intestine and tumour cytotoxicity.

Autopsy report of primary CNS B-cell lymphoma indistinguishable from multiple sclerosis: diagnosis with the immunoglobulin gene rearrangements analysis.

We report a case of primary CNS B-cell lymphoma indistinguishable from multiple sclerosis (MS). MRI of the head showed the spontaneous disappearance of the white matter lesions and the progressive cerebral atrophy. The brain biopsy failed to make a diagnosis of CNS lymphoma but rather suggested MS. Although the primary CNS lymphoma was suspected at autopsy, the immunohistochemical study showed the CNS-infiltrating lymphoid cells comprising both T-cells and B-cells. Analysis of the immunoglobulin and T-cell receptor gene rearrangements first provided evidence of primary CNS B-cell lymphoma.

Expression of hnRNP B1 in four major histological types of lung cancers.

Heterogeneous nuclear ribonucleoprotein B1 is one of the nuclear pre-mRNA binding proteins involved in RNA metabolism. Recently, over-expression of B1 has been reported to be useful in the early detection of squamous cell carcinomas of the lung. To elucidate its significance in other histological types of lung cancers, we carried out a comparative study, four major types of lung cancers and normal lung tissues. 37 surgical specimens were examined using a B1-specific monoclonal antibody (2B2). Immunohistochemically, 2B2 demonstrated B1 protein in the nuclei not only of squamous cell carcinoma (10/10) but also of adenocarcinoma (17/18), small cell carcinoma (5/5) and large cell carcinoma (3/4). A lesser amount of B1 protein was also detected in normal cells. Quantitative immunoblotting revealed that B1 expression was markedly higher in cancer tissues than normal tissues and it varied among the four histological types. To establish the usefulness of B1, a threshold should be set for over-expression.

Inflammatory and immunological nature of atherosclerosis.

Recent studies have revealed that atherosclerosis bears several similarities to chronic inflammation. One of the earliest events in both human and experimental atherosclerosis is adhesion of monocytes and T lymphocytes to endothelial surface followed by their migration into the intima. This intimal recruitment of blood derived cells, coupled with the enhanced endothelial permeability to plasma proteins, indicates a potential role for inflammatory mechanisms in early atherogenesis. Colocalization of T lymphocytes and macrophages in all stages of human atherosclerosis, from grossly normal prelesional intima to fully advanced atheromatous plaques, and expression of cytokines and MHC class II antigens by many types of cells of the lesion provide further evidence that atherosclerosis has both the inflammatory and immune nature. The presence of T lymphocytes and macrophages in pairs with a close contact to each other suggests that cognate cell to cell interaction also plays a pivotal role in the pathogenesis of atherosclerosis. It seems conceivable that the T lymphocyte-macrophage interaction particularly takes place in the areas where atherosclerotic lesions are in progress or being active. The pathogenic potentials of immunologic factors are fruitful subjects for further investigation.

Xanthogranulomatous cholecystis. Cell composition and a possible pathogenetic role of cell-mediated immunity.

Thirty-three cases of xanthogranulomatous cholecystitis (XGC) exhibiting the typical morphologic features were studied by light and electron microscopy and immunohistochemical techniques. Incidence of XGC was 4.2% of the surgically resected gallbladder diseases. Histologically, the granulomatous lesion of XGC principally consisted of accumulations of foam cells and lymphocytes. Variable numbers of multinucleated giant cells, granulocytes and fibroblastic cells were also noted. With respect to the origin of foam cells, it was considered that the vast majority of foam cells were derived from monocytes/macrophages because they were invariably positive for KP1, HAM56, CD11b and CD68. Interspersed among macrophage foam cells, many T lymphocytes were identified. The subtyping of T cells indicated a heterogenous population composed of both CD4+ and CD8+ lymphocytes typically in a ratio of 1:2. Macrophages and T lymphocytes demonstrated a marked expression of HLA-DR antigen. Electron microscopic and immunohistochemical double-staining observation demonstrated intimate apposition of T lymphocytes to macrophages or macrophage foam cells. The results indicate that XGC is a granulomatous disorder characterized by accumulations of macrophage foam cells and T cells. Delayed type hypersensitivity reaction of cell-mediated immunity may be implicated in the pathogenesis of XGC.