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A shortage of donors poses a serious problem for organ transplantation around the world. In response, the concept of the expanded criteria donor (ECD) has been defined to include donors with traditionally less favorable characteristics. That definition has now been accepted and is being applied in kidney transplantation in the United States and Europe. However, the ECD has not yet been defined for deceased donor kidney transplantation in Japan.We analyzed data on graft survival and relevant risk factors in patients who received deceased donor kidney transplants through the East Japan Branch of the Japan Organ Transplant network (n = 1051). Recipients were divided into two groups: the standard-function group (estimated glomerular filtration rate [eGFR] ≥20 mL/min/1.73 mThe 10-year survival rate was significantly lower in the poor-function group than in the standard-function group (85.5% vs 22.5%; P .0001). The two groups differed significantly in recipient and donor risk for graft failure. Recipient risk factors were length of time on dialysis before renal transplantation and incidence of acute rejection after transplantation. Donor risk factors were donor category (heart death), age, history of hypertension, presence of cerebrovascular disease, mean urine output, and donor creatinine level immediately before donor nephrectomy, total ischemic time, and warm ischemic time.Data from deceased donor transplantation should be analyzed in depth to determine which factors influence renal function after transplantation. In addition, ECD standards should be reconsidered for use in a Japanese context.

We studied the fine needle aspiration (FNA) cytology of high grade peripheral T-cell lymphomas from eight human T-lymphotropic virus-1 (HTLV-1) positive patients. FNA smears from seven lymphomas showed a distinctive cytologic pattern with a dominance of rounded cells with irregular nuclei and a moderately basophilic cytoplasm. Irregular cells with a pale abundant cytoplasm were present in varying amounts. Some smears contained a few giant cells with cerebriform nuclei. In addition, plasma cells and eosinophils were found. Epithelioid cells were an inconstant finding. On histology these seven lymphomas were assigned to the pleomorphic medium-large cell subtype and all but one were of T-helper phenotype with rearrangements of the T-cell receptor. FNA smears from a lymph node in a patient with a previous histological diagnosis of lymphomatoid papulosis of the gingiva showed a monotonous pattern of large immunoblastic cells with some binucleated variants consistent with a diagnosis of high grade immunoblastic lymphoma, which was confirmed histologically. Our results show that peripheral T-cell lymphomas from HTLV-1 positive patients have cytological patterns which are distinctive enough to allow a conclusive diagnosis of high grade T-cell lymphoma. However, we do not think that the cytology of HTLV-1 positive lymphomas can be differentiated from that of virus-unrelated high grade T-cell lymphomas.

Primary paraovarian cancer is a rare tumor occurring in the female pelvis. Magnetic resonance imaging features of paraovarian cancer have not been previously reported. In the present report, we describe a case of paraovarian cancer coexisting with cancer of the fallopian tube and the magnetic resonance features.

Investigators have used positron emission tomography with 18F-fluoro-D-deoxyglucose to obtain information not only for the diagnosis of cancers, but also for researching physiology in skeletal muscles. The aim of this study was to evaluate the activities of the jaw and tongue muscles during gum-chewing. Five volunteers aged 32-61 years were studied by positron emission tomography. They were requested to chew two pieces of chewing gum for 30 min after intravenous injection of 18F-fluoro-D-deoxyglucose. 18F-fluoro-D-deoxyglucose uptake in the intrinsic tongue muscle was significantly (p < 0.05) higher than that in the masseter, temporal, and medial pterygoid muscles. Heterogeneous uptake of 18F-fluoro-D-deoxyglucose was observed in the masticatory muscles. In addition, the tongue exhibited higher activity than the masticatory muscles. In conclusion, positron emission tomography with 18F-fluoro-D-deoxyglucose appeared to be a useful technique for investigating the physiologic activities of the skeletal muscles, which have been difficult to examine by conventional methods.

Some connective tissue diseases are characterised by specific autoantibodies. Although anticentromere or antikinetochore antibodies (ACA), and antitopoisomerase-I or anti-Scl-70 antibodies (ATA), have disease-specific meanings for systemic sclerosis and its CREST variant, respectively, the clinical significance of their concurrent existence has not been clarified. We investigated this condition in our case and with reference to the literature. For this purpose published reports between 1980 and 1998, where both ACA and ATA were measured simultaneously, were analysed by a MEDLINE search. In 10 papers 24 patients had both antibodies. In a further 25 reports, covering 3509 subjects who had either ACA or ATA, no concurrent existence was found. Prevalences of ACA (P(ACA)) and ATA (P(ATA)) in exclusive cases varied from 8.8% to 54.5%, and from 11.8% to 87.5%, respectively, whereas P(ACA) varied from 20.0% to 56.6%, and P(ATA) from 16.8% to 63.7% in the reports with patients positive for both. The actual prevalence of simultaneous presence was between 0.7% and 5.6%, significantly lower than the expected probabilities if both antibodies were to occur independently (p

The level of expression of midkine (MK), a heparin-binding growth factor, is increased in many types of human carcinomas. An enzyme-linked immunoassay, which utilizes a combination of rabbit and chicken antibodies revealed that serum MK level in the controls (n= 135) was 0.154 ± 0.076 (mean ± SD) ng ml–1with an apparent cut-off value as 0.5 ng ml–1. Serum MK level was significantly elevated in the cancer patients (n= 150) (P< 0.001); 87% of the patients showed levels of more than 0.5 ng ml–1. All ten types of cancer examined showed a similar profile of serum MK level. There was no or weak correlation between C-reactive protein level, a marker of inflammation, and serum MK level. Furthermore, in case of gastric carcinoma and lung carcinoma, patients with stage I carcinoma already showed elevated serum MK levels. The present results indicated that serum MK could serve as a general tumour marker with a good potential for clinical application. © 2000 Cancer Research Campaign

A new hemoglobin (Hb) variant, Hb Sagami [β139(H 17)Asn→Thr] was accidentally found through the assay of Hb A1c by high performance liquid chromatography (HPLC) in a screening test for diabetes mellitus (1). The amino acid substitution was determined by electrospray ionization mass spectrometry (ESI/MS) and confirmed by an automatic protein sequencer (1). The content of the abnormal β chain was about twice that of normal β chain, which was estimated by ESI/MS with intact globin mixture, and by high-resolution ion exchange column chromatography (PolyCAT A; Poly LC, Columbia, MD, USA) with Hb.

Lipoprotein-a, Lp(a), is a variant form of low density lipoprotein (LDL) that contains apolipoprotein-a, whose structure has 75-85% homology with plasminogen. Elevated plasma levels of Lp(a) are considered to be one of the independent risk factors for cardiovascular disease. We studied the effects of niceritrol, a nicotinic acid derivative, on plasma Lp(a) levels in 72 patients with hypercholesterolaemia. The dose of niceritrol was increased every 4 weeks, from 750 to 1500 and then to 2250 mg day-1. The final dose was adjusted to obtain a plasma cholesterol level less than 5.69 mmol l-1. Niceritrol led to significant decreases in plasma levels of median Lp(a), from 16.1 mg dl-1 (interquartile intervals, 8.7 to 32.8) to 11.1 mg dl-1 (interquartile intervals, 6.6 to 21), the mean reduction rate being 17.6%. In the group with pretreatment Lp(a) levels of over 20 mg dl-1, Lp(a) decreased by 10.0, 22.0 and 31.8% at the doses of 750, 1500, and 2250 mg day-1, respectively. In the group with levels less than 20 mg dl-1, only the dose of 2250 mg day-1 was effective in the reduction of Lp(a). The results suggest that the reduction of Lp(a) was dependent on the dose of niceritrol and on the pretreatment level of Lp(a). In conclusion, niceritrol is effective, in a dose-dependent manner, for reducing Lp(a) levels.

The relationship between serum angiotensin I-converting enzyme (ACE) activity, a possible marker of pulmonary endothelial injury, and the occurrence of pulmonary hypertension (PH) in patients with mixed connective tissue disease (MCTD) was investigated. Before corticsteroid therapy, the mean serum ACE level was 26.4 +/- 14.0 mU/ml in patients with MCTD and PH (n = 6), 16.8 +/- 4.1 mU/ml in patients with MCTD but without PH (n = 18), 16.8 +/- 4.1 mU/ml in patients with undifferentiated connective tissue disease (n = 14), and 16.5 +/- 3.9 mU/ml in controls (n = 18). No significant difference in the enzyme activity was found among the groups. However, 4 patients with MCTD showed increased ACE levels (> 28.3 mU/ml), and all of them had PH. Our results suggest that elevation of serum ACE activity may be related to the occurrence of PH in patients with MCTD.

Background and Study Aims: Endoscopic variceal ligation (EVL) is an alternative to sclerotherapy for the treatment of esophageal varices, but is associated with higher rates of recurrence and subsequent bleeding than sclerotherapy. To prevent recurrence of varices after EVL, we have developed a low-dose diode laser therapy combined with the injection of indocyanine green, which allows enhanced tissue absorption of the laser beam selectively around varices. In this study we investigated the efficacy and safety of this technique. Patients and Methods: Eight patients with F2 or F3 esophageal varices were enrolled. At 1 week after EVL, indocyanine green solution (1 mg/ml) was injected sub-mucosally around the remaining varices. A diode laser (power 10 watts) was applied to the surface from the esophagogastric junction to 5 cm above it. The spot size was kept to 5 mm in diameter. Results: Laser irradiation was performed safely, without bleeding from the varices, or perforation. There were no major complications. Endoscopy 1 month later showed F0 forms in seven patients, F1 in one patient, and no red color sign in any patient. No recurrence of varices has been observed in any of the patients during the follow-up period of at least 12 months. Conclusion: This technique may provide a simple, safe and effective procedure, as an additional treatment to EVL, for the prevention of recurrence of esophageal varices.

Plasma endotoxin concentrations were determined in 42 patients with burns covering more than 20 per cent of the body surface area, using the endotoxin-specific Endospecy assay and treatment of plasma by a new method developed by ourselves. The normal endotoxin level was 9.8 pg/ml or less. In the early period after injury when no infection was present, very few patients had an endotoxin level above 9.8 pg/ml and endotoxin levels did not correlate with the area of the burns or with prognosis. However, later in the clinical course, endotoxin levels were correlated significantly with the burned area and with the prognosis.

We studied rearrangement of human T cell receptor genes (TCR) of C beta, C gamma, V gamma and J gamma in 34 cases of adult T cell leukemia/lymphoma (ATLL), consisting of 29 cases with monoclonally integrated HTLV-I proviral DNA (ATLL-W) and five without monoclonal integration (ATLL-O), in comparison with 12 cases of other peripheral T cell lymphomas (non-ATLL). All cases of both ATLL and non-ATLL showed some rearrangement of T cell receptor genes (TCRs) of C beta, C gamma, V gamma, or J gamma. Rearrangement of TCR beta was found in 28 of 29 cases of ATLL-W, all cases of ATLL-O, and eight of 12 cases of non-ATLL. Rearrangement of TCR gamma was observed in 21 of 22 cases of ATLL-W, and in all cases of ATLL-O and non-ATLL. In TCR gamma, rearrangement of C gamma was seen in six of 20 cases of ATLL-W, none of three ATLL-O cases and three of six cases of non-ATLL. V gamma rearrangement occurred in 14 of 18 cases of ATLL-W, one of two cases of ATLL-O, and three of six cases of non-ATLL. Rearrangement of J gamma was found in 16 of 22 cases of ATLL-W, two of five ATLL-O cases, and six of seven non-ATLL cases. Rearrangement was more frequent in ATLL-W than in ATLL-O and non-ATLL. The incidence rate of rearrangement of V gamma families of V gamma 1, V gamma 2, and V gamma 3 was nearly the same in each group, except for deletion of V gamma 3, which was often observed in ATLL but was absent in non-ATLL. These results indicate the usefulness of detection of TCR and HTLV-I proviral DNA to differentiate ATLL from other T cell malignancies.

Objectives To clarify the role of granzyme B in acute coronary syndrome. Design and Setting Granzyme B is a member of the serine esterase family released from cytotoxic lymphocytes and plays an important role in cellular apoptosis by activating intracellular caspases. We compared the granzyme B expression between patients with stable and unstable angina pectoris (UAP). Patients We enrolled 173 patients with coronary artery disease (CAD). We found 84 patients with stable angina pectoris (SAP) and 89 patients with UAP. Methods Peripheral blood was drawn from the patients. Peripheral blood mononuclear cells (PBMCs) isolated by gradient centrifugation were cultured at a density of 2 X 10 6 cells/mL for 24 hours. The supernatants were collected 24 hours after incubation and the granzyme B level was measured by enzyme-linked immunosorbent assay. Polychromic flow cytometric analysis was performed to evaluate the expression of granzyme B in the cells. Results Granzyme B production from PBMCs of UAP patients was significantly higher than those in patients with SAP (39.1±6.6 versus 17.0±1.8 pg/mL, p

We investigated the pathology and the involvement of type II phospholipase A2 (type II PLA2), inflammatory cytokines, nitrite/nitrate (NOx), and endotoxin in generalized peritonitis. All of the factors except endotoxin were higher in the non-surviving group, the shock group, and the multiple organ dysfunction syndrome (MODS) group than in the surviving group, the shock-free group, and the MODS-free group, respectively. Significant differences were not found in endotoxin or other factors at sites of gastrointestinal (GI) perforation. These findings suggest that inflammatory cytokines, type II PLA2, and NO are highly involved in the evolution of the pathology of generalized peritonitis.

To compare the functional outcome of ultra-low anterior resection for rectal cancer with colonic J-pouch reconstruction with that of straight reconstruction.Twenty-three patients who underwent ultra-low anterior resection with or without J-pouch reconstruction underwent bowel transit study, videodefecography, and answered a questionnaire survey 4 months and 1 year after surgery. Eleven healthy subjects underwent similar testing as controls.Patients with a J-pouch had less frequent stools than patients with straight reconstruction 4 months after surgery (p0.05), but the two groups were similar at 1 year. Bowel transit time was similar at both study points. The evacuation ratio was higher after J-pouch than straight reconstruction 4 months after surgery (p0.05). However, the ratio improved in the straight group, and no difference existed at 1 year. Colonic contraction was seen only near the anastomosis 4 months after surgery, but the contraction proximal to the anastomosis improved over the next 8 months.J-pouch reconstruction facilitates evacuation by improving the evacuation ratio. Although straight anastomosis caused excessive stool frequency 4 months after surgery, colonic function continued to improve and was comparable with J-pouch and straight reconstruction 1 year after surgery because the contraction ratio proximal to the anastomosis improved.

Little is known about the mechanisms involved in skin-specific homing in CD30+ cutaneous lymphoproliferative disorders (CLPD). Chemokine/chemokine receptor interactions have been implicated in the homing of lymphoma cells to various tissue sites.To investigate tissue samples from patients with CD30+ CLPD for the expression of the chemokine receptors CXCR3, CCR4 and CCR3 and their ligands MIG, TARC and RANTES.Tissue samples from patients with primary cutaneous anaplastic large cell lymphoma (PCALCL, n=12) and lymphomatoid papulosis (LyP, n=13) were studied by immunohistochemistry on paraffin-embedded sections. Immunohistochemical analysis was also performed for CD20 (for B cells), CD45RO and CD3 (for T cells), CD30 and ALK-1. A portion of each skin specimen was stored at -80 degrees C and later examined using monoclonal antibodies against CD2, CD3, CD4, CD5, CD8, CD15, CD19, CD20 and CD30.CD30+ atypical lymphoid cells were frequently seen in PCALCL, and to a variable degree in LyP. In both disorders there were scattered CD3+ and CD45RO+ atypical lymphoid cells, but CD2, CD5, CD15, CD19, CD20 and ALK-1 showed negative reactivity. In addition, CD4+, but not CD8+, atypical lymphoid cells were occasionally seen in both disorders. CCR3 was expressed by atypical lymphoid cells in 10 of 12 (83%) cases of PCALCL, but in only five of 13 (38%) cases of LyP. CXCR3 was expressed in 11 of 13 (85%) cases of LyP, but in only one of 12 (8%) cases of PCALCL. CCR4 was expressed in 11 of 12 (92%) cases of PCALCL, but in only two of 13 (15%) cases of LyP. RANTES was strongly expressed by lymphoma cells in PCALCL (11 of 12: 92%), but was weak or sporadic in LyP (seven of 13: 54%). TARC showed weak or sporadic reactivity in both LyP and PCALCL, and MIG did not show a distinctive expression pattern in either disorder.We speculate that CCR3 is associated with the autocrine function in PCALCL, as evidenced by CCR3 coexpression with its ligand RANTES. We also found that LyP cells expressed CXCR3, which might support their migration towards the CXCR3 ligand MIG, which is expressed in stromal cells of the skin.

We report an unusual case of idiopathic internal and external jugular vein thrombosis. Positron emission tomography (PET) using (18)F-fluoro-2-deoxy-D-glucose (FDG), which was conducted to assess subclinical malignancy, revealed intense uptake of FDG, corresponding to thrombus within the left internal and external jugular veins. Although FDG-PET is widely used in differentiating between malignant and benign diseases, we should bear in mind that this benign entity can demonstrate high accumulation of FDG.

To study the clinicopathological and immunohistochemical features of 143 cases of primary small and large intestinal non-Hodgkin's lymphoma (NHL) in Japanese patients who presented between 1981 and 2000.The new World Health Organization (WHO) classification was used to classify NHL. The patients included 109 males and 34 females, with an average age of 54.1 years. Tumour sites were as follows: ileocaecal (n = 51, 35.7%), ileum (n = 29, 20.3%), rectum (n = 13, 9.1%), and duodenum (n = 11, 7.7%). Macroscopically, 124 cases (86.7%) were classified as tumorous type, 12 (8.4%) as diffuse infiltration type (erosion, superficial ulceration), five (3.5%) as polyposis type, and only two cases (1.4%) as ulceration type. Immunohistochemically, 122 lesions (85.3%) were of B-cell phenotype and 21 lesions (14.7%) were of T-cell phenotype. According to the WHO classification, of the B-cell lymphomas, 84 cases (68.9%) were large cell, 16 (13.1%) were Burkitt, 10 (8.2%) were marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT), and seven (5.7%) were mantle cell tumours. Among the T-cell lymphomas, 15 (71.4%) were of unspecified type, two (9.5%) were natural killer type, two were anaplastic large-cell lymphomas, one was lymphoblastic, and one was an adult T-cell leukaemia lymphoma. The survival rate for T-cell lymphomas was poorer than for B-cell lymphomas. Among the B-cell lymphomas, mantle cell lymphoma tended to have a poorer prognosis, whereas MALT lymphomas had a better prognosis than other B-cell tumour types.Our retrospective study of patients with primary malignant lymphomas in the small and large intestines has illustrated the clinical features and outcomes of patients with this disease.

Most primary gastrointestinal lymphomas are of B-cell origin and T-cell origin is very rare. Recent studies have suggested that human T-cell lymphotrophic virus type 1 (HTLV-1) may be involved in the development of primary gastric T-cell lymphoma. We analysed 31 patients with primary gastric T-cell lymphoma in south-west Japan, an area endemic for HTLV-1, and determined their phenotypes, genotypes, and HTLV-1 status.Here we present 31 cases of primary gastric T-cell lymphoma in a HTLV-1-endemic area in Japan and analyse the clinical status, histology, phenotype and virus status. The median age at onset of primary gastric T-cell lymphoma was 57 years with a gender ratio of M:F = 1.58:1. Six of the 31 primary gastric T-cell lymphoma cases had HTLV-1 proviral DNA (five males, one female), nine of the 31 cases were positive for anti-adult T cell leukaemia antibody, without examination of HTLV-1 proviral DNA (five males, four females), eight were non-HTLV-1-associated primary gastric T-cell lymphoma (four males, four females) and the other eight cases were unknown. Primary gastric T-cell lymphoma usually presented as a large ulcerated tumour at the corpus to the antrum and histologically consisted of anaplastic large cell type (n = 2), pleomorphic large cell type (n = 3), pleomorphic medium and large cell type (n = 14), pleomorphic medium cell type (n = 11), and angioimmunoblastic T-cell lymphoma type (n = 1). There were no clear macroscopic and microscopic differences between HTLV-1-associated and non-HTLV-1-associated primary gastric T-cell lymphoma. Most patients died within 2 years of diagnosis, and both types of primary gastric T-cell lymphoma (with and without HTLV-1) were associated with poor prognosis. Cytotoxic marker analysis showed that HTLV-1-associated lymphomas were negative for TIA-1, while non-HTLV-1-associated lymphomas were positive for TIA-1.Our results suggest that in HTLV-1-endemic areas, patients with HTLV-1-associated primary gastric T-cell lymphoma should be managed carefully and that TIA-1 seems to be useful for identifying the aetiology of this lesion.

Lymph nodes contain non-lymphoid accessory cells including follicular dendritic cells and interdigitating dendritic cells. Functionally, these cells belong to the category of immune accessory cells involved in antigen presentation to B or T-lymphocytes. Neoplastic proliferation of these cells is very uncommon. We present here the clinicopathological features of 16 cases of accessory cell tumour.We performed electron microscopic and immunohistochemical examinations, and used in-situ hybridization for EBV-encoded RNA (ISH-EBV) to detect the EBV genome in 11 cases, and Southern blot analysis to assess EBV clonality in two cases. Tumour cells were composed of oval-to-spindle cells arranged in diffuse, vague storiform, fascicular and sometimes whorled patterns in a background of small lymphocytes. In all cases, binucleated or multinucleated Hodgkin and Reed-Sternberg-like giant cells were encountered. Staining for CD68 was positive in all cases. CD21, CD35, Ki-M4p, Ki-FDC1p, and S100 exhibited variable reactivity. ISH-EBV yielded positive labelling in seven of 11 cases, of which five exhibited EBV only in Hodgkin and Reed-Sternberg-like giant cells. Southern blot analysis showed clonality of EBV terminal repeats (EBV-TR) in the two cases examined. Electron microscopic examination showed that many of the tumour cells had numerous interwoven long villous cell processes connected by occasional desmosomes. Many tumours were very refractory to chemotherapy and radiation, with a few exceptions, and half of the cases classified initially as stage IV. A short survival time, of 10 months or less, was observed in seven of 16 patients.Our study identified more aggressive behaviour of accessory cell tumours. Our results suggest that EBV may potentially induce activation of accessory cells to form Hodgkin and Reed-Sternberg-like giant cells, which correspond with poor prognosis.

Pyothorax-associated lymphoma (PAL) develops in the pleural cavity of patients with a long history of pyothorax. Epstein-Barr virus (EBV) is also involved in PAL, similar to lymphomas in immunodeficient patients. Here we examined T-lymphocyte subsets as well as c-myc and REL gene amplification in PAL tissues.We determined the number and distribution of CD4+ and CD8+ T-lymphocytes, to evaluate T-cells in the host immune reaction in seven cases of PAL. As controls, we also studied 10 cases of extranodal diffuse large B-cell lymphoma (DLBL) and 10 cases of nodal DLBL. Chromosomal imbalances in PAL were determined by using comparative genomic hybridization (CGH) analysis. The mean numbers of CD4+ and CD8+ and their ratio were significantly lower in PAL than in nodal DLBL. CGH analysis of PAL showed amplification of the 8q24 chromosomal region. In addition, c-myc amplification was found in four cases of PAL by Southern blot analysis.Our results suggest that the development of PAL may involve a local immunosuppressive environment and that amplification of c-myc might promote tumour progression, as has been described in the development of Burkitt's lymphoma.

We describe five cases of tumoral calcium pyrophosphate dihydrate crystal deposition disease (CPPDCD) and discuss the clinical, radiological and pathological features. Patients included 4 males and 1 female, ranging in age from 49 to 70 years (median, 63 yrs). The wrist was involved in two patients. The thumb, palmar aspect of the proximal phalanx of the middle finger and dorsum of the carpal bone of the hand were involved in one patient each. In one patient, a preoperative diagnosis of chondrosarcoma had been made. Macroscopically, the lesion was a circumscribed whitish-gray mass with a more or less chalky appearance, measuring between 1.0 to 6.2 cm (median, 2.5 cm). Histologically, all five lesions contained areas of calcification with crystal deposits and chondroid metaplasia. The majority of crystals were rhomboid in shape, characteristic of CPPD, but some needle-shaped crystals were also identified, which resembled urate crystals. A review of the 54 reported cases of tumoral CPPDCD including our series indicated that they could be divided into two categories based on anatomic location: central (head and neck) type (n = 33) and distal (extremity) type (n = 21). Patients of these two groups were not different with respect to age and gender, but those with the central type often presented with a painful mass (15 patients, 46%), or neurological disturbances (11 patients, 33%). Patients with the distal type presented with a painless mass or swelling (12 patients, 57%), but none had neurological signs, although 8 (38.1%) presented with acute attack similar to tophaceous gout. Tumoral CP-PDCD should be differentiated from tophaceous gout, tumoral calcinosis, and malignant or benign tumors.

A 55-year-old Japanese man was hospitalized on October 5, 1999, because of high fever. Physical examination revealed neither lymphadenopathy nor hepato-splenomegaly. Laboratory data on admission showed a white blood cell count of 1,580/microliter, a hemoglobin level of 9.1 g/dl, and a platelet count of 113 x 10(3)/microliter. A small percentage of abnormal mononuclear cells were present in the peripheral blood. A bone marrow biopsy specimen demonstrated myelofibrosis and diffuse infiltration of abnormal monoculear cells with a mature B cell phenotype. A bone marrow aspirate showed 29% abnormal mononuclear cells, which had an indented or folded nucleus and reticular nuclear chromatin. Moderate to strong tartarate-resistant acid phosphatase activity was detected in these cells. Although the cytoplasmic projections were poorly preserved in specimens stained with May-Giemsa, fresh preparations showed numerous slender cytoplasmic projections by phase-contrast microscopy. The hairy cells had the phenotype CD5-, CD10-, CD11c+, CD19+, CD20+, CD25+, lambda. The patient was diagnosed as having European-American-type hairy cell leukemia (HCL) without splenomegaly, which is quite rare in Japan. The value of phase-contrast microscopy for recognition of the hairy cells was emphasized. The patient was treated successfully with deoxycoformycin (DCF).

Mucosa-associated lymphoid tissue (MALT) lymphomas usually involve extranodal sites, especially the stomach, lung and salivary glands. The Bcl10 gene was recently isolated from the breakpoint region of t(1;14) (p22;q32) in MALT lymphomas, and considered to be an apoptosis-associated gene, and involves a caspase recruitment domain (CARD)-containing protein that activates NF-kappaB. We investigated the role of Bcl10 in MALT lymphoma by analyzing its expression, rearrangement and somatic mutation, by immunostaining, reverse transcriptase-polymerase chain reaction (RT-PCR), Southern blot and PCR in 20 cases of MALT lymphoma. Expression of NF-kappaB was studied by immunostaining. Five cases of reactive lymphadenitis (RLA) were used as the control. Bcl10 rearrangement was detected in 8 of 20 (40%) MALT lymphomas, but in none of RLA. Significant Bcl10 mutation was detected only in 1 case (5%) with MALT, but not in RLA. RT-PCR showed higher density bands of Bcl10 in MALT lymphomas than in RLA. Immunostaining showed a weak Bcl10 expression in the germinal center and very weak expression in the marginal zone B-cells in RLA, which was limited to the cytoplasm. In contrast, Bcl10 was strongly expressed in MALT lymphomas, and was mainly detected in the cytoplasm, as well as in the nuclei. Bcl10 expression did not correlate with Bcl10 mutation and re-arrangements. NF-kappaB was expressed in nuclei of MALT lymphoma cells, but not in RLA. Bcl10 expression in MALT lymphoma correlated closely with NF-kappaB expression. Our results suggest that activation of Bcl10 and NF-kappaB may be important in MALT lymphomagenesis, and that nuclear localization of Bcl10 may be important in the progression of MALT.

A 63-year-old woman underwent modified radical mastectomy with 3 cycles of adjuvant chemotherapy (cyclophosphamide, epirubicin, 5-fluorouracil) and MPA endocrine therapy for breast cancer. Because of nausea and general fatigue, she refused to continue this therapy and did not visit the hospital. When she came our hospital and 16 months later, she had developed multiple bone metastases. At the same time, she was suffering from lung tuberculosis. She was treated with toremifene at a dose of 120 mg/day without any side effects. After 3 months administration of toremifene, pain disappeared and her high serum CA15-3 and BCA225 dropped to within the normal range. On bone scintigrams, abnormal accumulation almost disappeared after 9 months of administration of toremifene. In this case, the patient was suffering from lung tuberculosis and did not desire intensive chemotherapy. Administration of high-dose toremifene was effective for multiple bone metastases without any side effects.

Hodgkin's disease (HD) is characterized by the presence of Hodgkin and Reed-Sternberg (H-RS) cells against a hyperplastic background of reactive cells such as lymphocytes, histiocytes, plasma cells, eosinophils, neutrophils, and stromal cells. There is ample evidence to suggest that proliferation and survival of HD-derived cells is due to cytokine signalling. Recently, high expression of interleukin (IL)-13 was described in HD-derived cell lines. Here we investigated the possible involvement of IL-13 in the pathophysiology, especially autocrine pathways of H-RS cells.The expression of IL-13 and IL-13 receptor (IL-13R) was determined by immunostaining and reverse transcriptase-polymerase chain reaction in 39 cases of HD, including 17 cases with nodular sclerosis (NS) type, 19 cases with mixed cellularity (MC), and three cases with lymphocyte predominance (LP) type. Expression of IL-13 was confined to H-RS cells and a few lymphocytes. IL-13R was expressed in H-RS cells, lymphocytes, histiocytes, fibroblasts, and endothelial cells. H-RS cells of MC and NS types frequently expressed both IL-13 and IL-13R. However, the number of IL-13-positive H-RS cells was statistically higher in NS-type than in MC-type, but the number of IL-13R was similar. IL-13R-positive fibroblasts were frequently encountered in NS-type. H-RS cells of LP type rarely expressed IL-13.Our results suggest that IL-13 might be involved in autocrine pathways of H-RS cells and fibrosis at least in NS-type. Our results also indicated that in addition to the morphological and phenotypic differences, the neoplastic cells of LP type might be functionally different from H-RS cells of MC- and NS-types.

CD56-positive nasal and nasal-type natural killer (NK)/T-cell lymphoma is now a well-defined disease entity. Rare cases of blastic NK-cell lymphoma positive for CD56 have been recently reported. However, CD56 expression is also identified in several types of non-hematopoietic small round cell tumors in which lymphoma is included as a differential consideration. Here, we present nine cases of CD56+ small round cell tumors of histological origin unrelated to nasal NK/T-cell lymphoma. Eight of the nine cases presented as solid tumors of the sinonasal region. Clinical, histological, ultrastructural, and immunohistochemical examination and gene analysis for T-cell receptor (TcR) and immunoglobulin heavy chain (IgH) genes and in situ hybridization (ISH) for Epstein-Barr virus (EBV) were performed. Two cases presented with features consistent with blastic NK-cell lymphoma or lymphoblastic lymphoma of NK-cell phenotype. These cases showed features of lymphoblastic lymphoma, phenotypes of sCD3-, cCD3+, CD45+, CD56+, TdT+, and human leukocyte antigen (HLA)-DR+, germline of IgH and TcR genes, and EBV negative reactivity. One case had myeloid/NK-precursor acute leukemia/lymphoma with a phenotype of CD13+, CD33+, CD34+, CD56+, and MPO-. Three cases were neurogenic, including one case of olfactory neuroblastoma and two of primitive neuroectodermal tumors (PNET). It was difficult to differentiate CD56+ PNET from blastic NK-cell lymphoma, especially when only paraffin-embedded sections were available. Myogenic markers, such as HHF35, alpha-sarcomeric actin, and desmin, were positive in three cases of rhabdomyosarcomas. Our findings suggest that as CD56 is used more routinely as a marker in immunohistochemical staining, the differential diagnosis of extranodal lymphohematological malignancies and small round cell tumors will become more complicated.

Multidrug resistance (MDR) is a major obstacle in the treatment of lymphoma. The expression of MDR-1 mRNA and P-glycoprotein (MDR-1/P-gp) has been linked to MDR. We aimed to investigate the expression of MDR-1/P-gp in B-cell lymphoma.Samples at diagnosis and relapse from 10 patients with B-cell lymphoma were obtained. We also obtained 14 unselected control cases of B-cell lymphoma at diagnosis. The expression of mRNA and protein were determined semiquantitatively by RT-PCR and immunohistochemistry. High MDR-1 and P-gp expressions were found in seven and seven of 10 samples obtained at diagnosis, eight and eight of 10 samples obtained at relapse, and three and four of 14 control cases at diagnosis, respectively. The results of RT-PCR paralleled those of immunohistochemistry. Concordance of high MDR-1/P-gp expression was noted in 27 of 34 samples (r = 0.73, P = 0.001). There were no significant changes in MDR-1/P-gp expression in all cases at relapse and during the clinical course following chemotherapy. In the 14 control cases, the average survival time was 12.7 months in MDR-1/P-gp positive cases and 29.0 months in the MDR-1/P-gp negative cases (P = 0.20).Our results showed that at least some B-cell lymphomas express MDR-1/P-gp, which could be detected by different methods, and suggested that high MDR-1/P-gp expression in tumour cells may be associated with a high probability of relapse and poor prognosis.

The myelodysplastic syndromes (MDS) are a group of disorders characterized by peripheral pancytopenia despite normo- or hypercellular bone marrow. This is thought to be as a result of the apoptosis of haematopoietic bone marrow cells resulting in ineffective haematopoiesis. To clarify the relationship between prognosis and apoptosis and/or cell proliferation in the bone marrow, we studied 51 cases with MDS. Bone marrow biopsies were stained immunohistochemically for MIB-1 (marker for proliferating cells) and CD34 (marker for stem cells). Apoptosis was visualized by detection of DNA fragmentation using TdT incorporation of nucleotides on 3' ends of DNA (TUNEL technique) and expressed as the apoptotic rate. MDS patients included 32 with refractory anaemia (RA), one RA with ringed sideroblasts (RARS) patient, seven RA with excess of blasts (RAEB) patients, eight patients with RAEB in transformation (RAEB-t) and three patients with chronic myelomonocytic leukaemia (CMMoL). In addition, we also studied six cases with acute myeloid leukaemia (AML) arising from MDS (AML-MDS) and ten control subjects. Fatal pancytopenia was the cause of death in 19 out of 51 patients. The apoptotic rate was higher in MDS patients (5.5%) than in control subjects (0.6%) and AML-MDS patients (0.4%). The percentage of MIB-1 positive cells was higher in MDS and AML-MDS than in control. The percentage of CD34-positive cells was higher in AML-MDS, RAEB, RAEB-t and CMMoL patients than control subjects and RA patients. Our findings indicate the activation of both the proliferative and apoptotic rates in MDS. Poor prognosis correlated significantly with higher apoptotic rates, but not with percentages of MIB-1 and CD34-positive cells. Our results suggest that apoptosis might be a useful prognostic factor and inhibition of apoptotic mechanisms may induce leukaemic transformation in MDS.

Nitric oxide (NO) acts as a vasorelaxant. We investigated the relationship between nitrite/nitrate (NOx), which are the final metabolites of NO, and hemodynamics during septic shock. We also examined tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8), and endotoxin. A significant negative correlation was observed between NOx levels and pulmonary capillary wedge pressure (PCWP; r = -0.6075, P = 0.0028). A significant positive correlation was noted between NOx levels and the cardiac index (CI; r = 0.5934, P = 0.0038). A significant negative correlation was found between NOx levels and the systemic vascular resistance index (SVRI; r = -0.4354, P = 0.0485). A significant positive correlation was observed between NOx levels and the stroke volume index (SVI; r = 0.5040, P = 0.0186). A significantly close positive correlation was also observed between TNF-alpha levels and NOx levels (r = 0.7848, P0.0001). These findings suggest that NOx levels are closely associated with hemodynamics during septic shock, resulting in a vascular relaxing effect.

A left radical mastectomy was performed on a 53-year-old woman, diagnosed with left inflammatory breast cancer, after local arterial chemotherapy with cyclophosphamide (CPA), doxorubicin and 5-fluorouracil (5-FU). Adjuvant therapy was added with irradiation and ECF. Four months after the operation, a red eruption was detected on the left upper chest wall. The lesion was diagnosed by skin biopsy as a recurrent breast cancer with carcinoma erysipeloides. Tumor marker levels suggested the recurrent cancer was ECF resistant, so we changed the chemotherapy regime to a single dose of TXT. Although tumor marker levels and the skin eruptions improved at the beginning of the therapy, pleuritis carcinomatosa was found. We changed the regime again to a continuous dose of 5'-DFUR and LV for day 1 to 7. With this regime the clinical symptoms improved, and 2 courses of this modified FL therapy were carried out. After the therapy, the tumor seemed resistant to this modified FL therapy. Therefore, we tried a sequential therapy with TXT and the modified FL, which induced an improvement in clinical symptoms. Two years later, the patient died from the breast cancer. Therefore, we conclude that the sequential therapy may be beneficial in managing untreatable carcinoma erysipeloides of recurrent breast cancer.

Epstein-Barr virus (EBV) is associated with numerous reactive and neoplastic lymphoproliferative disorders. In vitro, EBV infection can transform B-lymphocytes and induce phenotypic alterations. This study presents the clinicopathological features of four cases with malignant lymphoma, which showed phenotypic and/or genotypic alterations during the course of the disease.To determine the type of EBV genotype, we performed polymerase chain reaction (PCR) for lymphocyte-defined membrane antigen (LYDMA) of EBV, subtype A/B and latent membrane protein (LMP)-1 deletion. In addition, we analysed the terminal repeat (TR) band of EBV and receptor genes (T-cell receptor gene, TCR; immunoglobulin gene heavy chain, IgH) for EBV-infected cell clonality. Double staining of cell markers (B, T-lymphocytes; histiocytes), and in-situ hybridization (ISH) for EBV were performed using tissues obtained during the course of the disease. The first case showed genotypic and phenotypic alterations of T-cell type to B-cell type. The first TCR rearrangement and T-cell markers (CD3+, CD4+, CD8-) were lost and IgH rearrangement and B-cell markers (CD19+, CD20+) were identified. During the course of the disease, EBV-TR bands changed in size; however, the EBV genotype type B, LMP1 deletion type, and single LYDMA band remained the same. The initial T-cell lymphoma clone was considered to be different from the latter B-cell lymphoma clone. The second case showed phenotypic alterations. The first B-cell marker (CD19+, CD20+, CD68-) changed to histiocytic markers (CD19-, CD20-, CD68+). However, IgH rearrangement and EBV-TR bands remained the same throughout the course of the disease and EBV genotype type A, LMP1 deletion type, and single LYDMA band remained unchanged. The third case showed phenotypic alterations. The B-cell marker (CD20+) was lost; however, IgH rearrangement of PCR and EBV genotype remained the same. In the second and third cases, the initial lymphoma clones were considered to be same as the latter clones. The last case showed lineage alterations from Hodgkin's disease to natural killer (NK) cell leukaemia. However, EBV genotype did not change. The second case and Hodgkin's disease showed LMP expression, but the first and third cases showed no LMP, and EBNA2 was not detected in all cases.We report the genotypic and/or phenotypic alterations in four patients with EBV-associated lymphoma/leukaemia. However, EBV genotype did not change in all four. These findings suggest that EBV might induce the cell marker and lineage alteration in vivo, as in vitro.

The pathogenesis of histiocytic necrotizing lymphadenitis (HNL), which was reported first by Kikuchi et al. and Fujimoto et al. in 1972, is as yet unknown. HNL is frequently reported in Asian countries including Japan, however it is rare in Europe and North America. To elucidate whether the human leukocyte antigen (HLA) alleles and haplotypes are associated with HNL, we performed DNA typing of HLA class II genes (HLA-DR, -DQ, and -DP) in 86 patients with HNL and 525 unrelated healthy Japanese controls with polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP). In this study, we found DPA1*01 and DPB1*0202 allele frequencies in HLA class II genes are significantly higher in HNL patients than in normal controls. It is known that the frequency of DPB1*0202 alleles is extremely low or absent in Caucasians (e.g., French 0.4%, Italian 0.8%) and Negroid (e.g., South African 0%, Hottentot 0%), but relatively frequent in Asians (e.g., Korean 9.9%, Japanese 4.5%). Previous reports have said the incidence of HNL is frequent in Asians but rare in other races. In light of this background, HLA class II genes of HNL and the incidence of HNL in Asian countries, including Japan, might have a positive relationship to DPA1*01 and DPB1*0202 allele.

We studied the immunohistochemical localization of Fas and nicotinic acetylcholine receptor (nAChR) in the human thymus with myasthenia gravis (MG). Thymuses were obtained from thirteen patients with MG, (thymic hyperplasia 8; thymoma 5) and six normal controls. Antibodies against Fas, nAChR protein isolated from fetal calf thymus (nAChR-FCT), CD3, CD4, and CD8 were used. In both hyperplastic thymus and controls, Fas antigen was found in medullary epithelial cells especially in those around Hassall's corpuscle, in subcapsular epithelial cells, and partially in the cortex. There were no apparent differences between myasthenic thymus and the controls. In the thymic medulla the anti-nAChR-FCT antibody showed a similar staining pattern to the antibody against Fas. The nAChR and the Fas were suggested to be present in the same cell. Then six thymomas were double immunostained with antibodies against Fas and nAChR-FCT. A part of neoplastic epithelial cells were double positive for both Fas and nAChR. The present results show the first observation on the colocalization of the Fas and nAChR in thymic epithelial cells. These antigens were supposed to work on triggering mechanism of autoimmunity in MG.

Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of mature helper (CD4) T-lymphocytes. Human T-cell lymphotropic virus type-I (HTLV-I) is etiologically considered to cause ATLL. It has been suggested that HTLV-I integrates its provirus into random sites in host chromosomal DNA after infection. Clonal integration has been observed in patients with ATLL, including smoldering, chronic and acute leukemia states. Almost all cases with ATLL demonstrate clonal chromosome abnormalities, with karyotypes being very complicated in both number and structure. However, there are no specific karyotype abnormalities in ATLL. In order to examine the role of HTLV-I in the pathogenesis of ATLL, we investigated whether or not HTLV-I randomly integrates and whether the integration site in the human genome is associated with any chromosomal abnormality. We analyzed 18 cases with ATLL, which included 15 cases with acute states, two cases with chronic states and one case with a smoldering state. In four of the 18 cases, the HTLV-I provirus integrated into the 9th chromosome, while in three cases, it integrated into the 1st or 10th chromosome. However, the integrated site in the chromosome varied in each case and the random integration was considered to be true. All 15 cases with acute ATLL had complicated chromosomal abnormalities and two cases with chronic and smoldering ATLL showed simple abnormal karyotypes, while one case with chronic ATLL showed a normal karyotype. In 15 of the 18 cases, the chromosomes with HTLV-I integration showed abnormalities. In particular, in two cases with simple chromosome abnormalities, HTLV-I integrated into the abnormal chromosome, but not into the normal chromosome. The HTLV-I proviral integration thus seems to be associated with chromosome abnormalities. In the multistage leukemogenesis of ATLL, these findings indicate that HTLV-I integration might play an important role in the induction of chromosomal instability.

Five cases of a characteristic low-grade thymic epithelial tumour are described that we suggest calling metaplastic carcinoma of the thymus.The patients' ages ranged from 44 to 71 (mean 56.2) years. Four of the patients were male. Three of five tumours showed invasion into mediastinal fat or pleura but, otherwise, all were well circumscribed. No metastases were present. Histologically, the tumours showed a biphasic pattern with solid carcinomatous areas merging gradually with a spindle cell component. Lymphocytes were rare. Cytological atypia and mitotic activity were variable in the solid areas, but slight or absent in the spindle cell component. On immunohistochemistry, the tumours showed expression of cytokeratin, vimentin and/or epithelial membrane antigen, both in the carcinomatous and spindle cell components. In two cases, actin expression was also present in both components. In one case, chromogranin, S100 protein, glial fibrillary acidic protein and neuron-specific enolase were expressed in at least some cells of both components. None of the patients had myasthenia gravis. All patients are alive without evidence of recurrence or metastasis.Metaplastic carcinoma of the thymus is a distinct clinicopathological entity that should be distinguished from the usually benign medullary thymomas and from the clinically aggressive carcinosarcomas and sarcomatoid carcinomas.

The significant function of cytokines includes maintenance of cell survival as well as induction of cell differentiation and/or proliferation. We demonstrate here that interferon-gamma (IFN-gamma) plays a role for progression of Epstein-Barr virus (EBV)-infected natural killer cell leukemia (NK leukemia) through maintaining cell survival. NK leukemia cells obtained from 7 patients had clonal episomal forms of EBV, indicating that the leukemic cells were of clonal origin. Although normal NK cells constitutively expressed Bcl-2, the EBV-infected NK leukemia cells lacked endogenous Bcl-2 expression and were hypersensitive to apoptosis in vitro. The addition of IFN-gamma to the culture significantly inhibited their spontaneous apoptosis without inducing cell proliferation or upregulation of Bcl-2. The NK leukemia cells constitutively secreted IFN-gamma, and the patients' sera contained a high concentration of IFN-gamma, levels that were high enough to prevent NK leukemia cells from apoptosis. Bcl-XL was not involved in the IFN-gamma-induced NK leukemia cell survival. These data suggest that the acquisition of IFN-gamma-mediated autocrine survival signals, other than Bcl-2 or BCL-XL, might be important for the development of EBV-infected NK leukemia.

We studied clinical effect of a combination therapy with cefozopran (CZOP) and tobramycin (TOB) for infections in 80 patients with hematologic diseases in 15 institutes. Combined doses with CZOP 2 g and TOB 60-90 mg twice a day had been given intravenously. Of the 80 patients, 61 patients (42 with acute leukemia, 10 with malignant lymphoma, 3 with aplastic anemia, 2 with chronic myeloid leukemia, 2 with multiple myeloma, and 2 with myelodysplastic syndrome) were evaluable. Those consisted of 6 patients with septicemia, 49 with suspected septicemia, 3 with pneumonia, and 3 with other infections. Clinical efficacy by the treatment was excellent in 24, good in 17, fair in 9, and poor in 11 patients, and the overall efficacy rate including excellent and good was 67.2%. Microbiologically, 5 of the 6 patients with septicemia (1 coagulase negative Staphylococcus, 2 S. pneumoniae, 1 S. oralis, and 1 E. coli) were responded. The efficacy rate in patients with severe granulocytopenia showing 100/microliter or lesser neutrophil counts during the drug administration was 57.1% (12/21). Side effects and abnormal changes of clinical laboratory findings were observed in 5 patients, and 16 patients, respectively, but most of them were mild. The findings above suggested that the combination therapy with CZOP and TOB is useful as an empiric therapy for severe infections in patients with hematologic diseases.

We evaluated the serum level of soluble Fas ligand (sFasL) in patients with natural killer lymphocyte proliferative disorders (NK- LPD). The serum sFasL level was elevated in neoplastic groups of aggressive NK leukaemia, indolent NK leukaemia and NK lymphoma, all of which contained clonal EBV-DNA. In NK leukaemia the serum sFasL level was significantly higher than that found in others. However, it was not elevated in the patients with reactive NK-LPD and in one patient with NK leukaemia in remission. These findings indicate that the serum sFasL level is a useful indicator in evaluating disease activity.

A 45-year-old woman was incidentally suspected to have megacolon. Chest X-rays showed elevated left diaphragm due to colonic gas, and the heart was deviated to the midline. Barium enema revealed marked dilation of the sigmoid colon, confirming the diagnosis of megacolon. Maximal diameter of the sigmoid colon was 23 cm, but she had no gastrointestinal symptoms. During the work up for megacolon, the presence of myotonic dystrophy was suspected. She had hatchet face, but was not bald. Muscles of the neck and extremities were slightly atrophic. There was percussion myotonia of the tongue and both hands, and grip myotonia of the hands. Laboratory examinations showed impaired glucose tolerance and low level of serum IgG. EMG showed myotonic discharges and myopathic units in the limbs. Brain CT imaging revealed a thick skull. Cases of myotonic dystrophy associated with marked megacolon are rare in Japan. Megacolon presents a high risk for ileus, volvulus, and rupture, and myotonic dystrophy is associated with a high operative and anesthesic risk. Megacolon, therefore, is an important complication to look for in the management of myotonic dystrophy.

The effects of right ventricular outflow pacing were studied in 13 patients (mean [+/-SD] 69.8 +/- 8.2 years old). All patients received DDD pacemakers except two patients with implanted VVI pacemakers who had chronic atrial fibrillation. Cardiac output and pulmonary capillary wedge pressure were measured by Swan-Ganz catheter. Pacing rate was fixed at 70-80/min and atrioventricular delay was fixed at 165 msec. When the pacing site was changed from the right ventricular apex to the right ventricular outflow during right ventricular pacing in 11 patients, cardiac output increased from 3.3 +/- 0.6 to 3.4 +/- 0.5 l/min (p0.001), and wedge pressure decreased from 9.3 +/- 1.9 to 8.8 +/- 2.0 mmHg (p0.05). When the pacing site was changed from the right ventricular apex to the right ventricular outflow during atrioventricular pacing in eight patients, cardiac output increased from 3.9 +/- 0.4 to 4.0 +/- 0.4 l/min (p0.05), and wedge pressure decreased from 7.1 +/- 2.3 to 6.6 +/- 2.1 mmHg (p0.05). When the pacing site was changed from the right ventricular apex to the right ventricular outflow in seven patients with ejection fraction (EF) greater than 55%, cardiac output increased from 3.6 +/- 0.5 to 3.7 +/- 0.4 l/min (p0.05), and in four patients with EF less than 55%, it increased from 2.9 +/- 0.4 to 3.0 +/- 0.4 l/min (p0.01). Cardiac function was improved by right ventricular outflow pacing compared to right ventricular apex pacing regardless of the pacing mode or cardiac function.

Sleep apnea with neuromuscular disorders has been successfully treated with bi-level positive airway pressure ventilation (BiPAP), which, unlike continuous positive airway pressure ventilation (CPAP), creates pressure difference between expiratory and inspiratory phases. Hence if the respiration of patients stops longer than a pre-set duration, BiPAP can automatically force them to breath through a nasal mask. We report a 60-year-old woman with olivo-ponto-cerebellar atrophy (OPCA), whose mixed-type sleep apnea was difficult to treat with conventional CPAP. We therefore tried BiPAP on this patient at night. Nocturnal CO2 retention was nearly resolved, and unexpectedly daytime PaCO2 was also corrected with marked improvement of daytime somnolence. BiPAP is totally non-invasive, and may be one of the most effective treatments in patients with OPCA suffering from sleep apnea.

We investigated clinical features and immunological parameters in 40 patients with slowly progressive spastic paraparesis including 13 cases (4 men and 9 women, aged 43 to 71, mean 61 years) with positive antibody to hepatitis B virus (HBV), 13 (6 men and 7 women, aged 39 to 75, mean 63 years) with positive antibody to HBV and HTLV-I, and 14 (3 men and 11 women, aged 33 to 71, mean 55 years) with positive antibody to HTLV-I (HAM). None showed obviously organic changes of the spine on magnetic resonance image. Patients with positive antibody to HBV (hepatitis B virus associated myelopathy, HBM) were significantly lower in disability grade and had a fewer incidence of micturition than in the HAM. Furthermore, natural killer (NK) activities were in normal range and peripheral blood lymphocytes did not show autologous proliferation response (APR). Patients with positive antibody to both HBV and HTLV-I showed APR similar to HAM, but in most patients NK activities were within normal range. These results suggest that the mechanism of myelopathy in HBM may be different from that in HAM, and HBV infection may play a role as a cofactor in HAM.

Hemostatic molecular markers were serially monitored in a prospective fashion during remission induction therapy with all-trans retinoic acid (ATRA) in sixteen patients with acute promyelocytic leukemia (APL). One patient with leukocytosis before treatment and three patients who later developed hyperleukocytosis also received chemotherapy with behenoyl Ara-C and daunorubicin. Plasma levels of E-fragment of fibrin and fibrinogen degradation product (FDP-E), FDP-D dimer (D-D), thrombin-antithrombin complex (TAT), and plasmin-alpha 2 plasmin inhibitor complex (PIC) were markedly elevated in all but one patient before treatment, and these parameters decreased to normal or near normal ranges in most patients within the first 7 days of treatment. Interestingly, we have found that these parameters were again elevated during the later course of ATRA therapy (after day +7) in eleven patients for various reasons including cytotoxic chemotherapy (3 cases), fever (5 cases; 2 cases with apparent infection, 3 cases without known etiology), Caesarean section (1 case), and no apparent etiology (2 cases). Three patients showed bleeding complications during re-elevation of molecular markers, but none developed thrombosis. Plasma elastase-alpha 1 proteinase inhibitor complex (E-alpha 1 PI) was markedly elevated in all patients at diagnosis and did not decrease significantly during ATRA therapy. Plasma tissue factor antigen was mildly elevated in one out of four patients studied, and thrombomodulin was elevated in two out of ten patients tested. These results confirmed the rapid normalization of coagulopathy during the early phase of remission induction therapy with ATRA but suggest that re-elevation of molecular markers occurs frequently during the later course of ATRA therapy.

A new cell line MGM-1 was established from a primary tumor of the left temporal lobe with histological diagnosis of glioblastoma multiforme, removed from a 64-year-old Japanese male. The patient died of recurrence and unusual extracranial metastases of the tumor 7 months after the surgery. The cultured MGM-1 cells are spindle or polygonal in shape. After serial passages, glial fibrillary acidic protein became negative immunocytochemically in vitro. The modal chromosome number was 61-64. Doubling time and soft agar colony forming efficiency were 42.9h and 0.4%, respectively (at 25th passage). MGM-1 is a highly motile cell line in vitro and its serum-free conditioned medium is chemotactic and chemokinetic for other glioma cells. Secretion of gelatinases (probably MMP-2/72-kDa type i.v. collagenase) and MMP-9/92-kDa type i.v. collagenase) and urokinase-type plasminogen activator were also investigated. MGM-1 would therefore be useful for studying the mechanisms regulating glioma-cell motility and invasion. The MGM-1 cell line has been propagated continuously by serial passages (more than 100 passages) during the past 4 years.

We have examined 56 unrelated individuals from Malaysian aborigines for their DNA polymorphism of the HLA-B gene by sequence specific oligonucleotide probe (SSO) method. Using the SSO hybridization, we found that one specific DNA allele with a B*1513 like pattern of epitope combination (ECB1513) was dominant among the Melayu Asli (Af = 41.9%) and the Senoi (Af = 24%). To determine the nucleotide sequences of ECB1513, a DNA fragment spanning from the beginning of exon 1 to the middle of exon 4 of the HLA-B gene was amplified by polymerase chain reaction (PCR) from two ECB1513 positive individuals, and the PCR products were cloned and sequenced. This sequencing analysis confirmed that ECB1513 was identical to HLA-B*1513 in exon 1, 2, 3, and 4. Amino acid sequence of this major allele, HLA-B*1513, in the aborigines especially around the peptide binding groove (B and F pockets), was compared with that of African B*5301 that had been suggested to confer resistance to malaria infection in Africa. The amino acid residues composing of the F pocket were completely identical in B*1513 and B*5301. These observations suggest that a common environmental factor, the malaria infection, might have independently enhanced the selection of functional change in the polymorphic portion of HLA-B gene in Africa and in South-East Asia.

Japanese diabetic patients with diabetic mothers were screened, using peripheral leukocytes, for an A to G transition at nucleotide pair 3243, a tRNALeu(UUR) mutation of the mitochondrial gene. This mutation was identified in four pedigrees from among 300 unrelated patients. Diabetes mellitus cosegregated with the mutation, except in one young subject, and was maternally inherited. Long-term follow-up revealed that the underlying disorder, in affected individuals, is a progressive impairment of insulin secretion. In accordance with this finding, the mutation was found to be highly prevalent in a diabetes mellitus subset termed slowly progressive IDDM; the mutation was identified in 3 out of 27 subjects enrolled in the prospective study of islet cell antibody (ICA)-positive, initially non-insulin-dependent diabetic Japanese patients, who are at high risk of progressing to insulin dependence over several years. The histologic characteristics of slowly progressive insulin-dependent diabetes mellitus include substantial loss, though incomplete, of pancreatic beta-cells. Mitochondrial gene defects in beta-cells could therefore cause glucose-induced signalling defects as well as beta-cell loss. This would explain the wide range of diabetic phenotypes, from NIDDM to IDDM, in patients with this mitochondrial gene mutation.

Human T cell leukemia virus type I (HTLV-I) is associated with adult T cell leukemia/lymphoma (ATLL), which is well known as a T cell malignancy. In order to clarify whether HTLV-I plays a role as a virus-encoded superantigen in the neoplastic process, we examined the TCR V beta families in the peripheral blood at four different clinical stages: carrier, smoldering leukemia, chronic leukemia, and acute leukemia. An increased number of CD4 T cells was found in each of the four clinical stages. However, we found neither uniform specific losses nor uniform clonal expansion of particular TCR V beta gene families in any case from the four clinical stages. However, a suppression of the random TCR V beta families was found. Our data did not therefore directly suggest the existence of a common superantigen model of HTLV-I which induces an increase in CD4 T cells. The random suppression in the TCR V beta repertoire is most likely caused by the influence of HTLV-I neoplastic pathogenesis rather than by virus-encoded superantigens. In the patients with acute leukemia, one or two families of the V beta repertoires were very strongly expressed, while in chronic leukemia, no such repertoire of strong expression was observed. The immunological reaction of the hosts might thus be different between the above described groups.

To examine the relationship between human T-lymphotrophic virus type I (HTLV-I) proviral DNA and its expression in the lymph nodes, HTLV-I DNA and tax/rex mRDA were directly amplified by polymerase chain reaction in situ hybridization (PCR/ISH), and reverse transcription (RT)-PCR/ISH [RT-PCR/ISH]. We studied 24 lymph nodes from patients with adult T-cell leukemia/lymphoma (ATLL), incipient ATLL (I-ATLL), and HTLV-I associated lymphadenitis dermatopathic type (HAL-D) and enlarged paracortical type (HAL-EP). In ATLL, 40-60% of the nucleated cells were positive for for HTLV-I proviral DNA by PCR/ISH, while in I-ATLL and HAL, respectively 5-20% and less than 1-5% of cells were positive. The number of mRNA expressing cells was smaller than that of the proviral DNA-positive cells. The mRNA-expressing cells varied in number among the ATLL and I-ATLL cases, while they were only rarely observed in HAL-D and HAL-EP. These results show that HTLV-I infection and activation might increase with malignant transformation of the target T helper cells.