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Background Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit‐to‐visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐RHYTHM Registry was performed. Methods and Results Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 (age, 69.7±9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6±5.0 times) during the 2‐year follow‐up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP‐SD (P =0.015 for thromboembolism; HR, 2.60, 95% CI, 1.36–4.97, P =0.004 for major hemorrhage; and HR, 1.85, 95% CI, 1.11–3.07, P =0.018 for all‐cause death) after adjusting for components of the CHA 2 DS 2 ‐VASc score, warfarin and antiplatelet use, atrial fibrillation type, BP measurement times, and others. These findings were consistent when BP‐coefficient of variation was used instead of BP‐SD. Conclusions Systolic BP visit‐to‐visit variability was significantly associated with all adverse events in patients with nonvalvular atrial fibrillation. Further studies are needed to clarify the causality between BP variability and adverse outcomes in patients with nonvalvular atrial fibrillation. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique Identifier: UMIN000001569.

Objectives The objective of this study was to test the correlation of urinary podocyte number (U-Pod) and urinary podocalyxin levels (U-PCX) with histology of lupus nephritis. Methods This was an observational, cross-sectional study. Sixty-four patients were enrolled: 40 with lupus nephritis and 24 without lupus nephritis (12 lupus nephritis patients in complete remission and 12 systemic lupus erythematosus patients without lupus nephritis). Urine samples were collected before initiating treatment. U-Pod was determined by counting podocalyxin-positive cells, and U-PCX was measured by sandwich ELISA, normalized to urinary creatinine levels (U-Pod/Cr, U-PCX/Cr). Results Lupus nephritis patients showed significantly higher U-Pod/Cr and U-PCX/Cr compared with patients without lupus nephritis. U-Pod/Cr was high in proliferative lupus nephritis (class III±V/IV±V), especially in pure class IV (4.57 (2.02–16.75)), but low in pure class V (0.30 (0.00–0.71)). U-Pod/Cr showed a positive correlation with activity index ( r=0.50, P=0.0012) and was independently associated with cellular crescent formation. In contrast, U-PCX/Cr was high in both proliferative and membranous lupus nephritis. Receiver operating characteristic analysis revealed significant correlation of U-Pod/Cr with pure class IV, class IV±V and cellular crescent formation, and the combined values of U-Pod/Cr and U-PCX/Cr were shown to be associated with pure class V. Conclusions U-Pod/Cr and U-PCX/Cr correlate with histological features of lupus nephritis.

Background To clarify the influence of hypertension and blood pressure ( BP ) control on thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐ RHYTHM Registry was performed. Methods and Results A consecutive series of outpatients with atrial fibrillation was enrolled from 158 institutions. Of 7937 patients, 7406 with nonvalvular atrial fibrillation (70.8% men, 69.8±10.0 years) were followed for 2 years or until an event occurred. Hypertension was defined as a systolic BP ≥140 mm Hg, a diastolic BP ≥90 mm Hg, a history of hypertension, and/or antihypertensive drug use. Hypertension was an independent risk factor for major hemorrhage (hazard ratio 1.52, 95% CI 1.05–2.21, P =0.027) but not for thromboembolism (hazard ratio 1.05, 95% CI 0.73–1.52, P =0.787). When patients were divided into quartiles according to their systolic BP at the time closest to the event or at the end of follow‐up (Q1, CI 1.75–4.74, P CI 1.02–2.53, P =0.041) after adjustment for components of CHA 2 DS 2 ‐ VAS c score, warfarin use, and antiplatelet use. A systolic BP of ≥136 mm Hg was an independent risk factor for thromboembolism and major hemorrhage. Conclusions BP control appears to be more important than a history of hypertension and baseline BP values at preventing thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation. Clinical Trial Registration URL : http://www.umin.ac.jp/ctr . Unique identifier: UMIN 000001569.

Objective. Auto-antibodies to signal recognition particle (SRP) are known to be specific to PM among rheumatic disorders, but the specificity in myopathic diseases remains unclear. The clinical utility of anti-SRP antibody in the differential diagnosis of myopathies has not been studied. The aim of the present study was to elucidate whether detection of anti-SRP antibody can discriminate of PM from muscular dystrophy (MD). Methods. We report a patient with a childhood onset myopathy, in whom it was clinically difficult to make a differential diagnosis of PM or MD for 21 yrs, despite repeated muscle biopsies. Myositis-specific auto-antibodies to RNA-associated antigens were screened in this particular case as well as in 105 serum samples from various types of MD and 84 from PM patients using RNA immunoprecipitation. The MD and PM serum samples were obtained from different institutions. The presence of anti-SRP antibody was confirmed by RNA immunoprecipitation combined with immunodepletion of SRP from the antigen. Results. Anti-SRP antibody was positive in the present patient, supporting the diagnosis of PM. Anti-SRP antibody was detected in seven (8.3%) patients with PM, but in none of the patients with MD. Myositis-specific auto-antibodies were not detected in any of the patients with MD. Conclusion. Anti-SRP antibody is useful for discriminating PM from MD among patients with myopathies.

Although some molecular differences between flat-depressed neoplasias (FDNs) and protruding neoplasias (PNs) have been reported, it is uncertain if the BRAF mutations or the status of phosphorylated mitogen-activated protein kinase (p-MAPK) are different between theses two groups. We evaluated the incidence of BRAF and KRAS mutations, high-frequency microsatellite instability (MSI-H), and the immunohistochemical status of p-MAPK in the nonserrated neoplasias (46 FDNs and 57 PNs). BRAF mutations were detected in four FDNs (9%) and none of PNs (P=0.0369 by Fisher's exact test). KRAS mutations were observed in none of FDNs and in 14 PNs (25%; P=0.0002 by Fisher's exact test). MSI-H was detected in seven out of 44 FDNs (16%) and in one out of 52 of PNs (2%) (P=0.022 by Fisher's exact test). Type B and C immunostaining for p-MAPK was observed in 34 out of 46 FDNs (72%), compared with 24 out of 55 PNs (44%; P=0.0022 by chi(2) test). There was no significant difference in the type B and C immunostaining of p-MAPK between FDNs with and without BRAF mutations. BRAF and KRAS mutations are mutually exclusive in the morphological characteristics of colorectal nonserrated neoplasia. Abnormal accumulation of p-MAPK protein is more likely to be implicated in the tumorigenesis of FDNs than of PNs. However, this abnormality in FDNs might occur via the genetic alteration other than BRAF or KRAS mutation.

Hepatocyte nuclear factor-4alpha (HNF4alpha) exists in multiple isoforms that are generated by alternative promoter (P1 and P2) usage and splicing. Here we establish monoclonal antibodies (mAbs) for detecting P1 and P2 promoter-driven HNF4alpha, and evaluate their expression in normal adult human tissues and surgically resected carcinomas of different origins. Using immunohistochemical analysis, we demonstrate that, while P1 promoter-driven HNF4alpha is expressed in hepatocytes, small intestine, colon, kidney and epididymis, P2 promoter-driven HNF4alpha is expressed in bile duct, pancreas, stomach, small intestine, colon and epididymis. Altered expression patterns of P1 and P2 promoter-driven HNF4alpha were observed in gastric, hepatocellular and colorectal carcinomas. HNF4alpha was expressed in lung metastases from renal cell, hepatocellular and colorectal carcinoma but was not observed in lung tumours. The P1 and P2 promoter-driven HNF4alpha expression pattern of tumour metastases correlated with the primary site of origin. P1 promoter-driven HNF4alpha was also found in intestinal metaplasia of the stomach. These data provide evidence for the tissue distribution of P1 and P2 promoter-driven HNF4alpha at the protein level and suggest that HNF4alpha may be a novel diagnostic marker for metastases of unknown primary. We propose that the dysregulation of alternative promoter usage of HNF4alpha is associated with the pathogenesis of certain cancers.

Ophthalmoplegic migraine (OM) is a rare variant of migraine characterized by recurrent attacks of severe headache followed by oculomotor nerve palsy. The recent revision of the International Headache Classification has reclassified OM from a subtype of migraine, defined as a functional headache, to the neuralgia category. We describe a case of an 11-year-old girl with pathologically confirmed oculomotor nerve schwannoma who had been suffering from symptoms mimicking OM. For five years, she has been under treatment for OM, an initial diagnosis which was corroborated by brain magnetic resonance imaging (MRI). Usually, most OM attacks occur during one period in a lifetime and remit completely. In contrast, however, her attacks became more frequent and were not controlled by medication. After surgery, the frequency of OM attacks was reduced. From this experience, we hypothesize that optic nerve tumor is one condition that can mimic OM, without apparent signs suggestive of intracranial mass. To our knowledge, this is the first report to describe a pathologically confirmed case of oculomotor nerve schwannoma mimicking OM.

A 55-year-old man developing transfusion-dependant anemia was diagnosed with autoimmune hemolytic anemia (AIHA). Although he received prednisolone (PSL) (daily 60 mg), his hemoglobin level continued to decrease. After 3 weeks of treatment, he presented with a distension of the abdomen. Cytological examination of ascitic fluid revealed large, immunoblastic lymphocytes with plasmacytoid features and abundant IgM chains on the cellular surface; this was diagnosed as primary effusion lymphoma (PEL). Administration of CHOP (cyclophosphamide, Adriamycin, vincristine, and PSL) chemotherapy elicited regression of ascites as well as recovery of hemoglobin level. We hypothesize that PEL cells generated antibodies against red blood cells, resulting in AIHA resistance to PSL.

Jichi Medical School (JMS) was established in 1972 to supply graduates to rural areas where medical resources are scarce. JMS has several unique characteristics aimed at motivating graduates to work in a rural practice. These include financial aid for students, a home prefecture recruiting scheme, location in a non-urban area, management by prefectures and support from the national government. The achievements of JMS over the 24-year period since its foundation have been evaluated. A questionnaire has been mailed to all JMS graduates since the first year of graduation. Using a pro-active approach to follow-up, the return rate has been virtually 100%. The authors investigated annual changes in the distribution of the graduates as well as the present status of the graduates in 1995. At that time, JMS graduates were distributed all over Japan. Among the 1871 graduates, 792 (42%) were working in rural areas in 1995. Nine-hundred and twenty-four graduated in the period from the first to the ninth output of graduates. Among these, 858 (93%) completed the requisite 9 years of work contracted between JMS and the graduates, 620 (67%) had practised in the same prefecture, and 305 (33%) were still practising in a rural area. Although there are still improvements to be made, JMS has succeeded in achieving its aim of supplying doctors to rural areas. The recruiting system of JMS is an effective approach to overcoming the shortage of rural doctors, which has continued to be an unresolved global problem.

The Eker rat hereditary renal carcinoma is an excellent example of a Mendelian dominant predisposition to a specific cancer in an experimental animal. We recently reported that a germline insertion in the rat homologue of the human tuberous sclerosis (TSC2) gene gives rise to the dominantly inherited cancer in the Eker rat model. The function of the TSC2/Tsc2 gene product (called "tuberine" in the human case) is not yet understood, although it contains a short amino acid sequence homologous to the ras family GTPase-activating proteins (GAP3). In the study, we isolated subtracted cDNA clones having increased expression in Eker renal carcinoma cells, using a modified representational difference analysis method to search for additional genes specifically involved in renal carcinogenesis. Here we identified four genes: the third component of the complement (C3) gene, the fos-related antigen I (fra-1) gene, an unknown gene (designated as being expressed in renal carcinoma: erc) and the calpactine I heavy-chain (Annexin II) gene.

Two pediatric patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes were diagnosed with growth hormone deficiency with the primary lesion identified as the growth hormone-releasing factor producing cells of the hypothalamus. Stimulation tests with insulin, levodopa and sleep did not overcome the deficient pattern of growth hormone secretion. By comparison, the growth hormone-releasing factor stimulation test generated a normal growth hormone response in these two patients. Growth hormone supplementary therapy was effective in terms of growth gain without adverse effects.

The objective of this study was to clarify to what extent Japanese dentists recommend dental floss and what factors influence dentists in encouraging their patients to use dental floss.The subjects in this study were 291 dentists who were directors of dental clinics, selected by stratified sampling by age.Dentists whose teachers at dental school had demonstrated dental flossing tended to recommend patients to use dental floss 2.2 (1.0-4.6: 95% CI) times more frequently compared with those who did not see demonstrations of flossing at dental school. Respondents who considered that using dental floss was very easy and easy, moderate, and difficult recommended patients to use dental floss 45.4 (11.2-183.9), 17.4 (6.6-45.8) and 5.9 (2.5-14.1) times more frequently, respectively, compared with those who considered it very difficult. Respondents who considered that using dental floss was effective, fairly effective or very effective in preventing dental caries recommended patients to use dental floss 3.8 (1.7-8.6), 3.8 (1.7-8.8) and 9.1 (3.6-23.0) times more frequently respectively, compared with those who considered it ineffective or only slightly effective.The demonstration of the use of dental floss by teachers at their dental schools gave dentists a good impression and a positive opinion of dental flossing. This was closely associated with recommendations by dentists to their patients to use dental floss.

An electron microscopic study revealed disruption of capillary endothelial tight junctions (TJs) in both biopsied muscle, taken at 5 years and 1 month of age, and the autopsied brain, taken at 13 years and 6 months of age, in a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) and mitochondrial DNA (mtDNA) point mutation A3243G. This endothelial barrier disruption might result in vasogenic edema and systemic lactic acidosis, possibly the critical pathology of MELAS.

Although microsomal prostaglandin E synthase (mPGES)-1 is known to contribute to stroke injury, the underlying mechanisms remain poorly understood. This study examines the hypothesis that EP(3) receptors contribute to stroke injury as downstream effectors of mPGES-1 neurotoxicity through Rho kinase activation.We used a glutamate-induced excitotoxicity model in cultured rat and mouse hippocampal slices and a mouse middle cerebral artery occlusion-reperfusion model. Effects of an EP(3) receptor antagonist on neuronal damage in mPGES-1 knockout (KO) mice was compared with that in wild-type (WT) mice.In cultures of rat hippocampal slices, the mRNAs of EP(1-4) receptors were constitutively expressed and only the EP(3) receptor antagonist ONO-AE3-240 attenuated and only the EP(3) receptor agonist ONO-AE-248 augmented glutamate-induced excitotoxicity in CA1 neurons. Hippocampal slices from mPGES-1 KO mice showed less excitotoxicity than those from WT mice and the EP(3) receptor antagonist did not attenuate the excitotoxicity. In transient focal ischaemia models, injection (i.p.) of an EP(3) antagonist reduced infarction, oedema and neurological dysfunction in WT mice, but not in mPGES-1 KO mice, which showed less injury than WT mice. EP(3) receptor agonist-induced augmentation of excitotoxicity in vitro was ameliorated by the Rho kinase inhibitor Y-27632 and Pertussis toxin. The Rho kinase inhibitor HA-1077 also ameliorated stroke injury in vivo.Activity of mPGES-1 exacerbated stroke injury through EP(3) receptors and activation of Rho kinase and/or G(i). Thus, mPGES-1 and EP(3) receptors may be valuable therapeutic targets for treatment of human stroke.

Small cell carcinoma (SCC) in the head and neck region is an extremely rare high-grade malignant tumor. The authors report a case of an SCC occurring in the left buccal region. An 85-year-old man exhibited left cheek swelling that rapidly increased in size. Histopathological examination revealed invasive growth of an SCC into the musculo-adipose tissue. Immunohistochemically, the tumor cells were positive for cytokeratin (AE1/AE3), neuron-specific enolase (NSE) and CD56, but negative for cytokeratin 20. The patient received chemotherapy and radiotherapy, which resulted in marked regression of the tumor. Surgical resection was performed. The serum levels of NSE and pro-gastrin-releasing peptide (pro-GRP) increased and multiple metastases of the tumor occurred 1 month after surgery. SCCs tend to exhibit aggressive invasion and metastasis so chemotherapy for the whole body is recommended to prevent dissemination of the tumor cells. Serum levels of NSE and pro-GRP are considered to be useful tumor markers for understanding the status of the tumor and the clinical symptoms.

We investigated the cause of myelofibrosis and proliferation of megakaryocytes in myelodysplastic syndrome with myelofibrosis (MDS-MF (+)). Plasma-transforming growth factor-beta1 (PTGF-beta1) concentrations closely correlated with myelofibrosis grade in MDS-MF (+) and were higher than those in idiopathic myelofibrosis (IMF), essential thrombocythemia (ET), idiopathic thrombocytopenic purpura (ITP), MDS-without MF (MDS-MF (-)) or healthy volunteers (HV). Peripheral blood mononuclear cells from MDS-MF (+) patients expressed more TGF-beta1 mRNA than those from IMF, MDS-MF (-) or HV. When we immunostained bone marrow specimens of MDS-MF (+) for TGF-beta, the intensity of blasts was apparently higher than that of megakaryocytes, while in MDS-MF (-), megakaryocytes were immunostained with a similar intensity as that in MDS-MF (+), but blasts were negative for staining. In IMF, megakaryocytes, monocytes and small mononuclear cells representing CD34+ cells were all similarly stained with a much lower intensity than that of blasts in MDS-MF (+). The number of bone marrow megakaryocytes were increased the most in MDS-MF (+), followed by ET, ITP, MDS-MF (-) and NHL and correlated with plasma thrombopoietin (TPO) levels or with plasma TGF-beta1 levels, respectively, in each disease. Thus, in MDS-MF (+), both myelofibrosis and the increased megakaryocytes were ascribed to overproduction of TGF-beta1 from blasts.

We report here on a patient with splenic marginal zone lymphoma presenting diffuse fibrosis of bone marrow and spleen. After splenectomy and chemotherapy, bone marrow biopsy demonstrated an improvement of fibrosis. Plasma concentration of transforming growth factor (TGF)-beta was much higher in this patient than in those of age-matched non-Hodgkin's lymphoma patients ( n=5) at diagnosis, decreasing after resolution of myelofibrosis. Immunostaining with the TGF-beta antibody revealed that the lymphoma cells in bone marrow and spleen were positive for TGF-beta. TGF-beta secreted by tumor cells was thought to stimulate the growth of fibroblasts and synthesize collagen in bone marrow and splenic fibroblasts, and play an important role in the development of marrow and splenic fibrosis in this patient. This is the first report of a patient with splenic marginal zone lymphoma presenting as myelofibrosis associated with bone marrow involvement of lymphoma cells which secrete a large amount of TGF-beta.

An 11-year-old boy was diagnosed as having acute lymphoblastic leukemia (ALL, L1) in 1987 and underwent treatment with an ALL high-risk protocol (prednisolone, vincristine (VCR), daunorubicin, 1-asparaginase), which resulted in complete remission. In 1990 he developed chronic hepatitis C and received interferon therapy. In December 1994, ALL recurred, and the patient was treated with VCR. He subsequently developed severe hemolysis (Hb 12.5 g/dl--6.8 g/dl) with increases of indirect bilirubin, AST, and LDH. Furthermore, symptoms resembling a syndrome of inappropriate secretion of ADH (SIADH) and DIC developed. Upon incubation of the patient's red blood cells with VCR in vitro, extreme deformity of the cells was observed. These findings suggested that splenomegaly, due to liver cirrhosis which had developed rapidly from chronic hepatitis C while the patient was in an immunosuppressed state induced by anticancer drugs, had trapped the deformed red blood cells and resulted in severe hemolysis. The patient died on the 165th day after admission due to liver failure.

We present a rare case of diffuse large B-cell lymphoma transformed from immunoglobulin (Ig) A-secreting marginal zone B-cell lymphoma. A 62-year-old woman was admitted to our hospital for examination of a disseminated pulmonary shadow. Gradual swelling of bilateral axilla and right inguinal lymph nodes were noted after admission. Histological examination of the lymph node biopsy specimen revealed the appearance of marginal zone B-cell lymphoma. The surface Ig of lymphoma cells was IgA-kappa, which coincided with the class of monoclonal Ig found in the patient's serum. The lymph node swelling and pulmonary shadow subsided, and the serum IgA level was normalized by 3 courses of systemic chemotherapy. However, after 4 courses of treatment, new tumor lesions at the right chest wall and left arm progressively became apparent. The biopsy specimen of the tumor showed a feature of diffuse large B-cell lymphoma. Despite intensive chemotherapy, the patient died of spreading tumor burden into the central nervous system.

A 62-year-old woman was admitted because of leukocytosis, systemic lymph node swelling and erythroderma. Laboratory data disclosed a WBC count of 15,600/microliter (CD4-positive cells: 91%). CD25 and HTLV-1 were negative. A skin biopsy revealed the involvement of T cells. These data and findings were consistent with a diagnosis of Sézary syndrome. Although the patient was treated with 2 courses of CHOP, the leukocyte count did not decrease. We then treated the patient orally with etoposide (25 mg/day) and methotrexate (10 mg/week), and this resulted in reduction of the leukocyte count and lymph node swelling, and amelioration of the erythroderma. As Sézary syndrome is an extremely rare disease, it is worthwhile reporting cases like the present one, where therapy was successful.

A 48-year-old woman, who had been suffering from systemic lupus erythematosus (SLE), developed normochromic normocytic anemia after receiving clomipramine hydrochloride. Her reticulocyte count was low, and a bone marrow aspirate revealed erythroid hypoplasia without involvement of other cell lines. Thus a diagnosis of pure red cell aplasia (PRCA) was made. The anemia gradually resolved following withdrawal of the drug. Although several drugs are known to cause PRCA, this is the first time that clomipramine hydrochloride has been reported to have such an effect. The underlying SLE in this case suggested the possible immunological pathogenesis of drug-induced PRCA.

Twenty-seven Japanese patients with the tuberous sclerosis complex (TSC), consisting of 23 sporadic and 4 familial cases, were tested for mutations in the TSC1 and TSC2 genes, using single-strand conformational polymorphism analysis and direct sequencing. Four possible pathogenic mutations were found in the TSC1 gene, including three frame shifts and a nonsense mutation in a familial case. All mutations were expected to result in a truncated hamartin gene product. The TSC2 gene analysis identified six possible pathogenic mutations only in the sporadic cases, including two frame shifts, one in-frame deletion, and three missense mutations. Two of the TSC2 mutations were expected to result in a truncated tuberin gene product. These results of the Japanese TSC patients were compatible with the reports from Europe and the United States, i.e., (1) TSC1 mutations are rarer in sporadic cases than in familial cases, (2) substantial numbers of sporadic cases arise from mutations in the TSC2 gene, and (3) mutations of the TSC1 gene may cause premature truncation of hamartin.

A 61-year-old woman was referred to our hospital for refractory thrombocytopenia (3 x 10(3)/microliter) and massive melena. Bone marrow aspiration revealed normal cellularity and increased megakaryocytes (250/microliter). An abdominal computerized axial tomography scan showed isodensity masses on both adrenal glands. 67 Ga-scintigraphy exhibited strong uptake into the bilateral adrenal tumor and mediastinal region. IgM-type antibody against platelet glycoprotein Ib (GpIb) was detected in the patient's serum. A needle biopsy of the right adrenal tumor was performed, and histology was non-Hodgkin's lymphoma (NHL), diffuse large B-cell type. Following the diagnosis of autoimmune thrombocytopenia associated with lymphoma, administration of corticosteroid (predonisolone 60 mg/day) and high-dose intravenous globulin (15 g/day x 4 days) was carried out, but neither was effective in normalizing the thrombocytopenia. Immunosuppressive therapy (cyclophosphamide 500 mg and 1 mg of vincristine) markedly restored the platelet counts to 7.2 x 10(4)/microliter and ceased the melena; furthermore, the size of adrenal tumors decreased by more than 60% after therapy. We cultured the lymphoma cells drawn by needle biopsy with IL-6 in vitro and found that the lymphoma cells produced IgM-type antiplatelet antibodies against platelet GpIb in the culture supernatant. Thus this is a rare case of NHL in which the production of antiplatelet antibody from lymphoma cells was confirmed in vitro.

The present study was designed to test the concept that platelets release a humoral factor that plays a regulatory role in megakaryopoiesis. The results showed that, among various hematoregulatory cytokines examined, transforming growth factor-beta1 (TGF-beta1) was by far the most potent enhancer of mRNA expression of bone marrow stromal thrombopoietin (TPO), a commitment of lineage specificity. The TPO, in turn, induced TGF-beta receptors I and II on megakaryoblasts at the midmegakaryopoietic stage; at this stage, TGF-beta1 was able to arrest the maturation of megakaryocyte colony-forming units (CFU-Meg). This effect was relatively specific when compared with its effect on burst-forming unit-erythroid (BFU-E) or colony-forming unit-granulocyte-macrophage (CFU-GM). In patients with idiopathic thrombocytopenic purpura (ITP), the levels of both TGF-beta1 and stromal TPO mRNA were correlatively increased and an arrest of megakaryocyte maturation was observed. These in vivo findings are in accord with the aforementioned in vitro results. Thus, the results of the present investigation suggest that TGF-beta1 is one of the pathophysiological feedback regulators of megakaryopoiesis.

A 48-year-old man was diagnosed with isolated noncompaction of the left ventricular myocardium. He had been suffering from dyspnea during light exercise since early February 1997, which worsened with time. Eventually, he visited our hospital on February 14. He was admitted urgently because orthopnea was observed and chest radiogram showed massive left pleural effusion. The diagnoses were pulmonary tuberculosis and tuberculous pleuritis. Echocardiography at admission showed generalized hypokinesis of the left ventricle, so we suspected that his condition was complicated by myocarditis. However, virus antibody levels were not elevated, and no obvious findings compatible with myocarditis or cardiomyopathy were obtained by right ventricular myocardial biopsy. Left ventricular contractility remained low and a trabecular mesh structure was seen at the left ventricular apex. Thus, the diagnosis was isolated noncompaction of the left ventricular myocardium. This disorder has been highlighted in pediatric patients, but few adult cases have been reported.

We previously reported that the use of polymerase chain reaction (PCR) in detecting cytomegalovirus (CMV) DNA in serum (sPCR) enables the detection of CMV viremia, which has not been possible with other methods. In this study, the clinical usefulness of sPCR was investigated by comparison with the results of three other diagnostic methods, i.e., antigenemia assay (AG), shell vial culture test (shell vial), and complement-fixing (CF) antibody titer. The present study included 26 patients with hematological diseases who had undergone allogeneic bone marrow transplantation (BMT). A total of 347 samples were collected, and the results of the sPCR and AG methods were in agreement in 91.1% of the samples. When a subject was positive in both the sPCR and AG tests, and the other two tests (shell vial and CF) were also positive, CMV reactivation was surmised as definite. When only the result of the shell vial test or the CF test was positive, these results were taken as false-positives. The time at which the samples became positive in each of these four tests was 7.5 weeks post-BMT for sPCR, 7.0 weeks post-BMT for the AG test, 7.4 weeks post-BMT for the shell vial test, and 9.7 weeks post-BMT for the CF test. Thus, it was found that samples became positive at almost the same time for the sPCR, AG, and shell vial tests. Interstitial pneumonitis (IP) due to CMV developed in 3 subjects. These cases were positive in the sPCR, AG, and shell vial tests prior to the manifestation of symptoms of IP. The CF test did not become positive until after the onset of the disease. As the IP due to CMV was controlled with treatment, the sPCR and AG tests became negative. With the shell vial and CF tests, on the other hand, the test results continued to be positive even after the IP was cured. These findings demonstrate that the sPCR test method--like the AG test--yields few false-positive results. Therefore, the sPCR method is useful in early diagnosis of reactivation of CMV and for evaluation of the efficacy of therapy administered for IP. In addition, sPCR can be performed simultaneously on a large number of samples, and the evaluation of the test results is simple. We conclude that the sPCR test may be superior to the three other diagnostic methods for evaluation of serum samples from multiple institutions.

We investigated the possible usefulness of SEP to the posterior tibial nerve in children with cerebral palsy. Sixty-four children with cerebral palsy, aged between 6 months to 20 years, were studied. Twelve patients had hemiplegia (H), 24 spastic diplegia who were able to walk (SDW), 17 spastic diplegia who were impossible to walk (SDNW) and 11 spastic quadriplegia (SQ), respectively. We also studied with 40 normal controls. Informed consent was obtained from subjects and parents. A significant difference was found in an appearance rate of P37 between the control and cerebral palsy groups. Absent and shortening of P37 were recognized in 10 among 18 recordings in the paralytic side of patients with hemiplegia. The central conduction time was shortened gradually with age in the control group. There was difference in the central conduction velocity between SDW, SDNW or SQ. These results suggested that P37 was the first cortical response, and that it was useful for the diagnosis of cause of paralysis.

We describe a female infant with obstructive jaundice due to inflammatory stenosis of the choledochus. It was surrounded and narrowed by a xanthogranulomatous lesion, extending from xanthogranulomatous cholecystitis (XGC). The obstructive jaundice was released by a cholecystectomy, resection of the choledochus, and hepaticojejunostomy. This is the first reported case of infantile XGC associated with obstructive jaundice.

We report a childhood case of severe acute cerebellitis caused by Coxiella burnetii. After 10 days of fever and headache, the patient fell into a drowsy state. Examination of the cerebrospinal fluid (CSF) revealed pleocytosis, an increased level of protein, and negative results in bacterial and viral studies. Magnetic resonance imaging demonstrated a herniated tonsil compressed by the swollen vermis. Administration of minocycline relieved the patient's clinical symptoms. C. burnetii was isolated from the CSF obtained during convalescence.

A 69-year-old woman with pure red cell aplasia and granular lymphocytic leukemia was reported. Because her granular lymphocyte count was in the normal range at the time of admission, we diagnosed the patient as primary pure red cell aplasia (PRCA). The granular lymphocyte count increased slowly, and we find monoclonal T cell receptor rearrangement, the case was diagnosed as granular lymphocytic leukemia accompanied with PRCA. Although single administration of cyclosporin or cyclophosphamide induced severe side effects obtained combined administration of low doses of these agents obtained good Hb increase. This case was granular lymphocytic leukemia with normal granular lymphocytic count at the time of diagnosis, the tumor cell suppressed BFU-E colony formation, and combined administration of low dose CPM and CyA yielded good effects.

Human peripheral blood progenitor cells (PBPC) are currently used as a source of hematopoietic reconstitution by autologous transplantation after myeloabrative chemotherapy for malignancies. PBPC would also be useful for allogeneic transplantation since the collection of PBPC is much safer than that of bone marrow stem cells (BM). For allogeneic transplantation, it is imperative to confirm that PBPC contains self-renewable stem cells that can sustain a long lasting hematopoiesis. In the present study, we examined the reconstitution of human hematopoiesis in severe combined immunodeficiency (SCID) mice by transplanting peripheral blood CD34+ cells in which the neo gene was transduced as a marker. In 2 of 4 mice receiving PB-CD34+ cell transplantation, the neo gene appeared as early as 4 weeks and lasted as long as 24 weeks in all DNA preparations of bone marrow, peripheral blood and spleen cells from the SCID mice, while in 2 of 4 mice receiving BM-CD34+ cell transplantation, although the neo gene also lasted as late as 24 weeks, it did not appear as early as in the mice receiving PB-CD34+ cell transplantation. A similar observation was noted in clinical trials, i.e. the white blood cell and platelet recovered earlier by transplantation of PBPC than of BM. In mice who had the neo gene, we were also able to demonstrate by FACS the presence of human lineage specific antigen in the cells as late as 24 weeks after transplantation with PB-CD34+ cells, and the presence of human IgG in the sera 10 weeks after transplantation. These findings indicate that PB-CD34+ cells contain long-term repopulating stem cells which undergo differentiation in SCID mice.

A 34-year-old patient with follicular lymphoma who was treated with CHOP followed by COPP for 3 years, became resistant to treatment in December 1993. Histological findings and surface markers of cervical lymph node cells revealed no change from previous findings. Tumor cell involvement of bone marrow was also observed by molecular analysis of DNA fragments with bcl-2 oncogene and J-H gene probes. Following 2 courses of salvage chemotherapy with NOAC-M regimen (novantrone, cytarabine and methylprednisolone), There was an 88% reduction of tumor mass on computed tomographic findings. Through the use of polymerase chain reaction analysis of residual cells with the bcl-2 translocation, we confirmed the in vivo purging of tumor cells from bone marrow and we harvested marrow cells for autologous transplantation. After high-dose chemotherapy (HDC) with ranimustine, cisplatin, etoposide and cyclophosphamide followed by bone marrow transplantation (BMT), complete remission was achieved. The patient has survived for 16 months and remains disease free. The standard chemotherapy regimen for advanced low grade non-Hodgkin's lymphoma has not yet been defined. Although we must follow this patient carefully to determine the effect of HDC with BMT for a long time, this seems to be an effective complementary treatment for patients responding to conventional salvage regimens.

Although hepatic veno-occlusive disease (HVOD) is a common complication of allogenic bone marrow transplantation (BMT), pulmonary veno-occlusive disease (PVOD) is very rare. Only three cases have been described in the literature. We report the case of a 19-year-old woman who developed PVOD accompanied by microangiopathic hemolytic anemia (MAHA) and hemolytic uremic syndrome (HUS) 1 year after a second BMT for relapsed acute lymphoblastic leukemia (ALL). Autopsy examination revealed obstruction of the small pulmonary veins with edematous thickening of the intima. These findings are compatible with PVOD. Pulmonary GVHD and pulmonary aspergillosis were also observed. Various etiologic factors have been implicated in PVOD after BMT. We postulate that pulmonary GVHD and pulmonary infection including aspergillosis played an important role in the occurrence of both PVOD and HUS in our patient. Microangiopathic cytokines released in response to the GVHD and infection may damage the intima of microvessels that were previously injured by the two BMT. Despite appropriate therapy, the microangiopathic process was irreversible and the patient died. Thus, measures must be taken to prevent and treat PVOD after BMT.

In an attempt to establish an efficient method of collecting peripheral blood stem cells and to utilize them for allogeneic peripheral blood stem cell transplantation, the effect of a combined administration of recombinant murine interleukin-3 (IL3) and recombinant human granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow stem cells into the circulation was examined in C57BL/6 mice. Some appreciable numbers (796 +/- 112/ml) of CFU-GM were recovered 6 days after G-CSF administration (500 micrograms/kg per day), while by IL3 administration (100,000 units/kg per day), the CFU-GM count was much lower (61 +/- 9/ml) with a small peak at day 4. By a combined administration of IL3 (100,000 units/kg per day) and G-CSF (500 micrograms/kg per day), the CFU-GM count at the peak of day 5 was significantly augmented (1178 +/- 277/ml) as compared to that of G-CSF or IL3 alone (P0.05). The CFU-S counts at day 5 (168 +/- 12/ml) and at day 6 (172 +/- 27) were also significantly higher than those of IL3 alone (day 5, 30 +/- 15/ml; day 6, 20 +/- 10/ml) or G-CSF alone (day 5, 114 +/- 14/ml; day 6, 112 +/- 19/ml). Thus the combined administration of IL3 and G-CSF appears to be promising for high yield collection of peripheral blood stem cells.

We tried long-term oral administration of low-dose etoposide (LDE) for seven patients with adult T-cell leukemia . lymphoma (ATL) at Asahikawa Red Cross Hospital in 1988. Two long-term survivors are presented. Case 1: A 53-year-old man was diagnosed as acute ATL in 1987. Because VEPA therapy was not effective, LDE (50 mg/day) therapy was started. Five months after entering CR, a lymphoma recurrence in the skin was observed. Retreatment with LDE and radiation therapy was effective, but he died of reprogression of ATL three years and seven months following initial diagnosis. Case 2: A 43-year-old woman was diagnosed as acute ATL in 1989. With LDE (50 mg/day) therapy for 40 days, she entered CR. The lymphoma recurred in the central nervous system (CNS) and skin in 1992. After radiation of CNS and LDE therapy, she showed CR again. She is alive now over five years and eight months after diagnosis.

Recent development of chemotherapy enabled us to cure patients with malignancies including leukemia, malignant lymphoma, choriocarcinoma, ovarian cancer, breast cancer and so on. In order to obtain the definite effect, the quantities of chemotherapeutic agents should be increased and the major lethal side effect caused by bone marrow failure should be avoided. For this purpose, hematopoietic stem cells derived from either bone marrow or peripheral blood can be used for the rapid recovery of neutropenia and thrombocytopenia. We prepared stem cells both from bone marrow and peripheral blood by anti-CD34 monoclonal antibody bound on magnetic beads column and administered into severe combined immunodeficiency (SCID) mouse. Four and 20 weeks after transplantation, mononuclear cells bearing human hematopoietic antigens and human immunoglobulin G were appeared in the circulation, suggesting that stem cells from peripheral blood also possess long-standing capability of maturation as well as those from bone marrow. We next conducted clinical study of high dose chemotherapy combined with peripheral blood stem cell transplantation for patients with poor risk choriocarcioma. By this treatment, 4 complete response (CR) and 4 partial response (PR) were obtained, whereas 2 progressive disease (PD), 1 no change (NC) and 5 PR were obtained by the previous conventional chemotherapies. The results obtained were promising and this treatment regimen may become a good modality for the complete treatment of chemotherapy curable tumors.

A 57-year-old man was admitted to hospital because of leukocytosis. He showed mild splenomegaly and, laboratory studies revealed elevated mature neutrophil count without morphological abnormality, mild anemia and elevated neutrophil alkaline phosphatase score. The serum granulocyte colony stimulating factor concentration was below 30 pg/ml. Bone marrow was a dry tap, and biopsy specimen revealed severe fibrosis. The peripheral blood karyotype was 46, XY with no rearrangement of bcr-abl. The patient was diagnosed as having chronic neutrophilic leukemia (CNL) with bone marrow fibrosis. He was successfully treated with hydroxyurea (HU) 1000 mg/day. The peripheral blood leukocyte was decreased to the normal level and, the bone marrow biopsy specimen changed mild fibrosis. During the follow up period of 11 months, the neutrophil count was well controlled without any side effect. This is a rare case of CNL accompanied with bone marrow fibrosis which was effectively treated by the administration of HU.

The variable clinical courses of three cases of congenital fiber type disproportion (CFTD) over a period of 10 years are presented. All showed improvement in early childhood, but subsequently, varying degrees of deterioration were noted: specifically, marked deterioration in case 2 and decreased muscle strength in case 3. Maximal motor function levels were attained differently among the cases. Histological findings included type 1 fiber hypotrophy and increased internal nuclei in common in all cases. Fine structural changes, such as patchy areas of myofibrillar degeneration, were noted in cases 1 and 2 (second biopsy), and cytoplasmic bodies were seen in case 2 (second biopsy). Myotubes were noted in case 3. The degree of cyto-architectural changes did not correlate with clinical severity. The heterogeneity of CFTD is also discussed.

Chronic idiopathic neutropenia is an uncommon condition characterized by a low level of neutrophils without any causative disease. We report the details of 4 patients whose stromal cytokine mRNA expressions were examined by reverse transcription polymerase chain reaction. Three patients showed a lower expression of granulocyte colony-stimulating factor (G-CSF) mRNA both in constructive and lipopolysaccharide (LPS)-induced conditions and normal colony forming unit-granulocyte-macrophage (CFU-GM) from the bone marrow cells. One patient showed an increase of G-CSF mRNA and a decrease of CFU-GM. No abnormal expression of other cytokines including interleukin (IL)-1 beta, IL-6 and IL-8 were observed. These findings indicate that cytokine mRNA analysis of stromal cells is useful for elucidation of the etiology.

A cDNA clone encoding a zinc finger protein (AREB6) was isolated from a HeLa cell expression library using a positive regulatory element (-102 to -58) of rat Na,K-ATPase alpha 1 subunit gene (Atp1a1) as a probe. The clone is apparently an extended one of Nil-2-a originally isolated as a negative regulator of interleukin 2 gene [Williams, T.M. et al. (1991) Science 254, 1791-1794]. The open reading frame encodes 1,124 amino acids. It contains 7 zinc-finger motifs arranged in two widely separated clusters. A glutamic acid-rich region is observed at the C terminus from residues 989 to 1123. Co-transfection of the AREB6 cDNA with Atp1a1 fused to a reporter luciferase gene indicated that the AREB6 protein enhances or represses the promoter activity of the gene depending on the quantity of cDNA and on the cell type. The mRNA of AREB6 is expressed in heart and skeletal muscle, but not in liver, spleen, or pancreas. Genomic Southern analysis indicated that the gene encoding AREB6 is present as only one copy or two at most. Another cDNA clone obtained by using the same probe was identified as HEB [Hu, J.S., Olson, E.N.,Kingston, R.E. (1992) Mol. Cell. Biol. 12, 1031-1042]. Co-transfection of the cDNA enhanced or repressed the promoter activity of Atp1a1 depending on the cell type.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied severity, causes of the disabilities, complications due to disabilities, and past histories of the severely mentally and physically disabled whose guardians or parents were residents in Gunma prefecture on September 1, 1991. This survey was made on severely disabled schoolboys and girls aged 6 to 15 years with IQ of 35 or less who could not stand or walk, even if they were supported. The number of them was 133 at the moment of this survey. Asphyxia at birth and congenital but unknown etiology were the major causes in the institutionalized cases, but cerebral palsy of unknown etiology and "no information" were frequent in the cases cared at home. The institutionalized patients showed severer mental retardations, palsies and disabilities on activities of daily lives, though not with statistically significant difference, and contained significantly larger number of cases fed by gastric tube or having meals as blended foods and significantly smaller number of cases having conventional meals than cases cared at home. Furthermore, epilepsies or constipations as complications were found more frequently in institutionalized cases than in cases cared at home with significant difference. On past history, relatively large numbers of the disabled suffered from various infectious diseases, especially from measles, varicella, mumps and pneumonia. Histories of measles, varicella and mumps showed higher frequency in institutionalized cases than in cases cared at home, though not with significant difference. On the cases cared at home, some of them did not have their home doctors, though in small numbers.(ABSTRACT TRUNCATED AT 250 WORDS)

A twenty-six-year-old male patient with advanced choriocarcinoma originated from mediastinum was treated by high-dose chemotherapy with peripheral blood stem cell (PBSC) transplantation. He had massive tumors in the cervical, mediastinal and bilateral lung fields. After 3 kur of PVeBV therapy (CDDP 60 mg x day 1-3, etoposide 160 mg x day 1-3, BLM 30 mg x day 1, VBL 12 mg x day 1), he obtained complete remission. PBSC was collected at the time of hematopoietic recovery and high-dose chemotherapy with PBSC transplantation was conducted because of the high possibility of recurrence. The hematopoietic recovery was rapid, and the patient remained well with no sign of recurrence for 24 months.

We report a 19-year-old female with blastic transformation of chronic myelogenous leukemia whose blasts had CD33 and CD4 phenotypes, although no significant characteristics were detected by morphological and histochemical analysis. In a colony assay with hematopoietic growth factors, the blasts proliferated and differentiated into myelo-monocytic lineage, particularly in the presence of GM-CSF or IL-3 + G-CSF. The blasts transformed from CML were assumed to be myelo-monocytic progenitor cells, corresponding to GM colonies. Blastic transformation expressing such a phenotype has not been reported previously.

Children were studied on distribution of the severely mentally and physically disabled aged 6 to 15 years in Gunma Prefecture as of September 1, 1991. They were all bedridden or able to sit, but could not stand or walk, even with support. Today, all the Japanese should attend elementary school as well as junior high school. Even though they are severely disabled, they are all registered by the regional Board of Education, where we could get exact data on the disabled children throughout Gunma Prefecture. We collaborated with the regional Board of Education, the Child Consultation Center of Gunma Prefecture and 6 hospitals for the disabled. A total of 129 cases were found. The population of schoolboys and schoolgirls aged 6 to 15 years of age was 236,000, most of whose guardians were residents of this prefecture, and the prevalence rate was 0.55/1000. Among 129 cases, 53 cases (41.1%) were institutionalized and 76 cases (58.9%) were cared for at home. Fifty-nine cases (45.7%) were males and 70 cases (54.3%) were females. Thirty-four cases were aged 6 to 7 years (26.4%) and older cases declined probably due to premature deaths. Ninety-four of the 129 cases (72.9%) were bedridden and mentally retarded with IQs 20 or less.