A case of synthetic oestrogen-induced autoimmune hepatitis with microvesicular steatosis.

WHAT IS KNOWN AND OBJECTIVE: Drug-induced liver injury (DILI) is a leading cause of acute liver failure in developed countries. Hepatotoxicity is a well-recognized adverse effect associated with synthetic oestrogens, which can cause cholestasis. The current report describes ethinyloestradiol (EE2)-associated highly unusual adverse effects of autoimmune hepatitis (AIH) and microvesicular steatosis (MS). DILI that fulfils the criteria for AIH is referred to as drug-induced autoimmune hepatitis (DIAIH). MS is a potentially severe liver lesion that results from mitochondrial dysfunction. We explore the pathophysiological mechanisms underlying DIAIH and MS. CASE SUMMARY: A 51-year-old woman presented with jaundice, increased liver enzymes and IgG, and positive ANA. She had been taking EE2 for 3 years. Liver biopsy showed prominent interface hepatitis with MS. A drug-lymphocyte stimulation test (DLST) using EE2 was positive. The liver biochemical parameters had normalized after the EE2 discontinuation; however, they exacerbated 5 months post-onset. Repeated liver biopsy showed interface hepatitis with no MS. Considering EE2-induced DIAIH, corticosteroids treatment was initiated. Then, all liver biochemical parameters had normalized, and the corticosteroids were successfully withdrawn. The patient continued to be in complete remission over the next 3 years. WHAT IS NEW AND CONCLUSION: Five remarkable points should be emphasized: (i) a long latency interval, despite the acute presentation; (ii) exacerbation of liver biochemical parameters, even after drug cessation; (iii) the paired liver biopsies indicating continuing inflammation and disappearance of toxic features; (iv) a positive DLST and the absence of fibrosis consistent with DIAIH and not AIH; and (v) a rare histological feature of MS. Intense immunoallergic reactions were likely triggers of MS in the current case. A possibility of DIAIH should be considered in cases of DILI which exhibit overt jaundice, autoantibodies, intense histological inflammation and a long latency period.

Cranial base chordoma--long term outcome and review of the literature.

BACKGROUND: The purpose of this study is to clarify the latest long-term therapeutic result for cranial base chordomas. We are seeking an improvement of long term therapeutic outcome through a review of cranial base chordomas treated in our institute and of the published literature in the era of multimodality therapy. MATERIALS AND METHODS: We retrospectively reviewed 13 consecutive patients with cranial base chordoma, including ten males and three females with mean age of 39.5 years (range 5-76 years). RESULTS: The method of initial treatment included surgery and post-operative conventional local irradiation (IR) in 9 patients, surgery and IR followed by post-operative stereotactic radiosurgery (SRS) in 2 patients, surgery as well as SRS in one patients, and surgery as well as SRS followed by IR in one patient. Subtotal removal (over 95%) was accomplished in eight patients. The mean follow-up period after completion of surgery and initial radiotherapy was 122 months (median 108 months). According to the Kaplan-Meier estimate method, the 5-year survival rate was 82.5%: 11 out of 13 patients survived longer than 5 years and five patients survived longer than 10 years. With a longer follow-up period than the previous reports, our series has provided a 5-year survival rate comparable to that of proton beam therapy. Although our series indicates a favourable outcome, surgical resection followed by IR or SRS failed to control tumour growth in five patients. CONCLUSIONS: IR and/or SRS provided results comparable with proton beam or heavy particle therapy in our series of cranial base chordomas probably because the radiation field must have covered the target of the tumour volume sufficiently, and reduction of gross tumour volume reduced the target size for radiotherapy. Pursuit of further effective combinations of IR and stereotactic radiotherapy (SRS, proton beam, heavy particle) after tangible resection, especially for residual and recurrent lesions, will be an acceptable framework to achieve a better therapeutic outcome for cranial base chordomas than at present.

The effect on methamphetamine on the mRNA level for 14.3.3 eta chain in the human cultured cells.

14.3.3 protein, a brain-specific protein, is an activator of tyrosine and tryptophan hydroxylases, key enzymes for biosynthesis of dopamine and serotonin. In this article, we describe cloning of cDNA for human brain 14.3.3 eta chain and expression of 14.3.3 eta chain mRNA in some human cultured cells. The cloned cDNA is 1730 bp long and contains 191 bp of a 5'-noncoding region, the complete 738 bp of coding region, and 801 bp of a 3'-noncoding region, containing three polyadenylation signals. This cDNA encoded a polypeptide of 246 amino acids (M(r) 28,196). Furthermore, using in situ hybridization histochemistry, the expression of mRNA for this protein was examined in the rat central nervous system. In situ hybridization histochemistry indicated that 14.3.3 eta chain mRNA is detected not only in the monoamine-synthetic neurons, but also in other neurons in the discrete nuclei, which synthesize neither cathecholamine nor serotonin. Northern blot analysis demonstrated that the addition of methamphetamine into the cultured medium increased the mRNA level for 14.3.3 eta chain in U-251 cells, but did not increase that of GFAP.

cDNA cloning and mRNA expression analysis of the human neuronatin. High level expression in human pituitary gland and pituitary adenomas.

The authors cloned the nearly complete cDNA of human neuronatin with the aid of an expressed sequence tag (EST) database, and analyzed its expression in various human tissues by Northern blot analysis. The nucleotide and deduced amino acid sequences of the human neuronatin showed a high similarity to those of rodents. The Northern blot analysis revealed that the human neuronatin message was expressed predominantly in the fetal brain in the brain-specific manner, but only faintly in the adult brain. Among the various adult human tissues examined, the anterior pituitary gland was shown to be the only place where the neuronatin mRNA was strongly expressed. Intense neuronatin expression was also observed in several human pituitary adenomas, including ACTH-producing, GH-producing, and nonfunctioning adenomas, but hardly detected in other brain tumors.

15-Deoxyspergualin controls cyclosporin- and steroid-resistant intestinal acute graft-versus-host disease after allogeneic bone marrow transplantation.

We report a case of cyclosporin- and methylprednisolone-resistant intestinal acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation which responded to a new immunosuppressant, 15-deoxyspergualin (DSG). Endoscopy showed lymphoid hyperplasia with CD3+, CD4+, CD8- lymphocyte infiltration into the submucosa of the jejunum and colon. DSG effectively suppressed this intestinal acute GVHD.

Structure and expression of human and rat D2 dopamine receptor genes.

D2 dopamine receptor may be related with the pathogenesis of Parkinson's disease and schizophrenia. Furthermore, the antipsychotic drugs have high affinity for D2 dopamine receptor. We carried out the cloning of the genomic DNA for human D2 dopamine receptor and clarified the structure of this gene. Our isolated gene spans about 15 kbp and consists of seven exons interrupted by six introns. However, putative first exon was not yet identified. Spot blot hybridization analysis of cell sorter fractionated human chromosomal DNA with D2 receptor genomic DNA revealed the localization of this gene in the chromosome 11 fraction. We analyzed human genomic DNA by Southern blot hybridization with D2 dopamine receptor genomic DNA as a probe, but so far we could not find RFLP. Northern blot analyses of brain RNA of several animals and rat brain RNA after various treatments were carried out. Developmental changes of D2 dopamine receptor mRNA were observed in the rat brains.

T-cell mediated polyclonal B-cell activation in a case of B-cell lymphoma associated with polyclonal hypergammaglobulinemia.

The mechanism of abnormal immunoglobulin production in non-Hodgkin's lymphoma is still poorly understood. We report a case of B-cell type non-Hodgkin's lymphoma associated with marked elevated polyclonal hyper-gammaglobulinemia (serum IgG was 7598 mg/dl; IgM, 455 mg/dl). We conducted a mixed lymphocyte culture test using peripheral lymphocytes obtained from the patient and a healthy volunteer. After co-culture with the patient's CD3+ cells, not only the patient's CD3- cells but also control CD3- cells produced greater amounts of IgG and IgM. Elevated IL-6 was also detected from the patient's CD3+ cells. This strongly suggests that B-lymphoma cells stimulate CD3+ cells to produce IL-6 and hence activate normal CD3- cells.

Brain metastasis from germinal tumors of the testis. Case report.

Brain metastasis in patients with disseminated nonseminomatous germ cell tumor (NSGCT) has been considered to occur rarely. The authors present the case of a 43-year-old man with an enlarged left testicle, a palpable inguinal tumor, multiple lung tumors, and a large cerebellar tumor. In separate operations, performed 1 month apart, the large cerebellar tumor and the testicular tumor were excised. Elements of teratocarcinoma, embryonal carcinoma, and choriocarcinoma were present in both the brain and testicular tumors. After chemotherapy in which bleomycin, etoposide, and cisplatin were used, the lung tumors and also the surrounding metastasis disappeared; the patient now leads a useful life and remains free from cancer in all organs. The authors suggest that surgical removal of tumor before initiating radiotherapy and chemotherapy for large brain metastasis from NSGCT will produce better results than using the nonsurgical treatments alone.

Significant correlation between cerebrospinal fluid and brain levels of norepinephrine, serotonin and acetylcholine in anesthetized rats.

The present study was undertaken to determine cerebrospinal fluid (CSF) and brain levels of norepinephrine (NE), serotonin (5-HT) and their metabolites--3,4-dihydroxyphenylacetic acid (DOPAC), 4-hydroxy-3-methoxyphenylacetic acid (HVA) and 5-hydroxyindole-3-acetic acid (5-HIAA)--in rats pretreated with 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT). In the 6-OHDA pretreated rats, both CSF and brain concentrations of NE, DOPAC and HVA sustained significant decreases as compared with those in non-treated rats. Positive and significant correlations between CSF and brain levels were observed in respect to NE, DOPAC and HVA. In 5,7-DHT pretreated rats, both CSF and brain concentrations of 5-HT and 5-HIAA were significantly decreased. A positive and significant correlation between CSF and brain levels in respect to 5-HT and 5-HIAA was observed. Further studies were carried out to determine ACh levels of both the CSF and the brain in microspheres (MS)-treated rats, which are used as a model of microembolization. The CSF ACh concentrations in MS-treated groups were significantly decreased as compared with those in non-treated rats. The brain ACh contents also tended to decrease in this group. A positive and significant correlation was observed between CSF and brain levels of ACh. These findings suggest that NE, 5-HT and ACh concentrations in the CSF are direct indications of central noradrenergic, serotonergic and cholinergic nerve activity, respectively.

Membranous lipodystrophy: a clinicopathological study of six cases.

Membranous lipodystrophy apparently is a new disease, first reported and named by Nasu and associates 31 in 1971. We have collected six cases of this disease. The initial manifestation was articular pain at adolescence. Symmetrical changes in the bones of the extremities then appeared and the disease seemed to progress slowly with age. The younger patients exhibited only skeletal pain or fractures, while the older patients had some neuropsychiatric changes. Three of the patients died in middle age. The cystic bone lesions contained a yellow, lipid-like substance which histologically showed a characteristic membranocystic appearance. Electron microscopic study showed unique features, but biochemical analysis of the substance did not reveal a definable abnormality.

Brain metastasis in patients with sarcoma: an analysis of histological subtypes, clinical characteristics, and outcomes.

BACKGROUND: The clinical characteristics of brain metastasis from sarcoma are not well known. We examined the incidence and the characteristics of brain metastasis in patients with sarcomas. METHODS: All sarcoma patients treated at our institution from 1975 to 1998 were reviewed for brain metastasis. Diagnosis of the primary tumor was confirmed histologically, and brain metastasis was confirmed using computed tomographic (CT) brain scan. RESULTS: Brain metastasis was found in 27 (5.6%) of 480 patients with systemic sarcoma (7.2% soft part sarcoma, 3.5% bone sarcoma, 15.1% distant metastasis). Of these 27 sarcoma patients with brain metastases, lung metastasis occurred in 16 patients (59.3%). Out of 10 patients surgically treated, 8 patients survived more than 16 months. Median survival period after craniotomy was 25.4 months. CONCLUSIONS: We recommend aggressive treatment for those patients with brain metastases whose performance scores are over 70.

Characteristic features of malignant lymphoma with central nervous system involvement.

BACKGROUND: Cerebral lymphoma is becoming increasingly common. METHODS: We reviewed the records of all our patients with non-Hodgkin's lymphoma (NHL) seen from April 1987 to August 1996 in our institute. Our analysis of these patients with lymphomatous central nervous system (CNS) involvement documents the clinical features, histology, and prognostic factors in CNS lymphoma. RESULTS: A total of 351 cases of NHL were treated in our institute. CNS lymphoma was found in 58 of 351 (16.5%) patients in our series. Forty-nine of 58 (84.5%) patients with CNS involvement also had systemic disease. Primary CNS lymphomas were detected in nine patients. Leptomeningeal infiltration was seen in 31 of 58 patients, whereas intracerebral infiltration was detected in 28 patients. Initial symptoms of CNS involvement included severe headache, muscle weakness, and other neurological signs. Malignant cells were detected in 32 of 132 studies in the cerebrospinal fluid examination. In the nine patients with primary CNS lymphoma, the median survival time was 16.5 months (range, 4-28 months). The overall median survival of the 58 CNS lymphoma patients was only 13.4 months (range, 1 to 32 months). CONCLUSIONS: Because prophylactic treatment was only successful in systemically well-controlled patients, control of systemic lymphoma seems to be of great importance.

Neurohypophyseal germinoma traced from its earliest stage via magnetic resonance imaging: case report.

BACKGROUND: We report a case in which magnetic resonance imaging (MRI) documented the formation of a neurohypophyseal germinoma from its earliest stage. CASE DESCRIPTION: A 9-year-old girl presented with polyuria, polydipsia, and growth retardation. Urinary and endocrinological examination indicated diabetes insipidus (DI) and growth hormone deficiency. No clear evidence of a mass in the hypothalamo-pituitary area was apparent on the first MRI scan. Follow-up MRIs and endocrinological examinations revealed that a tumor, arising from the stalk and posterior lobe of the pituitary gland, formed a mass and caused anterior pituitary function to deteriorate. Histologic diagnosis was germinoma based on open biopsy. CONCLUSION: Radiologic findings in this case indicated the primary site of this intrasellar germinoma to be the hypothalamo-neurohypophyseal region, designating this a "neurohypophyseal germinoma."

Anti-C100-3 antibody status, viral genomic sequences, and clinical features in chronic hepatitic patients with hepatitis C virus RNA in sera.

Since detection of hepatitis C virus RNA by the polymerase chain reaction (PCR) showed that there existed anti-C100-3 (anti-HCV) antibody negative patients infected with HCV, we attempted to find out whether there were any clinical or viral genomic differences between the anti-HCV antibody positive and negative groups. One hundred and fifty-nine patients with chronic liver diseases with hepatitis C virus RNA in their sera were selected. Anti-HCV antibody was tested for anti-C100-3 antibody by an enzyme linked immunosorbent assay. The incidence of anti-HCV antibody was 129/159. The concentration of serum gamma-globulin, the titier of ZTT, and the positive rate of the PCR with the primers of the NS3/4 region (NS3/4PCR) were significantly higher in the anti-HCV antibody positive group than in the negative group. However, the other data such as alanine aminotransferase activity or past history were not significantly different. Nucleotide sequence of the cDNA fragments of NS3/4 region amplified by the PCR did not differ significantly between isolates from anti-HCV antibody positive and negative sera. The sequences observed in the present study did not differ significantly from those reported previously. Although there remains the possibility that the variation of viral genomic sequences may cause the absence of anti-HCV antibody, these results suggested that the individual clinical backgrounds or immunoreactivity of the patients might influence the antibody development.

Radiation-induced diffuse brain injury in the neonatal rat model--radiation-induced apoptosis of oligodendrocytes.

The mechanism of radiation-induced diffuse brain injury was investigated using a model of delayed myelination in the irradiated neonatal rat brain in which the number of oligodendrocytes decreases without associated necrosis of the cerebral white matter. Immunohistochemical analysis using antibody against the large myelin-associated glycoprotein, a specific marker of oligodendrocytes at an early stage of development, showed that the number of the oligodendrocytes associated with myelination decreased in the irradiated hemisphere 1 day after irradiation and remained low until 5 days after irradiation. In situ terminal deoxynucleotidyl transferase-mediated nick end-labeling assay revealed that apoptosis mainly occurred in the cerebral white matter of the irradiated hemisphere. Three hours after irradiation, apoptotic cells were found in the subcortical white matter and the periventricular white matter. Six hours after irradiation, apoptotic cells were found in the internal capsule, and the numbers of apoptotic cells in the periventricular white matter and subcortical white matter increased. One day after irradiation, the number of apoptotic cells in the periventricular white matter decreased. Three days after irradiation, apoptotic cells were not observed in the cerebral white matter. These results suggest that the oligodendrocytes associated with myelination may be damaged via radiation-induced apoptosis, and depletion of the oligodendrocytes may cause delay of myelination.

[Stereotactic aspiration in hypertensive pontine hemorrhage: comparative study with conservative therapy].

Recently, CT-guided stereotactic aspiration has been attempted as a useful method for hypertensive intracerebral hemorrhage. Since the CT scanner was introduced in our clinic, we have experienced 55 cases with hypertensive pontine hemorrhage. We carried out stereotactic aspiration in nine cases consisting of four men and five women, ranging in age from 34 to 66 years. Operation was performed on between 4 and 22 days after the hemorrhage (mean 7.7 days). On the other hand, 46 cases were conservatively treated. They consisted of 31 men and 15 women, aged from 31 to 79 years, with a mean age of 55.5 years. The purpose of this study is to review the outcome at three months after the onset, and then to evaluate the clinical value of this method for hypertensive pontine hemorrhage. We have analyzed the outcome from the viewpoint of consciousness level, CT classification, and maximum transverse hematoma diameter on CT scan. In the present study, there was a statistically significant correlation between consciousness level and outcome in the conservative group. The outcome in the operated-on group tended to be superior to that in the conservatively treated group. Particularly, in cases of Japan Coma Scale 10 to 100, functional favorable effects were considered to be obtained by stereotactic aspiration. According to CT classification, operation was considered to have exerted functionally favorable effects on unilateral basis-tegmentum type and bilateral tegmentum type. The conservatively treated group showed a statistically significantly correlation between maximum transverse hematoma diameter and outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical study of primary pontine hemorrhage].

Forty-three cases of primary pontine hemorrhage were seen in our hospital from 1979 to 1986. We studied the correlations between clinical signs, CT, ABR findings and their outcomes, and then reported surgical results. The case consisted of 30 males and 13 females between 32 to 73 years with an average age of 54.5. Thirty cases were confirmed to have had hypertension prior to the hemorrhage. In ten other cases hypertension was suspected, although their past histories were not obtained. In the remaining three cases, no hypertension was detected. On admission, comatose state, ocular fixation, absence of light reaction, tetraplegia, decerebrate posture, respiratory disturbance, tachycardia and hyperthermia were the signs of unlikely recovery. On the CT, the hematomas of the group of likely recovery patients were less than 25% of the cross section of the pons and lower midbrain in vertical. Greater size of hematomas were seen exclusively among the groups of death and severe disability cases. Acute stage ABR and CT findings showed discrepancy. We suggest, if ABR, CT findings and clinical symptoms were studied more in depth, it is possible to determine a patient's prognosis more precisely. Three cases were treated by Stereotactic Aspiration, three cases by ventricular drainage and the remaining thirty-seven cases conservatively. There was, however, no significant difference in recovery between surgically treated cases and conservatively treated one. We think that surgical indication is doubtful except for limited cases.

[TGF-beta and platelet].

In the present paper, we investigated the pathophysiological implication of TGF-beta from megakaryocytes or megakaryoblasts in the development of myelofibrosis. In the bone marrow of myelofibrosis, proliferation of megakaryocytes is often noticed. We therefore investigated the TGF-beta expression in the bone marrow megakaryocytes from 12 chronic myeloproliferative disorder patients with myelofibrosis by immunohistochemical analysis. About all the specimen showed strong positivity for TGF-beta. In order to examine whether megakaryoblasts produce TGF-beta, we then measured TGF-beta activity in the conditioned medium (CM) of megakaryoblasts from a patient with acute megakaryoblastic leukemia who had profound myelofibrosis. The CM showed strong collagen synthesis stimulating activity which was nullified by addition of anti TGF-beta antibody. Since TGF-beta exists as latent form in platelets, TGF-beta was considered to be altered from active to latent form during megakaryocytes differentiation. In this context, MEG-01, a megakaryoblastic cell line which produces active TGF-beta was underwent differentiation to produce platelet-like bleb with TPA treatment. During the differentiation, MEG-01 showed the decrease of active TGF-beta production and increase of latent TGF-beta together with the production of LTBP. These results suggest that megakaryoblasts produce active TGF-beta and may may cause myelofibrosis, while more differentiated megakaryocytes produce latent TGF-beta. Mechanism by which megakaryoblast escape from negative autocrine of active TGF-beta was also investigated. MEG-01 was found to express mutated p53 which is considered to be responsible for impaired signal transduction of TGF-beta.

[Severe hemolysis and SIADH-like symptoms induced by vincristine in an ALL patient with liver cirrhosis].

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.

[Primary Waldenström's macroglobulinemia associated with pure red cell aplasia in which Ts/c lymphocytes inhibiting erythroid precursors were detected].

Waldenström's macroglobulinemia (WMG) is a malignancy of B lymphocytes manifesting heavy accumulation of monoclonal IgM in the plasma. In about 80% cases of WMG, Normocytic normochronic anemia (NNA) is complicated. A case of WMG complicated with pure red cell aplasia (PRCA) and the results of in vitro CFU-E colony assay of bone marrow mononuclear cells (BMMNC) cultured with the patient's serum and/or peripheral lymphocytes were described. A 59-year-old male was admitted with serum total protein Level of 9.7g/dl and 48.2% of gamma globulin. The diagnosis of WMG was made by monoclonal IgM in immunoelectrophoresis. Severe NNA was initially demonstrated on admission and gradually deteriorated further. Both reticulocytes in peripheral blood and erythroid precursors in bone marrow were markedly decreased. Erythropoietin showed high values in plasma. Complication by PRCA was considered to be present in vitro study of a CFU-E colony formation of BMMNC from a normal volunteer showed significant suppression on addition of the patient's peripheral lymphocytes and adverse enhancement by adding the patient's serum. This inhibition of CFU-E colony formation was most prominent by the addition of suppressor/cytotoxic T lymphocytes (Ts/c) and was dose dependent. This result showed the existence of inhibitory Ts/c against proliferation of allogeneic erythroid precursors.