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Hematologic relapse of chronic myeloid leukemia developed in 37-year-old man 255 days after allogeneic bone marrow transplantation. The patient received a donor lymphocyte transfusion (DLT) twice at a dose of 5 x 10(6)/kg T cells. He achieved complete cytogenetic response (CCR) 14 weeks after DLT, and has remained in a CCR state for 17 months. Neither acute nor chronic graft-versus-host disease (GVHD) was observed. Natural killer (NK) cell activity was elevated. Also, analysis of the T cell receptor (TCR) repertoire disclosed oligoclonal expansion of T cells of the TCR V beta and J beta subfamilies. These observations provide evidence for the clonal expansion of allogeneic T cells that are capable of mediating antileukemic activity without causing GVHD.

The overnight 8-mg dexamethasone suppression test is often used to differentiate Cushing's disease, due to an oversecretion of ACTH from the pituitary gland, from other kinds of Cushing's syndrome. However, a few patients with ACTH-producing pituitary adenoma show no suppression of plasma cortisol after the administration of 8 mg of dexamethasone. To clarify the relationship between the level of glucocorticoid receptor (GR) in the pituitary adenoma and the sensitivity to dexamethasone in Cushing's disease, we thus examined the levels of GR alpha and GR beta mRNAs in the pituitary adenomas in six patients who were proven at surgery to have pituitary ACTH-producing adenomas.Total RNA was extracted from six pituitary adenomas and pituitary tissue adjacent to one of the adenomas, and the mRNA levels of GR alpha, GR beta, pro-opiomelanocortin (POMC) and beta-actin in these samples were sampled by quantitative RT-PCR.The GR alpha mRNA levels in the adenomas from the two patients who showed no response to the 8-mg dexamethasone suppression test were significantly lower than those in the adenomas of four patients who showed suppression. The GR beta mRNA level was much lower than that of GR alpha mRNA but not significantly different among the six adenomas.These results suggest strongly that decreased expression of GR alpha in pituitary adenomas may be the major reason for the marked insensitivity to the 8-mg dexamethasone suppression test observed in two patients with Cushing's disease.

Correspondence: Y Maeda, Third Dept of Internal Medicine, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589, Japan

Rapid atrial pacing in sinus rhythm may directly induce atrial flutter without provoking intervening atrial fibrillation, or initiate atrial flutter indirectly, by a conversion from an episode of transient atrial fibrillation provoked by rapid atrial pacing. The present study was performed to examine whether or not the direct induction of clockwise or counterclockwise atrial flutter was pacing-site (right or left atrium) dependent.We analyzed the mode of direct induction of atrial flutter by rapid atrial pacing. In 46 patients with a history of atrial flutter, rapid atrial pacing with 3 to 20 stimuli (cycle length = 500 - 170 ms) was performed in sinus rhythm to induce atrial flutter from 3 atrial sites, including the high right atrium, the low lateral right atrium, and the proximal coronary sinus, while recording multiple intracardiac electrograms of the atria. Direct induction of atrial flutter by rapid atrial pacing was a rare phenomenon and was documented only 22 times in 15 patients: 3, 11, and 8 times during stimulation, respectively, from the high right atrium, low lateral right atrium, and the proximal coronary sinus. Counterclockwise atrial flutter (12 times) was more frequently induced with stimulation from the proximal coronary sinus than from the low lateral right atrium (8 vs 1, P = .0001); clockwise atrial flutter (10 times) was induced exclusively from the low lateral right atrium (P = .0001 for low lateral right atrium vs proximal coronary sinus, P = .011 for low lateral right atrium vs high right atrium).Direct induction of either counterclockwise or clockwise atrial flutter was definitively pacing-site dependent; low lateral right atrial pacing induced clockwise, while proximal coronary sinus pacing induced counterclockwise atrial flutter. Anatomic correlation between the flutter circuit and the atrial pacing site may play an important role in the inducibility of counterclockwise or clockwise atrial flutter.

We report an autopsy case of 53-year-old male with poor controlled diabetes mellitus and hepatocellular carcinoma who developed rhino-orbito-cerebral mucormycosis. Initial complaints were epistaxis and headache followed by a sudden blindness, the 2nd through 7th cranial nerve palsy and diabetes inspidus. Laboratory data revealed that he had liver cirrhosis due to hepatitis C virus infection and diabetes mellitus. Head CT and MRI showed no significant findings. Eleven days after the onset, he died of subarachnoid hemorrhage. The postmortem examination revealed severe infiltration of numerous mucors in the sphenoid sinus, cavernous sinus and bilateral internal carotid arteries. Severe granulomatous vasculitis was seen in the cavernous portion of the bilateral internal carotid arteries. Thus, we considered that this case had been caused by the infiltration of mucors to the cavernous sinus, resulting in the obstruction of ophthalmic arteries. Rupture of the right internal carotid artery was seen at the branching portion of the ophthalmic artery, demonstrating the cause of his death. We would like to emphasize that rhino-orbito-cerebral mucormycosis should be ruled out if we examine a nondiagnostic case of diabetes mellitus or immunosuppressed disease associated with rapid multiple cranial nerve palsy following the orbital symptoms.

Nur77 is an orphan member of the steroid receptor superfamily (nuclear receptor). Nur77 family consists of three subtypes and the subtypes show functional redundancy. Nur77 family plays an important role in the apoptotic process of negative selection of T-cells. Moreover, nur77 seems to play a pivotal role in the hypothalamic-pituitary-adrenal axis (HPA axis) during stress response. Nur77 antagonizes the negative feedback effect on the production and secretion of ACTH by glucocorticoid in corticotrope cells of the pituitary gland.

Androgen plays an important role in male sexual differentiation and the defect of androgen action mainly due to androgen receptor abnormality causes androgen insensitivity syndrome (AIS). The number of the reports of AR gene mutations is AIS reaches more than 250, including structural mutations such as gene deletion and single base mutations. The intriguing characteristics of the single amino acid substitutions by single base mutations are that they tend to occur in restricted areas and on restricted bases, and that the same mutation sometimes shows phenotypic variation even among the family members. In addition, in some AIS cases, neither androgen binding abnormality nor AR gene mutation is detected. In these cases, other factors which take part in transcriptional activation by AR might be affected.

An orphan nuclear receptor, DAX-1, is known to be involved in the development and differentiation of anterior pituitary cells. The present study aimed to examine 1) whether DAX-1 is expressed in human pituitary adenomas, and 2) if it is expressed, what types of adenoma express the factor.Adenoma tissues examined included 18 clinically non-functioning adenomas, 14 GH-secreting adenomas and 7 PRL-secreting adenomas. The expression of the following genes were tested by reverse transcription-polymerase chain reaction (RT-PCR): DAX-1, Adrenal-4-binding protein/steroidogenic factor-1 (Ad4BP/SF-1), Pit-1, LH beta, FSH beta, gonadotrophin-releasing hormone receptor (GnRH-R), GH, PRL, and TSH beta, as well as beta-actin as a control.Eleven clinically non-functioning adenomas expressed DAX-1, 10 of which also expressed Ad4BP/SF-1. Nine out of the 11 DAX-1 expressing adenomas also expressed LH beta, FSH beta and GnRH-R as well, indicating that these adenomas possessed gonadotrophic properties. Nine clinically non-functioning adenomas expressed Pit-1 as well as GH, PRL and/or TSH beta, thus having somatomammotrophic or thyrotrophic properties, 3 of which overlapped with the above DAX-1-expressing adenomas. One non-functioning adenoma expressed Ad4BP/SF1 and FSH beta but not DAX-1, and another one expressed DAX-1 and Ad4BP/SF-1 with PRL. On the other hand, all GH-secreting and PRL-secreting adenomas expressed Pit-1 and GH and/or PRL, but neither DAX-1 nor Ad4BP/SF-1.The results shown here indicate that DAX-1 is expressed in the majority of human pituitary adenomas of gonadotrophic origin in parallel with Adrenal-4-binding protein/steroidogenic factor-1.

We demonstrated significant growth inhibition by retinoic acid (RA) of HTLV-I (+) T-cell lines (ATL-2 and HUT102), but not HTLV-I (-) T-cell lines (MOLT-4 and Jurkat). We hypothesized that the mechanism of growth inhibition by RA depends on an imbalance in redox potential. To examine the effect of exogenous thiol compounds for the growth of HTLV-I (+) T-cell lines by RA, HTLV-I (+) T-cell lines were cultured with several thiol compounds (thioredoxin, L-cystine, and GSH), following addition of 13-cis RA or ATRA, respectively, in cultured with thiol free medium. Unexpectedly, thiol compounds alone did not restore growth inhibition of HTLV-I (+) T-cell lines. However, when those cells were preincubated with thiol compounds for 24 hours, no growth inhibition by 13-cis RA or ATRA was observed. These results suggest that thiol compounds are associated strongly with sensitivity to RA of HTLV-I (+) T cells, but not of HTLV-I (-) T cells and that thiol compounds serve an important role on HTLV-I (+) T cells.

X-linked adrenal hypoplasia congenita (AHC) is characterized by primary adrenal insufficiency and is frequently associated with hypogonadotropic hypogonadism (HHG). Mutations of the DAX1 gene have been reported in patients with AHC and HHG. We found a novel DAX1 mutation in our patient. Sequence analysis of the patient's DAX1 demonstrated a 1-bp (G) deletion at codon 49 in exon 1. The mutation shifts the reading frame, resulting in completely different amino acid sequences from codon 49 to the premature stop codon at 84. The G was present at this position in the sequences of the father and 2 younger brothers. Direct sequence and single-strand conformation polymorphism analyses of polymerase chain reaction fragments revealed that the mutation at codon 49 was heterozygously present in the mother's DAX1 gene. The codon 84 is located in the first half of the DNA binding domain, and the mutation site is closer to the N-terminus than those in previously reported cases. The onset of adrenal insufficiency in the neonatal period as seen in our patient has also been reported in other patients with different DAX1 mutations, especially in a patient with DAX1 protein lacking 11 amino acids at the C-terminus. Therefore, it is less likely that position of termination codons correlate to clinical manifestations.

Severe virilization syndrome is seen in testosterone-producing ovarian or adrenal tumor while symptom in late-onset congenital adrenal hyperplasia (CAH) are usually mild hirsutism and amenorrhea. We determined the serum levels of 17 alpha-hydroxy pregnenolone (17P5) and 17 alpha-hydroxyprogesterone (17P4) 60 min after the intravenous injection of 250 micrograms of ACTH in 10 normal Japanese females with age ranging from 18 to 29 years old. In this test, 1 mg of dexamethasone had been administered orally at 11 p.m. on the previous day to suppress the effect of endogenous ACTH. The ratio of 17P5 to 17P4 was 10.0 +/- 3.6 (mean +/- SD). Five females with hirsutism of no ovarian origin showed normal responses to this rapid ACTH test, suggesting that the incidence of the late-onset CAH is not so high as reported previously.

We report a case of giardiasis in the pancreas in a patient with diabetes mellitus. The patient is interesting in the following: 1) Giardia lamblia was found only in the pancreas and not in the gall bladder by cytology on endoscopic retrograde cholangiopancreaticography (ERCP) and by cerulein-secretin test (CST). 2) ERCP revealed multiple small cysts scattered throughout the pancreas. 3) Decreased pancreatic exocrine function was recovered by treatment with metronidazole.

Meckel's diverticulum is a common anomaly of the GI tract that is known to cause small intestinal obstruction. A 17-yr-old male who had no history of previous surgery was admitted with intermittent abdominal pain. A barium enema showed extraintestinal compression of the ascending colon, suggesting the existence of a congenital band. Laparoscopy revealed that the ascending colon was lifted up and compressed by the intestinal end of a Meckel's diverticulum with a fibrous band connecting to the umbilicus. The portion of the ileum including the Meckel's diverticulum was resected. This is the first case of stenosis of the colon caused by a Meckel's diverticulum.

The ras GTPase activating protein (ras GAP), a regulator of Ras activity, has two isoforms; ras GAP 120 and ras GAP 100. The latter, whose molecular size is about 100 kDa, is generated alternative splicing from the ras GAP 120 gene and is considered placenta-specific, while the former is expressed ubiquitously. As point mutations of ras are frequently observed in human tumors, we investigated the expression of ras GAP in several human cancer cell lines and samples of human colon cancer using immunoprecipitation and immunoblot analysis with an anti-GAP monoclonal antibody, B4F8, as well as reverse transcription-polymerase chain reaction (RT-PCR). ras GAP 100 protein was detected in 4 of 9 colonic, 1 of 6 gastric and 1 of 4 lung cancer cell lines as well as ras GAP 120, but not in colon cancer specimens. In contrast, ras GAP 100 mRNA was present in all tested cell lines and colon cancer specimens. Then, we investigated ras GAP 100 expression in normal tissues, ras GAP 100 protein was not detected in human normal tissues except placenta. Contrary, ras GAP 100 message was expressed in normal tissues derived from liver, stomach, colon and lymphocyte although the level of which was smaller than that in placenta. These findings demonstrate that ras GAP 100, reportedly placenta-specific, is distributed in other normal tissues at least at mRNA level and its expression is augmented in some cancer cell lines.

In the research field of nuclear receptors, the studies on the protein factors which interact with the steroid hormone receptors and regulate the transcriptional activity, and on the alpha and beta isoforms of glucocorticoid receptor have been in great progress. The include "intermediary Factors" such as RIP140, TIF-1, for the AF-2 which contribute to ligand-dependent transactivation function of the receptors. ARA70 which specifically interacts with androgen receptor was also cloned recently. Informations obtained from steroid hormone receptor knockout-mice experiments can also be available for the estrogen, glucocorticoid, and progesterone receptors. Furthermore, there have been more than sixty orphan receptors identified in these eight years, including HNF, Ad4BP, DAX-1, and nur77/NGFIB, some of which are mutation target genes of human congenital diseases.

The most common forms of chronic pancreatitis are related to alcohol ingestion, whereas the entity of non-alcohol-associated (idiopathic) pancreatitis is poorly understood. Autoimmunity has been suggested as a possible etiologic factor of idiopathic chronic pancreatitis. A total of 362 Japanese patients underwent endoscopic retrograde pancreatography (ERP) for suspected pancreatic disease, and 161 were diagnosed with chronic pancreatitis. Among them, we found three cases (1.86% incidence) of unique chronic pancreatitis, in which ERP revealed diffuse narrowing of the main pancreatic duct with an irregular wall. We diagnosed these three patients as having pancreatitis associated with an autoimmune mechanism morphologically and biochemically and started them on steroid therapy. The characteristics of the these three patients were as follows: hypergammaglobulinemia, eosinophilia, ultrasonography showing hypoehoic diffuse swelling in the pancreas (sausage-like appearance), ERP showing diffuse narrowing of the main pancreatic duct with irregular like thumbprint-like marks, reversible exocrine insufficiency, and positive anti-carbonic anhydrase II antibody. After one month of the treatment with steroids, pancreatitis dramatically improved morphologically and enzymatically. Here we describe these cases of the suspected autoimmune chronic pancreatitis. We must recognize the concept and the features of autoimmune pancreatitis in order to avoid unnecessary surgery as pancreatic cancer.

To determine whether a decrease in prostacyclin production is involved in the increase in endothelial permeability induced by a high concentration of glucose, we evaluated the effect of beraprost sodium, a stable prostacyclin analog, on the transendothelial permeation of albumin in cultured aortic cells. Permeation of albumin across an endothelial cell monolayer was significantly greater when the cells were cultured with a high concentration of glucose (400 or 800 mg/dl) than when they were cultured with 100 mg/dl glucose. No significant change in the permeation of albumin was observed when cells were cultured with 100 mg/dl glucose as compared with 100 mg/dl glucose plus 700 mg/dl mannitol. The addition of beraprost sodium to the culture medium completely restored the increase in the permeation of albumin brought about by 400 mg/dl glucose. These results suggest that increased transendothelial permeation of albumin by high glucose may be due in part to a decrease in prostacyclin production by the endothelial cells. Beraprost sodium may restore the endothelial barrier function affected by a high concentration of glucose.

The tyrosine kinase activity of BCR-ABL fusion proteins plays an important role in the pathogenesis of leukemia that is for the Philadelphia chromosome (Ph1). Because nuclear c-ABL is regulated during the cell cycle through a specific interaction with the retinoblastoma protein (pRB), the possible interaction of BCR-ABL with pRB in Ph1-positive cell lines was investigated. P145 c-ABL as well as P190 and P210 BCR-ABL proteins interacted with pRB. Furthermore, c-ABL and BCR-ABL associated with both phosphorylated and nonphosphorylated forms of pRB. These findings suggest that BCR-ABL interferes with pRB function and thereby regulates cell growth.

We report a L-tryptophan-induced case of eosinophilia-myalgia syndrome in a Japanese woman and describe the time course of changes in tryptophan metabolism observed during steroid therapy. She had taken 1.0 g of the implicated L-tryptophan daily. When admitted due to painful swelling of her extremities, eosinophil count was 22.3 x 10(9)/L. Before prednisolone treatment, her serum L-kynurenine level was 10.2 mumol/L, a level about three-fold higher than the normal value, while serum tryptophan level was abnormally low (23.1 mumol/L). On the 14th day of prednisolone treatment (40 mg daily), L-kynurenine was declined to 8.1 mumol/L and, concomitantly, L-tryptophan level increased to the normal range (51.0 mumol/L). Subsequently, on the 42nd day of therapy, serum L-kynurenine was normalized. In contrast, serum serotonin level was unchanged throughout the course of this therapy. Prednisolone dramatically reduced the elevated serum L-kynurenine with a reciprocal increase in serum L-tryptophan indicates that abnormal tryptophan metabolism, may play a role in the pathogenesis of eosinophilia myalgia syndrome, and that the observed effect of steroid treatment was due to suppression of elevated activity of indoleamine 2, 3-dioxygenase, a first rate-limiting enzyme of the kynurenine pathway.

Serum 7B2 concentrations in control subjects and patients with diabetes mellitus were measured following a 75 g oral glucose load and following intravenous glucagon infusion. In response to oral glucose, serum 7B2 levels increased in the controls (n = 10) and in the diabetic patients (n = 7). The increment of the serum 7B2 level was smaller in the diabetic patients than the controls. During the 75 g oral glucose tolerance test (75g OGTT), serum 7B2 levels were significantly positively correlated with serum C-peptide levels. In contrast, following intravenous glucagon infusion, serum 7B2 levels increased only in diabetic patients treated with oral hypoglycemic agents (n = 20) and did not increase in controls (n = 5): the group having the highest insulin secretion activity in the present study, nor in diet or insulin-treated diabetic patients. No correlation between serum 7B2 levels and serum CPR levels was observed in the intravenous glucagon infusion study. These data suggest that an extra-pancreatic source which produces the observed serum 7B2 increase following oral glucose intake can not be excluded and that 7B2 may not be secreted concomitantly with insulin from the pancreatic beta cell in response to intravenous glucagon injection.

NGFI-B/nur77 is a member of the steroid receptor superfamily. NGFI-B/nur77 and its related genes constitute a family and the NGFI-B/nur77 family consists of three subtypes, named nur77 alpha, nur77 beta, nur77 gamma. We cloned human nur77 beta cDNA, called TINUR. Although NGFI-B/nur77 is essential for TCR-mediated apoptosis in T-cell hybridomas, the reports on nur77 knock-out mice and nur77 dominant negative transgenic mice suggest that there is a functional redundancy among NGFI-B/nur77 family. NGFI-B/nur77 binds to the response element by monomer or heterodimer with retinoid X receptor (RXR). Assuming that 9-cis-retinoic acid (9-cis-RA) inhibits TCR-mediated apoptosis, nur77 may cause apoptosis by monomer in the absence of 9-cis-RA and may inhibit apoptosis by heterodimer with RXR in the presence of 9-cis-RA.

The endoscopic ultrasonography (US) characteristics of early scirrhous carcinoma of the stomach (ESS) were evaluated in four patients. ESS was defined as the presence of poorly differentiated carcinoma cells spreading through the submucosa and muscularis propria in association with a marked desmoplastic reaction without serosal invasion. ESS was characterized by localized irregular hypoechoic enlargement of the third (submucosal) and the fourth (muscularis propria) layers. The fifth (serosal) layer was normal. The third and fourth layers showed a threefold increase in thickness compared with the thickness of these layers in healthy subjects. Our results suggest that endoscopic US is useful for diagnosis of ESS.

A rare case of severe small bowel hemorrhage due to jejunal metastases from a large-cell type carcinoma of the lung is reported. A 69-yr-old Japanese woman presented with complaints of mild abdominal pain and liquid tarry stools 6 months following surgery for lung carcinoma. Gastroduodenoscopy and barium enema yielded unremarkable findings, although a subsequent small bowel enema revealed a large, 15-cm ulcerated mass in the jejunum. This tumor was resected and histology confirmed to be consistent with a metastasis from the primary undifferentiated large-cell carcinoma of the lung. The patient had an uneventful postoperative course and survived for 9 months. There have been only two prior case reports of major intestinal hemorrhage secondary to pulmonary carcinoma metastases in the English literature. Previous reports of such metastases of the small bowel have bowel have documented a very poor prognosis and our patient demonstrated the longest survival period to date. The clinical course of this patient suggests that the early diagnosis and palliative surgery for this complication provide a more favourable outcome.

Lck protein is expressed in some colon carcinoma cell lines but its expression in colon cancer cells in vivo has not been clarified. LCK transcription is regulated from two distinct promoters and initiated exclusively from the downstream promoter in colon carcinoma cell lines in contrast to peripheral lymphocytes. We investigated the expression of the downstream promoter-initiated LCK transcript in 18 colorectal primary cancer and normal mucosae, and two hepatic metastases, using a RNase protection assay with the Eco RI- Bgl II fragment of human LCK cDNA, YT16. In normal tissues, only traces of the LCK transcript were detected. The expression of the LCK transcript was augmented in 318 cancer specimens. The relative level of the LCK transcript in the cancer tissue compared to the average value of normal adjacent tissue was 10–60 in 3 cases, and 3–10 in 7 cases. One hepatic metastasis expressed more LCK message than the primary lesion. Our results indicate that the LCK message is strongly expressed in some colorectal cancers.

This is the first case of primary macroglobulinemia with t(11;18) (q21;q21) reported in the literature. A 77-year-old man was admitted to a hospital in December, 1994, with acute renal failure and pleural effusion. He was treated with prednisolone pulse therapy and his symptoms improved. He was referred to our hospital for further examination. Analysis of blood chemistry revealed macroglobulinemia (IgM-kappa). There were no other findings that would indicate a diagnosis of malignant lymphoma. A complete blood count revealed a hemoglobin level of 8.7 g/dl and a white blood cell count of 5,300/microliters with 11% abnormal lymphoid cells. Immunologic and karyotype analyses revealed that these abnormal cells were positive for IgM-kappa, CD19, and CD20, negative for CD5, and CD10, and had t(11;18) (q21;q21). The bone marrow had also been infiltrated by 8.6% abnormal lymphoid cells. Six other cases with t(11;18) (q21;q21) have been reported including 5 of small lymphocytic lymphoma and 1 of mucosa-associated lymphoid tissue-type lymphoma. The tumor cells in these cases were the same as in our case. Therefore, our report is in agreement with the finding that t(11;18) (q21;q21) might be one of the characteristic chromosomal abnormalities in mature B-lymphoid neoplasms.

36-year-old-female admitted because of jaudice and ascites. T-bil was 18.5 mg/dl and transaminase, ALP, LDH and gamma-GTP was elevated. Ultrasonography (US) showed that right lobe was atrophy and left lobe was swelling. Plain computed tomography (CT) showed right lobe was low density. Magnetic resonance (MR) finding was T1-weighted image of right lobe was low intensity and T2-weighted image was high intensity. Angiography showed right lobe was more stained than left lobe. Histologically, right lobe was massive necrosis. These findings suggested that right lobe was liver scar. Biliary imaging showed right lobe was delayed. A 23-year-old-female admitted because of fever and abdominal tumor. Transaminase was normal, only gamma-GTP was elevated. US, plain CT, enhanced CT, MR imaging finding was as same as that of the first case. Similarily, biliary scintigraphy showed right lobe was delayed. Causes of the two liver scars was not clear, whereas liver scar detected after delivery was rare case.

We report two patients with acute leukemias who expressed two types of bcr/abl mRNA. The first case was an 8-year-old boy with acute mixed leukemia in whom the Ph1 chromosome and p210/p190 types of bcr/abl mRNAs were detected at diagnosis. The second case was a 39-year-old male with acute nonlymphocytic leukemia transformed from myelodysplastic syndrome (refractory anemia with excess of blasts). In the latter case, the p210-type mRNA appeared after leukemic transformation, and the p190-type transcript was detected only during the late stage when the Ph1 chromosome was first observed. The leukemias in these two patients were aggressive in their clinical courses. We conclude that the dual expression of p210 and p190 types of bcr/abl is a factor indicating a poor prognosis, and that, in some patients, p190-type bcr/abl may contribute to disease progression.

The aim of this study was to investigate the effect of endogenous cholecystokinin (CCK) on pancreatic regeneration after acute hemorrhagic pancreatitis. Acute hemorrhagic pancreatitis was induced in rats by two intraperitoneal cerulein injection (20 micrograms/kg BW) with 5h water-immersion stress once a day for successive 3 days. After the cessation of repetition of acute pancreatitis the rats were treated with successive feeding with 0.1% camostat-containing diet or SC injection of CR-1505 (CCK receptor antagonist, 50 mg/kg BW x 2/day) for 7 days. Zymogen enzymes and protein contents per DNA in pancreatic tissue were significantly higher in rats treated with camostat compared with control rats, and plasma CCK level was elevated. To the contrary, pancreatic regeneration was retarded in the rats treated with CR 1505. It is concluded that endogenous CCK has a trophic effect during regeneration after acute hemorrhagic pancreatitis.

We compared the etiology and prognosis of liver cirrhosis in patients age 60 and older with that of patients under age 60 during the 1980s (1981-89, n = 207). Non-A, non-B hepatitis (NANB) was significantly more prevalent in the elderly (p0.05), and the mean age of NANB and alcoholic cirrhosis (Alc) were significantly older than those with hepatitis B virus (HBV) (p0.05). Evaluation using hepatitis C virus (HCV) antibody also revealed significantly higher mean age of HCV (p0.05). Male patient was predominant in the younger patients than in the elderly patients. (M/F = 2.94 and 1.33, respectively) The estimated 5-year survival rate was 73.1% in the younger patients and 60.2% in the elderly patients (p0.05). Multivariate analysis revealed that male sex, a lower serum albumin level, and the presence of the encephalopathy were significantly associated with poor prognosis in the elderly, while a lower serum cholinesterase level and a higher indocyanin green retention rate at 15 minutes (ICGR15) were significantly associated with poor prognosis in younger patients. However, causes of deaths were not significantly different between the younger patients and the elderly patients, the proportion of deaths unrelated to liver disease predominated in the elderly patients. Thus, the etiology and the prognostic factors of liver cirrhosis in elderly patients differ from those in younger patients.

To examine bile acid synthesis in chronic liver diseases, serum total 7 alpha-hydroxycholesterol level was measured by gas-liquid chromatography-mass spectrometry in patients with cirrhosis (n = 23), patients with chronic hepatitis (n = 21), and control subjects (n = 18). The serum 7 alpha-hydroxycholesterol levels were significantly lower in patients with cirrhosis than the controls (78 +/- 59 pmol/mL vs. 237 +/- 97 pmol/mL; mean +/- SD). However, in patients with chronic hepatitis, the level was fully retained (262 +/- 102 pmol/mL). Serum 7 alpha-hydroxycholesterol levels of 17 patients with cirrhosis classified as Child B and C ranged from 33 to 69 pmol/mL, and all were less than the normal range (between 104 and 466 pmol/mL), however, those levels of some patients classified as Child A were within the normal range. Serum 7 alpha-hydroxycholesterol levels significantly correlated with serum albumin, cholinesterase, total bile acid, direct bilirubin, alkaline phosphatase, indocyanine green (ICG) retention rate, hepaplastin test, and lecithin-cholesterol acyltransferase activities. We conclude that bile acid synthesis is well preserved in patients with chronic hepatitis and that it is decreased in most patients with cirrhosis. Serum 7 alpha-hydroxycholesterol may be a new parameter of liver function testing to assess hepatic bile acid synthesis in patients with chronic liver diseases.

We report here the establishment and characterization of a human melanoma cell line derived from the ascitic fluid of a patient with metastatic malignant melanoma with peritonitis carcinomatosa. This cell line was easily transplanted into nude mice. Flow cytometry and immunocytochemical analyses demonstrated that the cells expressed melanotransferrin and S-100 protein. Expression of cell adhesion and HLA molecules on the cells was also investigated. The results indicate that the cell line possesses some metastatic characteristics.

Forty patients with hepatocellular carcinoma were treated with percutaneous ethanol injection therapy. All patients had fewer than three tumors of less than 30 mm in diameter. Additionally, all recurrences with fewer than 3 tumors of less than 30 mm in diameter was repeated for 33 recurrences and discontinued in 17 cases. Duration between treatments became significantly shorter with successive treatments. There was no significant difference in the duration between treatments in patients classified by tumor size (less than 20 mm vs. 20 mm or more), whereas there was a significantly lower recurrence rate in patients with solitary tumors as compared with those with multiple HCC. Laboratory data before successive PEI-treatments were also compared, and showed that hepatic functional reserve did not decrease with repeat percutaneous ethanol injection. The cumulative survival rate in all 40 patients after the first treatment was significantly higher than in the 17 patients for whom treatment was discontinued.

Acute promyelocytic leukemia (APL) is a subtype of acute myelogenous leukemia (AML) that is characterized by the presence of a PML/RAR alpha fusion gene resulting from t(15;17). Peripheral stem cell transplantation (PSCT) has been used to treat patients with AML. To assess the presence of minimal residual disease (MRD) and the contamination of leukemic cells in peripheral stem cells (PSCs), we examined six patients with APL who were undergoing PSCT, using reverse transcriptase polymerase chain reaction analysis to detect the mRNA of the PML/RAR alpha fusion gene. The fusion gene was expressed in the bone marrow cells during the early phase of a complete remission and in some of the PSCs. Detection of the fusion gene can be useful in monitoring for leukemic cell contamination of PSCs and for predicting a relapse of APL.

Using endoscopic ultrasonography, we diagnosed a gastric antral submucosal cyst with a papillous protrusion in a 71-yr-old woman, apparently the first such case to be detected by this method. Endoscopic ultrasonography demonstrated a well-marginated hypoechoic area with papillary tumor in the submucosal layer that did not extend to the muscularis propria. The lesion was diagnosed as a gastric submucosal cyst. CT and transabdominal ultrasound each failed to detect the intracystic papillary tumor. Follow-up endoscopic ultrasonography performed 6 months later revealed an increase in the diameter of the cyst and the papillary tumor. The patient then underwent a partial gastrectomy for a suspected malignancy. The resected specimen showed a cystic lesion with papillary tumor. Although no malignancy was present, examination of cross-sections of the resected specimen gave results consistent with the endoscopic ultrasonographic findings. Endoscopic ultrasonography is thus useful in assessing the nature of a submucosal gastric cyst in detail and in monitoring patients with this lesion.

Smooth muscle cells isolated from the gastric muscle layers of the guinea pig were used to examine the functional endothelin receptor subtype responsible for gastric smooth muscle contraction by endothelin. Endothelin-1 induced the contraction of these cells in a dose-dependent manner, with an ED50 value of 0.2 nM. Endothelin-3-induced contraction was significantly less than that of endothelin-1. Sarafotoxin 6c (10(-11)-10(-7) M), endothelinB highly selective agonist, did not elicit the contraction of gastric smooth muscle cells. BQ-123, endothelinA selective antagonist, inhibited the contractile response produced by 10(-7) M endothelin-1 in a dose-dependent manner, with an IC50 value of 5 nM. These results strongly suggest that endothelin elicited the contraction of gastric smooth muscle cells via functional endothelinA receptor subtype.

In order to investigate the age-related changes in neuropeptide Y (NPY) in cerebrospinal fluid (CSF) of men and women, we examined the concentration of NPY-like immunoreactivity (NPY-LI) in CSF of a large population of Japanese men and women by specific radioimmunoassay (RIA). The dilution curve of CSF extract paralleled the standard curve of RIA for human NPY. Gel chromatographic studies revealed the presence of two peaks of NPY-LI, one emerging at the elution position of synthetic NPY and another emerging at a higher-molecular-weight position. NPY-LI in the CSF in 201 men (aged 17 to 69y) and 118 women (aged 17 to 69y) was 124 +/- 4 and 136 +/- 6 pg/ml (mean +/- SE), respectively. NPY-LI in the CSF of women, but not of men, increased significantly with aging. This finding suggests that the level of NPY with aging in the central nervous system (CNS) may be regulated somewhat differently in men and women.

A 60-year-old man was admitted to the Kyushu University Hospital because of poor glycemic control of diabetes mellitus. Although he had been treated with glicrazide and nifedipine for his diabetes and hypertension, the controls of the diseases were unsatisfactory. Plasma triglyceride level was 186 mg/dl. Furthermore, extreme insulin resistance was found by measuring glucose infusion rate with an euglycemic hyperinsulinemic clamp method. These findings were compatible to those seen in syndrome X. After admission, diet therapy of 1,800 Cal was started and his metabolic disorders such as hyperglycemia, hyperlipidemia, and hypertension were all improved. Moreover, euglycemic hyperinsulinemic clamp study also revealed a decreased insulin resistance after diet therapy. Our experience from the case suggested that insulin resistance may closely related with the metabolic disorders of the disease "syndrome X".

All diabetic patients should be screened for the early stage of diabetic nephropathy, because microalbuminuria has a great prognostic significance. The albusure test (AT), alatex agglutination nephelometric immunoassay, is a rapid and low cost test for the detection of microalbuminuria of 30 mg/L or more. We compared the results of AT and of radioimmunoassay (RIA) for urinary albumin to evaluate the clinical utility of AT using fresh urine samples from 74 diabetic patients without persistent proteinuria and from 11 healthy subjects. Urinary albumin levels measured by RIA were 6.0 +/- 2.3 mg/L in the healthy subjects, 11.0 +/- 8.7 mg/L in the AT-negative group (n = 61), and 38.1 +/- 10.2 mg/L in the AT-positive group (n = 13). Using a cut-off value of 30 mg/L by RIA, the rate of coincidence between AT and RIA was 89.2%, although five subjects were false-positive by AT, and three were false-negative. These results show that AT may provide a useful monitor microalbuminuria, a reliable early mark of diabetic nephropathy.

We describe the polymerase chain reaction (PCR) method using stained bone marrow smears as sources of RNA. The amount of extractable RNA decreased during the process of making and staining bone marrow smears. The sensitivity of the reverse transcriptase-based polymerase chain reaction (RT-PCR) method for detecting target mRNA-positive cells in 5 x 10(5) suspended cells and stained bone marrow smears were 1:10(5) and 1:5000, when we used K562 cells. The bone marrow smears of 21 patients with chronic myelogenous leukemia (CML) were examined using this method. We extracted RNA from stained specimens stored at room temperature for 5-14 years. Twelve of 21 (57%) smears showed positive results for bcr/abl. The carrier RNA improved the recovery when added at the step of RNA extraction. These data indicate that mRNA is present in stained bone marrow smears for at least 14 years and that the sensitivity of RT-PCR is adequate for molecular analysis.

We report on a case with a 50-year history of benign recurrent intrahepatic cholestasis, including 33 years of follow-up at our hospital. The attacks of jaundice began at the age of 1 year and have been repeated more than 14 times to date. During the follow-up period at our hospital, the patient has suffered 6 attacks of cholestasis. During the episodes of cholestasis, a dissociation between the serum level of bilirubin and that of bile acids was observed. The analysis of serum bile acids during cholestasis showed that cholic acid and chenodeoxycholic acid were the main bile acids, and no appreciable amounts of the secondary bile acids were detected. Between episodes the liver function tests, including serum bile acids, were normal. Despite multiple attacks of cholestasis over many years, no permanent liver damage has occurred. This case reaffirms the essentially benign nature of this disease.

We report unique features of computed tomography (CT) and magnetic resonance (MR) imaging in the metastatic lesion of the liver in a case of gastric leiomyosarcoma. A CT scan and MR image demonstrated presence of a huge multilocular cystic lesion in the liver, of which finding were unlike to those of usual smooth muscle tumors, but mimicked to those of cystadenomatous tumors. In addition, this case had an extremely long elapsing time over ten years from the radical operation for the primary site.

We examined the serum levels of testosterone (T), androstenedione (delta 4-A), estrone (E1), estradiol (E2), and dehydroepiandrosterone sulfate (DHEA-S) in the non-alcoholic cirrhotic male patients when divided into compensated or decompensated state. Serum level of T was significantly elevated in compensated cirrhotic patients (9.63 +/- 1.00 ng/ml, mean +/- SE) compared to that in decompensated cirrhotic patients (5.63 +/- 0.69 ng/ml, p0.01) and in aged-matched normal controls (4.95 +/- 0.38 ng/ml, p0.01). Serum levels of E1, E2 and delta 4-A tended to be increased in decompensated cirrhotic patients, while there was not a significant difference decompensated cirrhosis compared to those of normal controls. Serum concentration of cholinesterase, indicative one of the representative residual liver function, showed a good positive correlation to T (r = 0.53, p0.01), and a negative correlations to E1 (r = -0.67, p0.01), E2 (r = -0.77, p0.01), delta 4-A (r = -0.57, r = p0.01). Also, we examined the relationship of the serum levels to gynecomastia or esophageal varices. The cirrhotics with gynecomastia showed significantly higher serum levels of E1, E2, and delta 4-A, and lower level of T than those without gynecomastia. And the cirrhotics with esophageal varices showed the greater level of T than those without esophageal varices. Our study suggests that low serum testosterone level of men with nonalcoholic cirrhotic is not a common finding, especially in compensated state.(ABSTRACT TRUNCATED AT 250 WORDS)

We isolated a genomic clone containing 2558 bp of the 5'-flanking region and 217 bp of the first exon for the human type-1 angiotensin II receptor (AT1) gene. Primer extension and RNAase protection analyses identified a transcriptional start site (+1) at 39 and 114 bp downstream of putative TATA and GC boxes, respectively. Chimeras containing 2.6 kbp(-2558 to +79) of the 5'-flanking region and chloramphenicol acetyltransferase (CAT) gene expressed a significant CAT activity when transfected into bovine aortic smooth muscle cells (BASMC), but not the cells which had no detectable AT1 receptors, such as HeLa cells and primary cultured human skin fibroblasts. Deletion of the 5'-flanking region up to position -114 resulted in more than 20-fold increase of the reporter activity in BASMC, suggesting the presence of negatively regulating element(s) in the upstream promoter region. These results indicate that we have cloned a functional promoter for the human AT1 receptor gene.

To clarify the Sertoli cell and Leydig cell function in hypogonadic male patients with myotonic dystrophy (DM), serum concentrations of inhibin, total testosterone (TT), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured by radioimmunoassay in 6 male DM patients (41 to 56 years old, 47.7 +/- 5.05 years old) and compared with those in normal adult men. In 116 healthy men aged from 24 to 92 years, serum inhibin and TT levels decreased and serum FSH and LH concentrations increased with advancing age. There was an inverse correlation between serum inhibin and FSH. These results support the concept of negative feedback regulation system of FSH secretion by inhibin. Male DM patients showed significantly lower serum TT and higher concentrations of FSH and LH, compared with the age-matched 39 normal adult men (49-59 years old, 48.2 +/- 6.14 years old). However, there was no significant difference in serum inhibin levels between the patients and normal counterparts. These results indicate that the Sertoli cell function is reserved in male DM patient, although the Leydig cell function is impaired. It is also suggested that in these patients a negative feedback control system between inhibin and FSH may be disordered to some extent.