Correlation between alterations in blood flow of malignant lymphomas after induction chemotherapies and clinical outcomes: a pilot study utilising contrast-enhanced ultrasonography for early interim evaluation of lymphoma treatment.

AIM: To clarify the utility of contrast-enhanced ultrasonography (CEUS) for interim evaluation of response to chemotherapy in lymphoma treatment. MATERIALS AND METHODS: CEUS was performed both before (day 0) and after the treatment (7 and/or 14 days), and a time-intensity curve was obtained. The patients were divided into two groups (complete remission [CR] group and non-CR group) according to the results of conventional response evaluation, and peak enhancement (PE), time to peak enhancement, perfusion index (PI), the total area under the curve during wash-in (AUC-in), and the total AUC were compared between the groups. RESULTS: Among 27 patients with various types of lymphoma, the median change ratio of PE and PI at day 7 evaluation were significantly different between the CR group and the non-CR group (0.81 versus 1.39, p=0.017 for PE and 0.92 versus 2.09, p=0.010 for PI). The change ratio of PE < 1.09 (specificity: 86%; sensitivity, 88%) and PI < 1.65 (specificity: 86%; sensitivity: 94%) distinguished CR from non-CR. Patients who achieved a PE change ratio <1.09 or a PI change ratio <1.65 had significantly better estimated progression-free survival (p<0.001). CONCLUSION: The present study demonstrated that changes in tumour perfusion parameters evaluated with CEUS at 1 week after the treatment initiation were significantly different between lymphoma patients in CR group and non-CR group. Alterations in perfusion parameters evaluated via CEUS could impact the prognosis of lymphoma patients.

Durable molecular complete remission induced by low-dose imatinib plus low-dose interferon alpha in a patient with chronic myelogenous leukaemia.

A 50-year-old male was diagnosed with chronic myelogenous leukaemia (CML) in chronic phase in March 2000. He was treated initially with hydroxyurea, administered orally. This was changed to interferon alpha (IFN) 5 million units (5 MIU) subcutaneously daily in May 2000; complete cytogenetic response was achieved 11 months later. IFN dosage was reduced to 5 MIU, alternate days, in June 2001 and a cytogenetic relapse occurred 3 months later. Since April 2002, he has received IFN 5 MIU three times weekly in combination with imatinib 200 mg/day. The Philadelphia chromosome disappeared from his peripheral blood cells in July 2002 and a complete molecular response was achieved in January 2003. Serial molecular studies between January 2004 and January 2005 showed no detectable major BCR/ABL chimeric transcript. Grade 2 neutropenia and grade 1 non-haematological adverse effects have been observed. This case report suggests the combination of low-dose imatinib and IFN would be tolerable and effective for CML patients in chronic phase.

Allelotype analysis of childhood acute lymphoblastic leukemia.

To identify the genetic events that may play an important role in leukemogenesis of childhood ALL, we report for the first time the allelotyping of childhood ALL. Twenty-four cases of childhood ALL were screened for loss of heterozygosity (LOH) using 101 highly polymorphic microsatellite markers, which are distributed among all autosomal chromosomes. For LOH analysis on both chromosomes 9 and 12, 54 childhood ALL samples were examined. The most frequent allelic loss was found on chromosomal arm 9p, where 20 of 50 (40%) informative samples showed LOH. Moreover, nearly 30% of samples that did not have either homozygous deletions or point mutations of the putative tumor suppressor genes CDKN2/INK4A/p16 and INK4B/p15 on chromosomal arm 9p had LOH at D9S171. Loss of chromosomal arm 12p was also frequent (26%). Mutational analysis suggested that the altered gene on 12p is not the cyclin-dependent kinase inhibitor p27/Kip1, which is also on 12p. Several other regions that had LOH included 1p, 4q, 5p, 6q, 7p, 8p, 9q, 10q, 13q, 17p, 17q, 18q, 19q, and 22q. Of 24 patients, 19 (79%) showed allelic loss on at least one chromosomal arm. Samples of two patients (8%) showed LOH on almost all chromosomes. Fractional allelic loss, calculated for each sample as the total number of chromosomal arms lost/total number of arms with information, showed a median value of 0.04 and a mean of 0.123 (range, 0 to 0.95). This fractional allelic loss is lower than those reported for many solid tumors. This analysis shows the extreme power of LOH analysis using microsatellite markers in childhood ALL.

Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies.

Cyclin and cyclin-dependent kinase (CDK) complexes play important roles in controlling the cell cycle. The CDK inhibitors (CDKIs) inhibit the kinase activities of the complexes and block transitions of the cell cycle. Recently several CDKI genes have been cloned, and evidence suggests that at least a couple of these may be tumor suppressor genes. In this study, the partial structure of a CDKI gene, p27/Kip1, was determined. In addition, a large number of human cancers (432 cases) and cancer cell lines (20 lines) were analyzed for alterations of the p27/Kip1 gene by Southern blot analysis and PCR/single-strand conformation polymorphism. The coding region of the p27/Kip1 gene consists of at least two exons and an intron of about 600 bp. In 140 tumors of various tissues and 18 transformed cell lines, no deletions or rearrangements of the gene were detected by Southern blot analysis using a part of the coding sequence as a probe. One polymorphism and one silent mutation were detected by PCR/single-strand conformation polymoprhism. The polymorphism was a nucleotide substitution of guanine for thymine (GTC-->GGC) at codon 109, resulting in an amino acid substitution of glycine for valine (Val-->Gly). In summary, no abnormalities of the p27/Kip1 gene were detected in human malignancies. Now, two groups of CDKIs are classified based on the structure of the proteins. One group includes the p15, p16, and p18 CDKIs, which have ankyrin repeat motifs. The p15 and p16 CDKI genes are very frequently mutated in a variety of cancers. The p27/Kip1 and p21 CDKIs belong to the other group. We reported previously that abnormalities of the p21 gene were very rare. The latter group of the CDKIs, including p27/Kip1 and p21, are rarely mutated in human malignancies.

Deletions of p15 and/or p16 genes as a poor-prognosis factor in adult T-cell leukemia.

PURPOSE: To determine the frequency of the deletions of p15/p16 genes in adult T-cell leukemia (ATL) cells and to evaluate their value in the diagnosis of clinical subtypes of ATL patients and the prediction of their clinical outcome. MATERIALS AND METHODS: Peripheral-blood samples from 114 patients with ATL were examined by Southern blot analysis. In five chronic-type patients who showed disease progression to acute type, serial samples also were examined. RESULTS: Among 114 patients, 28 (24.6%) showed the deletions of p15 and/or p16 genes. The results were well correlated with the clinical subtypes. Patients with deleted p15 and/or p16 genes had significantly shorter survival times than the patients in whom both genes were preserved (P < .0001). A similar decline in survival time was observed in the analyses within the same subtypes. In multivariate analysis using the Cox proportional hazard model, the deletions of p15 and/or p16 genes emerged as an independent prognostic indicator. Moreover, three of the five chronic-type patients who progressed to acute type lost the p16 gene alone or both the p15 and p16 genes at their exacerbation phase. CONCLUSION: The results suggest the following: (1) that the deletions of p15 and/or p16 genes play a key role in the progression of ATL; and (2) that these deletions are reliable prognostic factors that predict shortened survival times.

Role of tumor suppressor genes in the development of adult T cell leukemia/lymphoma (ATLL).

Adult T cell leukemia/lymphoma (ATLL) is one of the peripheral T cell malignant neoplasms strongly associated with human T cell leukemia virus type-I (HTLV-I). Although the viral transactivating protein Tax has been proposed to play a critical role in leukemogeneis as shown by its transforming activity in various experimental systems, additional cellular events are required for the development of ATLL. One of the genetic events in ATLL is inactivation of tumor suppressor genes. Among many candidates for tumor suppressor genes, the main genetic events have been reported to center around the cyclin-dependent kinase inhibitors ((CDKIs) p15INK4A, p16INK4B, p18INK4C, p19INK4D, p21WAF1, p27KIP1, and p57KIP2), p53 and Rb genes; all of them play a major regulatory role during G1 to S transition in the cell cycle. Acute/lymphomatous ATLL has frequent alterations of p15 (20%) and p16 (28-67%), while chronic/smoldering ATLL has fewer abnormalities of p15 (0-13%) and p16 (5-26%). Most of these changes are deletion of the genes; fewer samples have mutations. ATLL patients with deleted p15 and/or p16 genes have significantly shorter survival than those individuals with both genes preserved. Although genetic alterations of p18, p19, p21, p27 have rarely been reported, inactivation of these genes may contribute to the development of ATLL because low expression levels of these genes seem to mark ATLL. The p53 gene is mutated in 10-50% of acute/lymphomatous ATLL. Functional impairment of the p53 protein, even if the gene has wild-type sequences, has been suggested in HTLV-I infected cells. Each of these genetic events are mainly found in acute/lymphomatous ATLL, suggesting that alterations of these genes may be associated with transformation to an aggressive phenotype. The Rb tumor suppressor gene is infrequently structurally altered, but one half of ATLL cases have lost expression of this key protein. Notably, alterations of one of the CDKIs, p53 and Rb genes appear to obviate the need for inactivation of other genes in the same pathway. A novel tumor suppressor gene on chromosome 6q may also have a critical role in the pathogenesis of ATLL. Taken together, tumor suppressor genes are frequently altered in acute/lymphomatous ATLL and their alteration is probably the driving force fueling the transition from chronic/smoldering to acute/lymphomatous ATLL.

Extensive analysis of the retinoblastoma gene in adult T cell leukemia/lymphoma (ATL).

The retinoblastoma susceptibility gene (Rb) plays a key role in regulating the cell cycle in association with cyclins and cyclin-dependent kinases (CDKs). Alteration of the Rb gene as well as CDK inhibitors (CDKIs) leads to deregulated cellular growth which promotes cancer formation. We examined the genomic configuration of the entire Rb gene in 40 primary adult T cell leukemias/lymphomas (ATL) and two ATL cell lines by Southern blotting and also by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analyses. Homozygous loss of exon 1 was identified in one of 21 acute ATL, one of 15 chronic ATL, and none of four lymphomatous ATL samples. No point mutations were identified. Previously, we found that 10 of these same ATL samples had alterations of either p16(INK4A) (homozygous deletion) or p27(kip1) (homozygous deletion or point mutation). Although the numbers are very low, none of the samples with an aberrant Rb gene had an altered CDKI and vice versa, suggesting that both genes probably operate in a common pathway and alteration of either can provide these cells with a growth advantage.

Alterations of the cyclin-dependent kinase inhibitor p19 (INK4D) is rare in hematopoietic malignancies.

Cyclin-dependent kinase inhibitors (CDKIs) can be classified into two groups based on the structure of the proteins. One group includes the p21 (CIP1, WAF1, CAP20), p27 (Kip1), and p57 (Kip2) CDKIs, which contain a homologous amino-terminal cyclin-dependent kinase (cdk) inhibitory domain. The p16 (INK4A), p15 (INK4B), and p18 (INK4C) CDKIs, which have an ankyrin repeat motifs, belong to the other group. The p16 and p15 CDKI genes are very frequently altered in a variety of cancers including hematopoietic malignancies. The p19 (INK4D) gene is a newly cloned CDKI which belongs to the latter group. To determine if p19 genetic alterations play a role in hematopoietic malignancies, we examined DNA from 45 childhood newly diagnosed acute lymphocytic leukemias (ALLs), 30 acute myeloblastic leukemias (AMLs), 10 chronic myelocytic leukemias (CMLs), 45 adult T cell leukemias (ATLs), 70 non-Hodgkin's lymphomas (NHLs), and 20 multiple myelomas (MM) as well as 14 ALL, 20 AML, two ATL, and five lymphoma cell lines. Using Southern blot analysis, one homozygous deletion of the p19 gene was detected in a human immunodeficiency virus (HIV)-related Burkitt-like lymphoma sample. No point mutations in any of the samples were found by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Our investigation suggests that alterations of p19 do not play an important role in the development of most hematopoietic malignancies.

WT1 expression level and clinical factors in multiple myeloma.

Although Wilm's Tuomor gene (WT1) was first identified as a tumor suppressor gene for Wilm's tumor, WT1 overexpression has been detected in different malignant cell types including leukemia. Increased expression of WT1 in acute leukemia is potentially used as a marker of minimal residual disease. However, the significance of the gene for multiple myeloma is still not clear. To determine the clinical relevance of WT1 expression in multiple myeloma, we examined the association of clinical parameters and WT1 expression in bone marrow for 17 newly diagnosed multiple myeloma patients. WT1 was assessed by real-time quantitative polymerase chain reaction (RQ-PCR) and calculated standardized WT1 expression level per 100 plasma cells in the bone marrow specimen as "corrected WT1". The expression of standardized WT1 and corrected WT1 in myeloma was 59 to 1,600 copies/microg RNA and 0.05 to 406.3 copies/microg RNA/100 plasma cells, respectively, lower than in leukemia. WT1 transcripts increased when clinical factors worsen, including the stage, amount of M protein, Hb, platelet count, blood urea nitrogen (BUN), creatinine, serum alkaline phosphatase (ALP), calcium, beta2-microglobulin, thymidine kinase activity (TK), and C-reactive protein (CRP). In conclusion, the expression level of WT1 could be an additional marker to the standard parameters considered in risk assessment for multiple myeloma.

Pure red cell aplasia and myelofibrosis in B-cell neoplasm.

We describe an unusual case of B-cell neoplasm accompanied by pure red cell aplasia (PRCA) and myelofibrosis in a 67-year-old male presenting with severe anaemia. A few unclassified, myeloperoxidase-negative blastoid cells were seen on bone marrow aspiration, and erythroid cell hypoplasia and myelofibrosis on bone marrow biopsy. An autoimmune PRCA was suspected, as serum CH50, C3 and C4 levels were consistently low. Ciclosporin was effective in treating the anaemia, but anaemia returned when the drug was discontinued. Thirteen months later, the patient was admitted with pleural effusion and ascites that contained monoclonal CD19+ CD20+ immature blast cells with a complex karyotype, thought to be neoplastic B-cells. The unclassified blastoid cells seen earlier may therefore have been from the same origin. The patient deteriorated rapidly and died. Only one case of non-Hodgkin's lymphoma with PRCA and myelofibrosis has been reported previously. We discuss the possibility that dysregulated T-cells induced by neoplastic B-cells may have given rise to concomitant PRCA and myelofibrosis.

Cytotoxic effect of extracellular ATP on L1210 leukemic cells and normal hemopoietic stem cells.

The cytotoxic effect of extracellular adenosine triphosphate (ATP) was examined on normal murine hemopoietic stem cells and a representative leukemic cell line (L1210). After L1210 cells were incubated with 4 mM ATP for 3 h, 3H-thymidine incorporation was almost completely inhibited. The number of viable L1210 cells was also significantly decreased and L1210 colony formation was suppressed to approximately 30% of the control level after treatment. The CFU-GM survival rate was reduced to 70%, however, CFU-S and marrow nucleated cell numbers were not changed after the same treatment with ATP. All mice that were injected with the untreated mixture of normal marrow cells (3.3 x 10(4)) and L1210 cells (3.3 x 10(3)) died of leukemia within 18 days. On the contrary, 85% of the recipients given ATP-treated grafts survived more than 70 days. These findings indicate that ATP extra vivo treatment is useful for purging the residual leukemic cells in autologous bone marrow transplantation.

Infrequent microsatellite instability during the evolution of myelodysplastic syndrome to acute myelocytic leukemia.

Microsatellites are highly polymorphic, short-tandem repeat sequences dispersed throughout the genome. Instability of these repeat sequences at multiple gentic loci may result from mismatch repair errors and occur in hereditary nonpolyposis colorectal cancer and several other sporadic cancers, including chronic myelocytic leukemia as it progresses to blastic crisis. We investigated whether genetic instability occurred as myelodysplasia progressed to acute myelocytic leukemia. To this end, we studied microsatellite instability in 20 patients with myelodysplastic syndrome (MDS). These included five patients with refractory anemia (RA), three with refractory anemia with ringed sideroblast (RARS), nine with refractory anemia with excess blasts (RAEB) and three with chronic myelomonocytic leukemia (CMML). All of these patients transformed to acute myelocytic leukemia (AML) of various subtypes: three patients with M1, 11 with M2 and six patients with M4 (according to FAB classification). The DNA from both the MDS and AML phases of their disease was analyzed at 16 loci, and only four microsatellite instabilities were found in the 240 paired samples (1.6%) analyzed. These results indicate that mismatch repair errors such as microsatellite instability are not important in the evolution of MDS to AML.

DPC 4/SMAD 4 in non-pancreatic tumors with frequent LOH 18q21 and in hematological malignancies.

Recently, a novel candidate tumor suppressor gene, DPC 4/SMAD 4, has been implicated in the development of pancreatic cancers. Its location at human chromosome 18q21 prompted us to investigate this gene in a large series of primary tumors located outside the gastrointestinal tract which have been associated with loss of heterozygocity (LOH) at this locus. One hundred and thirty primary solid tumor samples (28 breast, 34 non-small cell lung, and 20 prostate cancers, and 40 osteosarcomas), 32 cell lines as well as 162 leukemia and lymphoma cases were analysed by Southern blotting and PCR-SSCP for deletions and mutations of the DPC 4 gene. In the breast cancer cell line MDA-MB-468, the gene was found to be homozygously deleted. Neither the primary solid tumor samples nor hematological malignancies had detectable abnormalities. Our study suggests that alterations of the DPC 4 gene, unlike in pancreatic cancer, are rare in breast, nonsmall cell lung and prostate cancers, osteosarcomas and hematopoietic malignancies.

Mutational analysis of the hMSH2 gene in a wide variety of tumors.

The hMSH2 gene participates in DNA mismatch repair and its mutation can result in genetic instability of the human genome which is an important feature of tumorigenesis. In this study, genetic alterations of the hMSH2 gene were examined in 43 ovarian, 36 non-small cell lung (NSCL), 31 poorly differentiated gastric, 15 endometrial, and 11 colon cancers, nine gastric cancer cell lines, 41 adult T-cell leukemias (ATLs), two ATL cell lines, and 37 non-Hodgkin's lymphomas (NHLs), using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique. Microsatellite instability (MSI) was also investigated for ovarian, NSCL, and colon cancers. The incidence of MSI was 1/36 (3%) for NSCL, 2/23 (9%) for ovarian, and 1/11 (9%) for colon cancers. Missense base changes of the hMSH2 gene were identified in two gastric cancer patients (ATG to ATA resulting in Met changing to Ile at codon 688 in exon 13 and ACA to GCA resulting in Thr changing to Ala at codon 803 in exon 14). These mutations were found in samples with no MSI. One ovarian and one gastric cancer, and six ATL samples showed two types of polymorphisms of hMSH2 (CTT to TTT resulting in Leu changing to Phe at codon 390 in exon 7 and CAG to AAG resulting in Gin to Arg at codon 419 in exon 7). Our data suggest that MSI and hMSH2 mutations are uncommon in sporadic tumors.

Effects of ceruletide on the dopamine receptor-adenylate cyclase system in striatum and frontal cortex of rats chronically treated with haloperidol.

Chronic treatment of rats with haloperidol decanoate (30 mg/kg and 100 mg/kg IM every 4 weeks for 52 weeks) increased [3H] SCH 23390 binding in striatal membranes by 25% and 50% and in frontal cortical membranes by 56% and 125% in 30 and 100 mg/kg haloperidol treatment groups, respectively. These increases in [3H] SCH 23390 binding to the membranes were restored to control levels after ceruletide treatment (100 micrograms/kg IP twice a day for 5 days). [3H] Spiperone binding to the rat striatal and cortical membranes also increased after chronic haloperidol treatment (by 66% and 99% in striatal membranes and by 27% and 62% in cortical membranes in the 30 and 100 mg/kg haloperidol treatment groups, respectively). Administration of ceruletide to haloperidol-treated rats reduced the increased [3H] spiperone binding to the cortical membranes toward the control level, but ceruletide was not effective in reducing the haloperidol-induced increase of [3H] spiperone binding to the striatal membranes. Activation of adenylate cyclase by dopamine (1 microM or 100 microM) or Gpp(NH)p (1 microM) was reduced in striatal and cortical membranes from haloperidol-treated rats. Ceruletide restored the lowered level of dopamine-stimulated or Gpp(NH)p-stimulated adenylate cyclase activity in the membranes from haloperidol-treated rats to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Bile alcohol profiles in bile, urine, and feces of a patient with cerebrotendinous xanthomatosis.

Bile alcohols in bile, urine, and feces of a patient with cerebrotendinous xanthomatosis have been analyzed by a combination of capillary gas-liquid chromatography and mass spectrometry after fractionation into groups according to mode of conjugation. The presence of at least 18 bile alcohols, which were excreted mainly as glucurono-conjugates in bile and urine, and as unconjugated forms in feces, was demonstrated. The following bile alcohols were identified with certainty by direct comparison with reference compounds: 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol; (23R)-5 beta-cholestane-3 alpha,7 alpha,12 alpha,23-tetrol; 5 alpha- and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24-tetrols; 5 alpha- and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrols; 27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentol; (22R)-5 beta-cholestane-3 alpha,7 alpha,12 alpha,22,25-pentol; (23R)- and (23S)-5 beta-cholestane-3 alpha,7 alpha, 12 alpha,23,25-pentols; 3 alpha,12 alpha,25-trihydroxy-5 beta-cholestane-7-one; (24R)- and (24S)-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentols; 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25,26-pentol. Although the bile alcohol profile in urine was quite different from those in bile and feces, the determination of urinary bile alcohols as well as of biliary and fecal bile alcohols could be used for diagnosis of cerebrotendinous xanthomatosis.

Analysis of 20-year follow-up study of LVP regimen for adult acute lymphoblastic leukemia.

In an attempt to develop a new intensive chemotherapy for adults with untreated acute lymphoblastic leukemia (ALL), 3 sequential programs were designed for 62 patients (age range, 15 to 74 years; median age, 32 years) consisting of the LVP-79 (1979-1984, 27 patients), LVP-85 (1984-1986, 14 patients), and LVP-87 (1987-1989, 21 patients) regimens. The influence of clinical and biologic characteristics on the patient outcome was also examined. L-asparaginase (L-asp), vincristine, and prednisolone, defined collectively as LVP, were administered for induction chemotherapy in all protocols. After achieving complete remission (CR), patients underwent 2 years of multi-agent consolidation, intensification, and maintenance therapy consisting of various combinations. No significant differences were noted between the 3 groups regarding CR rate or survival. In total, 47 of 62 patients (75.8%) achieved CR. The median overall survival (OS) and median CR durations were 550 days and 341 days, respectively. Overall, the estimated survival rate at 20 years was 18.1%. The disease-free survival rate at 20 years was 26.2%. According to univariate analysis, the most favorable pretreatment characteristic for achieving CR was age. A younger age (<40 years of age), platelet count >30 x 10(9)/L, having L1 morphology (French-American-British [FAB]classification subtype), female sex, and the absence of chromosomal abnormalities also helped improve survival rate. According to multivariate analysis, presence of Ph chromosome was found to be a major influencing factor for OS. Although higher doses of L-asp were administered than those used in previous studies, the adverse effect of L-asp was rarely identified. Therefore, it should be considered one of the key drugs for treatment of adult ALL. Further strategies still need to be developed to obtain better survival in adult ALL.

Changes in immunoreactive insulin, C-peptide immunoreactivity, and immunoreactive glucagon in acute viral hepatitis.

Insulin and glucagon are thought to play important roles as hepatotrophic factors in acute viral hepatitis (AVH); however, few reports have investigated the responses and relationships of each of these hormones to liver damage in detail. We studied insulin and glucagon responses during the acute and recovery phases of AVH. We performed a glucose tolerance test (GTT) and an insulin sensitivity test (IST) in each phase in 11 patients with AVH. In 8 additional patients in the acute phase (total n = 19), were compared immunoreactive insulin (IRI) and C-peptide immunoreactivity (CPR) levels with transaminase levels. In the acute phase, IRI concentrations were normal from fasting to 60 min, despite an increased CPR level. In the recovery phase, IRI and CPR levels increased significantly. Immunoreactive glucagon levels in both phases did not differ significantly from those in controls. During the IST, the insulin sensitivity index in both phases was significantly lower than that in the controls. Fasting IRI and sigma IRI showed significant negative correlations with transaminase levels. We found enhanced insulin secretion and a decrease in plasma insulin in the acute phase of AVH. The discrepancy between IRI and CPR responses in the acute phase suggests an increase in the degradation or consumption of insulin in the liver.

Bile acid profiles in bile, urine, and feces of a patient with cerebrotendinous xanthomatosis.

Bile acid profiles of bile, urine, and feces obtained from a patient with cerebrotendinous xanthomatosis on the same day have been analyzed by gas-liquid chromatography-mass spectrometry after fractionation into groups by mode of conjugation by an ion-exchange chromatography. The predominant biliary bile acid was cholic acid conjugated with glycine and taurine. Lesser amounts of the amino acid conjugates of chenodeoxycholic acid, ursodeoxycholic acid, 7-ketodeoxycholic acid, allocholic acid, and deoxycholic acid, and of unconjugated norcholic acid and allonorcholic acid were also present in the bile. The major fecal bile acid was 7-epicholic acid. Relatively large amounts of bile acids were excreted in the urine. Unconjugated 7-epicholic acid, norcholic acid, allonorcholic acid, and cholic acid predominated. The bile acid profiles of the patient were different from those of normal subjects and should be useful for the diagnosis.