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To investigate walking ability in Japanese patients with Rett syndrome (RTT).Walking ability was assessed in 100 female Japanese patients with RTT using univariate and multivariate analysis in all age groups, and in patients over 10 years of age. We analyzed walking ability and confounding factors including prenatal-perinatal histories, developmental milestones, somatic and head growth, anthropometric data, body mass index, age of loss of purposeful hand use, age at onset of stereotypic hand movement, history of autistic behavior, age at regression, presence or absence of seizures, and the results of MECP2 genetic examination from the Japanese Rett syndrome database.Univariate analysis revealed that acquisition of walking in all age groups was significantly correlated with the acquisition of meaningful words, microcephaly, and crawling (P 0.0001, P = 0.005, P 0.0001, respectively). Univariate analysis revealed that walking ability over 10 years of age was significantly correlated with acquisition of meaningful words, microcephaly, and body mass index (P 0,0001, P = 0.005, P = 0.0018, respectively). MECP2 mutations R306C, R133C, and R294X were significantly associated with different acquisition of crawling (P = 0.004) and walking (P = 0.01). Multivariate analysis revealed that only acquisition of meaningful words was significantly correlated with walking ability over 10 years of age. This trend excluded the genetic effects of R306C, R133C, and R294X.Meaningful word acquisition was robustly associated with walking ability over 10 years. Prognosis of walking ability may be predicted by the acquisition of meaningful words. This information is potentially useful for early intervention and the planning of comprehensive treatment for young children with RTT.

The aim of this study was to investigate the arterial hypoxemia in Japanese patients with alcoholic liver disease (ALD) with regard to alcohol consumption and/or disease severity. Hypoxemia was observed in 78% patients with ALD and in all 46 patients with alcoholic liver cirrhosis (ALC) and 33 (56%) of 59 patients with noncirrhotic alcoholic liver disease (NCALD) (P < 0.0001). The partial pressure of oxygen (P aO2) was 71.1 ± 5.2 mm Hg in ALC and 78.7 ± 6.3 mm Hg in NCALD (P < 0.0001). The oxygen consumption in ALD was significantly higher than that in control subjects (P < 0.0001), and a high oxygen consumption was seen in 88% of the patients with ALD, in all 46 ALC patients, and in 46 (78%) of 59 NCALD patients (P < 0.01). Following abstinence from alcohol, the P aO2 and oxygen consumption significantly recovered after day 2 (P < 0.0001), whereas the prothrombin index did not change in either NCALD or ALC patients. Multivariate analysis showed that alcohol consumption and oxygen consumption were significant independent predictors of P aO2. In conclusion, the present findings suggest that increased oxygen consumption due to alcohol ingestion is principally responsible for the hypoxemia in ALD patients.

Although antiviral agents have been adopted for the management of chronic hepatitis B, they have only limited efficacy because of the underlying impaired immune status. Propagermanium, a hydrophilic polymer of 3-oxygermyl propionate, has been reported to have potent immune modulatory activity associated with antiinflammatory and antineoplastic properties. For example, propagermanium augments lymphocyte functions in CD4 and CD8 cells, and in natural killer (NK) cells, and induces the production of several cytokines. A controlled pilot study of 16-week treatment with propagermanium for chronic hepatitis B (of moderate and mild grades on hepatic histology) revealed a sustained clearance of hepatitis B e (HBe) antigen and a favorable biochemical response at week 16 of treatment and at week 48 post-treatment. An open study also supported the clearance of hepatitis B virus from the blood and the possible improvement of histologic grading in the liver. There were few adverse events. A postmarketing survey, however, revealed the occurrence of moderate to severe liver damage after the treatment in about 4% of patients. Despite the exact nature of the liver damage being unclear, a putative cause is the swift removal of virus-infected hepatocytes by an immune reaction through the treatment. A subtle balance between host and viral conditions is the factor which most determines hepatitis B virus persistence. The rationale for a nonspecific immune modulator for the treatment of chronic hepatitis B will be the restoration of cellular immune responsiveness to viral infection. Although the cellular immunity for hepatitis B virus prior to the treatment should be studied, adequate observation of hepatic functions and viral markers in the recipients is clinically useful to predict liver failure during the treatment. In summary, the propagermanium regimen offers a potent and safe approach that is cost-effective for appropriate chronic hepatitis B patients with reserve hepatic capacity, and will provide new perspectives for immune therapy in chronic hepatitis B.

Hepatobiliary cystadenoma was suggested to be uncommon and it is often difficult to make a differential diagnosis. We report a case of a 65-year-old woman who presented with changes in the structure of a cyst that had been observed for the previous 10 years. Diagnostic imaging revealed a 7-cm-diameter cystic lesion with internal septations and papillary projections in her liver. All laboratory test results were normal; however, cystic fluid carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were raised, at 160 ng/ml and over 200 000 U/ml, respectively. Owing to changes in the structure of the cyst and the difficulty of differential diagnosis from cystadenocarcinoma, a complete surgical excision was performed. The histological findings indicated that the tumor consisted of a multilocular cyst lined by glandular cells (with cuboidal or tall columnar cystoplasm), which were immunohistochemically positive for cytokeratin, CEA, epithelial membrane antigen, and CA 19-9. The underlying stroma was composed of proliferating primitive spindle cells which were immunoreactive for vimentin, alpha-smooth muscle actin, muscle-specific actin, and desmin, and resembled ovarian stroma. From these findings, this tumor was diagnosed as hepatobiliary cystadenoma with mesenchymal stroma. Even though the tumor was previously diagnosed as a simple liver cyst, it was necessary to pay special attention to the changes in the structure of the cyst, using ultra sonography and/or computed tomography, bearing in mind hepatobiliary cystadenoma with mesenchymal stroma. The malignant potential of this tumor is stressed, and complete surgical resection is the recommended therapy.

Plasma endothelin (ET) levels are generally increased in cirrhosis patients in line with the severity of disease; however, the pathophysiological significance remains to be clarified. We evaluated the plasma ET levels in 49 patients with alcoholic cirrhosis and in 53 patients with nonalcoholic cirrhosis of the same disease severity. The plasma ET level was significantly elevated in alcoholic patients (P < 0.0001) and slightly so in nonalcoholic patients (P < 0.01); the difference was significant between the groups (P < 0.0001). The plasma ET level was positively correlated with the Child-Pugh score (P < 0.0001) and negatively correlated with prothrombin index (P < 0.001) and indocyanine green (ICG) clearance (P < 0.0001). The plasma ET level decreased 32% in alcoholic patients after abstinence (P < 0.001), but remained correlated with ICG clearance (P < 0.001) and the Child-Pugh score (P < 0.01), but not with prothrombin index. Regression analysis revealed that the plasma ET level was correlated with estimated hepatic blood flow and alcohol abuse. These findings suggest that hyperendothelinemia in cirrhosis patients is related to alcohol abuse and disease severity, especially to impaired hepatic hemodynamics.

Macrocytosis is most commonly associated with vitamin B(12) and folic acid deficiency, followed by alcoholism, liver disease, and other pathologic conditions. We studied the red cell and vitamin status in 423 consecutive patients with various liver diseases, including 31 with acute viral hepatitis (AVH), 105 with chronic hepatitis (CH), and 134 with alcoholic liver disease (ALD), who consisted of 84 with non-cirrhotic alcoholic liver disease (NCALD) and 50 with alcoholic liver cirrhosis (ALC), 60 with non-alcoholic liver cirrhosis (NALC), and 93 with hepatocellular carcinoma (HCC). The mean corpuscular volume (MCV) and red cell distribution width (RDW) were significantly higher in patients with ALD and NALC, and among them macrocytosis occurred more frequently in patients with ALC. Macrocytic anemia was mostly found in cirrhotic patients, in which the Child-Pugh score was closely related to the development of macrocytic anemia. In ALD, the MCV was significantly correlated with the estimated alcohol consumption and inversely correlated with the serum folic acid level, which, however, was often maintained within the normal range in patients with macrocytic ALC. After abstinence from alcohol, the MCV and RDW were reduced significantly and were associated with an increasing serum folic acid level. This suggests that macrocytic anemia was a common feature of alcoholic and non-alcoholic liver cirrhosis and that alcohol abuse and folic acid deficiency play a secondary role in macrocytosis.

A 47-year-old woman was diagnosed as having chronic active hepatitis C in February, 1995. She was administered 6 MU of interferon (IFN) β daily, beginning on March 8. After 6 weeks of the treatment she complained of chest pain and she entered a state of shock 1 h after administration of IFN. On the electrocardiogram, negative conversion of the T wave at leads: II, III, AVF and V3-6 was seen. Since myocardial ischemia was suspected, catecholamine and nitroglycerin were administered; the symptoms abated, however the electrocardiogram on the fifth day indicated junctional rhythm. The patient was diagnosed as having myocarditis based on the findings of strongly positive C-reactive protein and elevated erythrocyte sedimentation rate together with the features seen on electrocardiograms, echocardiograms and myocardial scintigrams. After the IFN-β treatment was discontinued, the clinical symptoms, electrocardiographic and echocardiographic findings improved. The myocarditis in this case was interpreted as being due to the treatment of IFN-β, because the patient presented no evidence of previous heart disease.

Two female breast cancer patients who received combined tamoxifen and tegafur as postsurgical adjuvant therapy developed severe hepatotoxicity after being treated for three and eight months, respectively. Shortly after the cessation of the treatment, routine liver tests showed gradual recovery, but liver biopsies revealed chronic active hepatitis in one patient and liver cirrhosis in the other. Four and five years, respectively, after the cessation of the treatment, the results of liver tests were normal and distinct histological improvement was observed in both patients. Because these patients had no viral and immunoserological markers nor any history of alcohol abuse, this study suggested that the tamoxifen and tegafur regimen induced reversible chronic active liver disease.

Lysyl oxidase was partially purified from serum by a diethylaminoethyl batch procedure in the presence of 6 mom/L urea and dialyzed against 3 mol/L KSCN. Using this method, we determined serum lysyl oxidase activity in 52 patients with liver disease and in 14 healthy controls, and we examined usefulness of serum lysyl oxidase in assessing liver fibrogenesis. For this purpose, serum lyayl oxidase activity in chronic liver disease was compared with serum levels of prolyl hydroxylase and laminin P1. As compared with controls, serum lysyl oxidase activity increased 1.6-fold in chronic persistent hepatitis, 4.4-fold in chronic active hepatitis and 11.8-fold in cirrhosis, indicating an increase in concert with the development of liver fibrosis. In hepatocellular carcinoma, the serum activity, although signiscantly increased, was lower than that in cirrhosis. Serum prolyl hydroxylase was significantly increased in chronic active hepatitis, in liver cirrhosis and in hepatocellular carcinoma Serum laminin P1 was significantly increased in chronic active hepatitis, in cirrhosis and in hepatocellular carcinoma Serum lysyl oxidase activity did not correlate significantly with serum levels of prolyl hydroxylase and laminin P1 in any subject or in any subgroup. The magnitude of the increase and the abnormal percentage of serum lysyl oxidase activity were larger than those for serum prolyl hydroxylase and laminin P1. These results suggest that serum lysyl osidase activity is a more sensitive indicator of liver fibrosis than serum prolyl hydroxylase and laminin P1. (HEPATOLOGY 1991;14:1167–1173.)

To examine the synthesis of hepatic collagen in patients with alcoholic and nonalcoholic liver disease, liver biopsy specimens were incubated in vitro with 14C-proline, and the radioactivity of the newly synthesized protein-bound 14C-hydroxyproline was measured. Mean hepatic collagen synthesis was 0.82 +/- 0.19 pmole of 14C-hydroxyproline/g liver/2 h in control subjects without histological liver fibrosis. Hepatic collagen synthesis was increased in patients with alcoholic and nonalcoholic liver diseases, especially in those with alcoholic fibrosis, alcoholic cirrhosis and chronic active hepatitis. The raised collagen synthesis in alcoholic liver disease rapidly decreased after withdrawal of alcohol. When alcoholic liver disease were compared with nonalcoholic liver disease, there was no significant difference in hepatic collagen synthesis.

During the 12 years from 1977 to 1988 in Tottori University Hospital, 6 cases (4.2%) with chronic active "lupoid" hepatitis were encountered among 143 patients with histologically proven chronic active hepatitis. HLA antigens were studied; BW 22 and CW 1 were strongly associated, and A 11 was rather associated with the rare disorder in Japan. These results suggested that Japanese patients with chronic active "lupoid" hepatitis have different HLA markers from those in Caucasian patients, which may be attributable to rare specificity in the HLA system rather than different mechanisms of pathogenesis.

正常健康人100例, 慢性肝炎78例, 肝硬変83例について, 血清ハプトグロビン (Hp) およびα1アンチトリプシン (PI) 表現型をそれぞれポリアクリルアミドゲル電気泳動, および等電点電気泳動法によって測定した. その結果, Hp1およびPIM3は, 肝硬変, とくに非アルコール性, 非代償性肝硬変において増加しており, Hp1とPIM3の組合せはウイルス性慢性肝疾患の重症度を支配する一因子となりうるものと推定された.

Collagenase and collagenolytic cathepsin activities in normal and carbon tetrachloride-induced fibrotic livers of rats were simultaneously determined at 35 and 25 degrees C for 18 h, using the same 14C-labeled neutral soluble collagen as a substrate. Collagenolytic cathepsin had higher activity under the assay conditions at both 35 and 25 degrees C than collagenase in normal and fibrotic livers. On sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis, the collagen was visibly degraded by collagenolytic cathepsin, but not by collagenase. These results indicate that, unlike collagenase, collagenolytic cathepsins exist as active forms in the rat liver, and can participate in the degradation of collagens, especially of soluble collagens including procollagens.

Following a single oral dose of 10 mg/kg of [15N]glycine, plasma [15N]glycine kinetics and urinary 15N excretion were measured in 12 cirrhosis patients and in 6 control subjects. Cirrhosis patients were divided into two groups of 6 patients with and without a history of hepatic encephalopathy designated as group II and group I, respectively. Thirty minutes after oral administration of labeled glycine, the plasma concentration of [15N]glycine was significantly higher in both cirrhosis groups than that in the control group (P less than 0.05 and P less than 0.01). The elimination constant of plasma [15N]glycine slightly decreased in group II, but not significantly. Urinary 15N excretion did not differ among the three groups, but the rate of urinary ammonia 15N in urinary 15N was significantly increased in group II (P less than 0.05). The whole-body protein flux did not differ among the three groups, but whole-body protein breakdown was significantly increased in group II cirrhosis patients (P less than 0.05). These findings indicated that the kinetics of glycine were substantially altered in severe cirrhosis patients. Because hepatic uptake and oxidation of glycine was well maintained even in group II, increased endogenous protein breakdown seemed to be responsible for hyperglycinemia and also for the negative nitrogen balance seen in this group.

Alcohol dehydrogenase activity and fatty acid ethyl ester synthase activity were measured in various organs of male Wistar strain rats. The mean (+/- SE) values of alcohol dehydrogenase activity in liver, testis, pancreas and brain were 223 +/- 34, 35 +/- 13, 27 +/- 17 and 24 +/- 15 nmol/hr/mg protein, respectively, but not detectable in heart and skeletal muscle. Fatty acid ethyl ester synthase activity in pancreas, liver, testis and heart were 1348 +/- 263, 23 +/- 14, 17 +/- 3 and 2 +/- 1 nmol/hr/mg protein, respectively, but not detectable in brain and skeletal muscle. Alcohol dehydrogenase activity, fatty acid ethyl ester synthase activity, fatty acid ethyl ester content and amylase activity were measured in pancreas of rat after 7 weeks of ethanol feeding. Compared with control rats, ethanol-fed rats had normal fatty acid ethyl ester synthase activity and alcohol dehydrogenase activity. However, fatty acid ethyl ester content increased five-fold and amylase activity decreased up to 20% of the control group. Fatty acid ethyl ester content was inversely correlated with amylase activity. These results suggest that fatty acid ethyl ester may be responsible for the development of pancreatic damage by ethanol.

Moderate polyclonal hypergammaglobulinemia is a common finding in chronic viral liver disease; however, its clinical significance has not been completely elucidated. We attempted to determine whether serum immunoglobulin levels were correlated with the disease severity and the treatment outcome in patients with chronic hepatitis C.In a total of 102 patients with chronic hepatitis C, we performed serum tests on immunoglobulins and determined the histology activity index (HAI) score by liver biopsy. In 97 patients, immunoglobulin levels were followed prior to and 6 months after interferon (IFN) therapy.Serum gamma (y)-globulin and immunoglobulin (IgG) were well correlated with HAI score (both; p0.0001), grading score (both; p0.01), and staging score (both; p0.0001). Among the 97 patients who received 6 months of IFN monotherapy, 31, 29, and 37 patients were complete, transient and non-responders, respectively. In the three subgroups, a significant difference was found in histological HAI, grading, and staging scores (p0.01, p0.05 and p0.0001, respectively), and in serum levels of gamma-globulin and IgG (both; p0.0001). Following IFN treatment, serum gamma-globulin and IgG were significantly decreased in the complete responders (both; p0.0001). Furthermore, serum levels of gamma-globulin and IgG of 1.5 g/dL were useful for predicting the treatment outcome of IFN monotherapy.The measurement of serum gamma-globulin and IgG is a valuable non-invasive tool for assessing the disease severity and treatment outcome in patients with chronic hepatitis C.

Hepatobiliary cystadenoma was suggested to be uncommon and it is often difficult to make a differential diagnosis. We report a case of a 65-year-old woman who presented with changes in the structure of a cyst that had been observed for the previous 10 years. Diagnostic imaging revealed a 7-cm-diameter cystic lesion with internal septations and papillary projections in her liver. All laboratory test results were normal; however, cystic fluid carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were raised, at 160 ng/ml andover 200,000 U/ml, respectively. Owing to changes in the structure of the cyst and the difficulty of differential diagnosis from cystadenocarcinoma, a complete surgical excision was performed. The histological findings indicated that the tumor consisted of a multilocular cyst lined by glandular cells (with cuboidal or tall columnar cystoplasm), which were immunohistochemically positive for cytokeratin, CEA, epithelial membrane antigen, and CA 19-9. The underlying stroma was composed of proliferating primitive spindle cells which were immunoreactive for vimentin, alpha-smooth muscle actin, muscle-specific actin, and desmin, and resembled ovarian stroma. From these findings, this tumor was diagnosed as hepatobiliary cystadenoma with mesenchymal stroma. Even though the tumor was previously diagnosed as a simple liver cyst, it was necessary to pay special attention to the changes in the structure of the cyst, using ultra sonography and/or computed tomography, bearing in mind hepatobiliary cystadenoma with mesenchymal stroma. The malignant potential of this tumor is stressed, and complete surgical resection is the recommended therapy.

Plasma endothelin (ET) levels are generally increased in cirrhosis patients in line with the severity of disease; however, the pathophysiological significance remains to be clarified. We evaluated the plasma ET levels in 49 patients with alcoholic cirrhosis and in 53 patients with nonalcoholic cirrhosis of the same disease severity. The plasma ET level was significantly elevated in alcoholic patients (P0.0001) and slightly so in nonalcoholic patients (P0.01); the difference was significant between the groups (P0.0001). The plasma ET level was positively correlated with the Child-Pugh score (P0.0001) and negatively correlated with prothrombin index (P0.001) and indocyanine green (ICG) clearance (P0.0001). The plasma ET level decreased 32% in alcoholic patients after abstinence (P0.001), but remained correlated with ICG clearance (P0.001) and the Child-Pugh score (P0.01), but not with prothrombin index. Regression analysis revealed that the plasma ET level was correlated with estimated hepatic blood flow and alcohol abuse. These findings suggest that hyperendothelinemia in cirrhosis patients is related to alcohol abuse and disease severity, especially to impaired hepatic hemodynamics.

Stronger neo-minophagen C (SNMC), a glycyrrhizin (GL) preparation, has been extensively used with considerable success in Japan for the treatment of chronic hepatitis. The aim of the present study was to elucidate the efficacy of administering massive doses of 100 ml/day to patients in whom standard administration (40 ml/day) for 2 weeks did not show sufficient improvement. A comparative study was conducted by dividing at random 100 cases (56.2%), out of a total of 178 enrolled, into two groups, one for the administration of 100 ml/day for 3 weeks (group A) and the other for administration of 40 ml/day for 3 weeks (group B). Cases were rated 'markedly improved'or 'improved' according to their ALT levels (defined respectively as

The clinical significance of the immunoreactive triple helical domain of type IV collagen in serum was evaluated in 73 healthy controls and 161 patients with various biopsy-proven liver diseases. Although serum levels of type III procollagen peptide were increased in all liver diseases, those of type IV collagen, 7S collagen, and laminin were principally increased in chronic liver diseases associated with hepatic fibrogenesis/fibrosis. In both non-alcoholic and alcoholic liver diseases, 7S collagen was increased in serum, while type IV collagen and laminin in serum were particularly increased in alcoholic liver diseases and in hepatocellular carcinoma, in which latter the sensitivity was greater for type IV collagen than for laminin. Gel filtration analysis in Sephacryl S-400 revealed type IV collagen in serum to be a single molecular form with a molecular weight that correspond to type IV collagen, whereas 7S collagen was recognized as several heterogeneous macromolecules. These findings indicate that serum type IV collagen is derived from the type IV protocollagen pool, and is a sensitive marker for the fibrogenetic process in hepatic basement membranes.

In two clinical studies with 155 subjects, we investigated the polysaccharide Sizofiran (SPG) for its efficacy and optimal dosage as an immunotherapeutic agent in patients with chronic hepatitis B. Hepatitis B e antigen (HBeAg)-positive patients were given 20 mg, 10 mg, 5mg or 1 mg of SPG intramuscularly once a week for 16 weeks. In the first study, 9 of 25 patients (32.1%) receiving 10 mg became seronegative for HBeAg during the follow-up period of 6 months. In the second study, treatment with SPG was effective in 5 of 25 patients (20.0%) on 10 mg during the follow-up period of 3 months. Response rates were significantly lower for all other dose groups. Thus polysaccharide SPG appears to be effective in some patients with chronic hepatitis B and its optimal dose is estimated to be 10 mg once a week.

Urinary 15N-ammonia and 15N-urea were measured by gas chromatography-mass spectrometry after the intravenous administration of 15N-ammonia (0.2 mumol/kg/hr) to 6 volunteers and 11 patients with cirrhosis. Urinary 15N-nitrogen excretion as ammonia and urea was measured during the 210-min infusion period, and urea synthesis and ammonia conversion to amino acids were analyzed with a three-compartment model using the nonlinear least-squares method. The rate of urea synthesis in control subjects was 14.1 +/- 1.2 mg/kg/hr (mean +/- S.E.M.), and in cirrhotic patients it was 11.0 +/- 3.2 mg/kg/hr. The cirrhotic group was divided into those with compensated cirrhosis (Child class A patients) and those with decompensated cirrhosis (Child classes B and C patients), and the rates of urea synthesis for these groups were 14.5 +/- 1.5 and 8.9 +/- 1.6 mg/kg/hr, respectively. The difference between decompensated cirrhotic patients and control subjects was statistically significant (p less than 0.001). The percentage of ammonia reutilization of a given dose of 15N-ammonia was 75.9% +/- 2.4% in compensated cirrhotic patients and 82.9% +/- 3.6% in decompensated cirrhotic patients (p less than 0.05). Fasting venous ammonia levels correlated inversely with urea synthesis (p less than 0.001) and correlated positively with ammonia reutilization (p less than 0.05). These results are consistent with a decreased capacity to synthesize urea and an increased capacity to convert ammonia to amino acids in chronic liver failure.

To clarify the significance of free and small peptide-bound hydroxyproline synthesis in ethanol-induced liver injury, we measured the in vitro synthesis of [ 14 C]hydroxyproline in the 67% ethanol-soluble fraction in rat liver slices, together with hepatic protein-bound [ 14 C]hydroxyproline synthesis. The synthesis of free and small peptide-bound [ 14 C]hydroxyproline was 11.1 ± 2.0 dpm × 10 −4 / g liver/3 hr and the synthesis of protein-bound [ 14 C]hydroxyproline was 10.1 ± 3.3 dpm × 10 −4 /g liver/ 3 hr in control rat liver. In the ethanol-fed rat liver, the synthesis of free and small peptide-bound [ 14 C]hydroxyproline significantly increased 1.5-fold and the synthesis of protein-bound [ 14 C]hydroxy-proline significantly increased 1.6-fold, while the hepatic collagen content did not change. There was a significant correlation between free and small peptide-bound [ 14 C]hydroxyproline synthesis and protein-bound [ 14 C]hydroxyproline synthesis. These results suggest that free and small peptide-bound hydroxy-proline synthesis plays an important role in regulating the content of hepatic collagens.

Using affinity chromatography on ATP-agarose, we have identified a major ATP-binding protein in Nonidet P-40 extracts of avian and mammalian cells labeled with [35S]methionine. After washing ATP-agarose beads with high-ionic-strength buffer (0.4 M NaCl), the 37-kD protein was shown to be one of the major ATP-binding proteins while p72 and grp78, which are members of the hsp70 family, also bound to ATP-agarose. This protein consisted of several spots on two-dimensional gel electrophoresis. The isoelectric point of the most basic spot was approximately 9.2 in chick embryo fibroblasts, whereas it was about 8.8 in mouse 3T3 cells. The identities of these proteins in mouse and chick cells were confirmed by peptide mapping. After heat-shock treatment of BALB/3T3 cells, the major heat-shock protein, hsp70, was shown to be induced very rapidly after heat shock and was recovered in the ATP-binding fraction. Besides hsp70, a 37-kD protein was also found to be induced by heat shock. This protein was drastically induced by treating the cells with alpha,alpha'-dipyridyl, an iron chelating reagent, but not with sodium arsenite, calcium ionophore, or tunicamycin. The synthesis and the total amount of this ATP-binding protein increased in mouse 3T3 cells transformed by simian virus 40, methylcholanthrene, or activated c-Ha-ras oncogene compared to their normal counterparts. The incorporation of [32P]orthophosphate was not detected in either normal or transformed cells. These studies established that a major ATP-binding protein of Mr = 37,000 is a heat-inducible protein and that the synthesis of this protein is regulated by malignant transformation.

The phenotypes of alpha-1-antitrypsin have been analyzed by isoelectric focusing on polyacrylamide gels in 232 healthy Japanese blood donors and in 240 Japanese patients with chronic liver diseases: 69 with chronic active hepatitis, 122 with liver cirrhosis, 41 with hepatocellular carcinoma and 8 with primary biliary cirrhosis. The liver cirrhosis patients had a gene frequency of 0.07 for P1*M3, which was significantly higher (P less than 0.01) than that (0.03) in blood donors. The gene frequency of P1*M3 was significantly increased in cryptogenic liver cirrhosis (P less than 0.05), and there was a tendency toward an increased frequency of P1*M3 in post-transfusion groups, and in primary biliary cirrhosis. There were also tendencies toward increased frequencies of P1*M3 in cryptogenic and post-transfusion groups of patients with chronic active hepatitis. The present study indicates that P1*M3 is a genetic or predisposing factor for chronic liver diseases, especially for cryptogenic and/or non A-non B viral chronic liver disease and also for primary biliary cirrhosis.

We report a patient with chronic active hepatitis C developing acute anosmia during interferon (IFN) therapy. On July 31, he bagan receiving 6 MU of IFN-α daily. On September 26, he failed to smell gas leaking from a gas cooker, so IFN therapy was discontinued. He showed no reaction on a standard olfactory acuity test. As the patient had borderline diabetes, the association of anosmia with impaired glucose tolerance cannot completely be excluded, but his anosmia was probably induced by IFN therapy, since anosmia developed 10 days after the initiation of the IFN therapy, without any deterioration of his glucose intolerance.

The fecal bacterial flora was examined in multiple stool specimens from 14 subjects with gastrointestinal disorders before, during and after the oral administration of bifidobacterial preparation (BBG, viable B. breve and B. bifidum, 3 X 10(9) or 6 X 10(9) per day) for 2 or 3 weeks. Enumerations of fecal bacterial flora showed no conspicuous alterations in total anaerobic bacterial counts during the BBG therapy, however the total number of bifidobacteria in feces increased significantly, and of E. coli and other aerobacteria showed a tendency to decline. The administered B. breve and B. bifidum were recovered in the feces at a concentration of 10(8)/g and of 10(7) to 10(8)/g, respectively. Both species continued to be excreted over 2 weeks after completion of the medication in the feces at concentrations of 10(6) to 10(7)/g and of 10(5) to 10(6)/g respectively, and diminished rapidly in 5 patients and continued at essentially the same level as during the medication in 6 patients. During the treatment the pH, urease activity and ammonia content in feces became lowered and showed a rerise after therapy. Symptomatic discomforts including abdominal distension and pain, anorexia, edema and fever of undetermined origin were reduced during the therapy. Urinalysis, hematological examinations and blood biochemical tests including blood ammonia level, however revealed no significant change.

Human hepatic collagenolytic cathepsin consisted of a major component having a molecular weight of 25000 and a minor one of 35000; the former is indistinguishable from cathepsin B in its enzymatic properties. Hepatic collagenolytic cathepsin increased in chronic active liver disease in proportion to hepatic hydroxyproline content. The ratio of collagenolytic cathepsin to hepatic hydroxyproline content remained within the normal range in chronic hepatitis, but decreased significantly in cirrhosis. These results suggest that collagenolytic cathepsin participates, at least partly, in the progress of hepatic fibrosis.

正常ならびに各種肝疾患患者血清について胆汁酸をAmberlite XAD-2で分離後非アルコール性溶媒にとかし,酵素法による蛍光度測定によって定量した.正常健康人の空腹時血清胆汁酸は,3±2nmole/mlであり,急性肝炎で著明に増加,慢性肝疾患では,その重症度に比例して増加した.血清胆汁酸は,慢性肝疾患において,血清ビリルビンのほか,アルブミン,γグロブリン,BSP試験などと有意の相関関係がみとめられた.

Serum hydroxyproline-containing peptides were separated into three fractions, i.e. large protein, polypeptide and smaller peptides, by gel filtration on Sephadex G-200. The large protein was presumed to be the Clq subunit of the first component of complement by an immunological analysis. The polypeptide had an electrophoretic mobility corresponding to β-globulin and its molecular weight was estimated between 35 000 and 45 000 by gel filtration analysis. The polypeptide might well be defined as hyproprotein. The molecular weight of smaller peptides was estimated between 1400 and 3000. As compared with the control value, hyproprotein levels were significantly increased in rheumatoid arthritis, systemic lupus erythematosus and chronic liver disease. Clq levels were slightly lowered in rheumatoid arthritis and systemic lupus erythematosus, and were slightly increased in chronic liver disease but were not significant. In all patient groups smaller peptides levels remained in the normal range. These results suggest that serum hyproprotein levels are raised in some fibroproliferative disorders, probably reflecting collagen metabolism.

In a double-blind clinical trial, 24 patients with advanced chronic liver disease received 1.2 g of nicotinohydroxamic acid daily and 23 patients received 1.5 g of neomycin. Patients receiving nicotin

A 43-yr-old man with abdominal fullness was treated with oral cimetidine during remission of acute intermittent porphyria. Urinary prophobilinogen and porphyrins were not altered by the treatment, but urinary delta-aminolevulinic acid decreased, and abdominal fullness disappeared. Thus, cimetidine may control acute intermittent porphyria by inhibiting hepatic delta-aminolevulinic acid synthetase.

正常および各種疾患患者に非抱合ビリルビンを静注後,4時間までの血漿ビリルビン消失曲線をtwo compartment modelで解析して,移行率および4時間停滞率を算出した.正常対照7名の肝摂取率(a),肝より血漿への逆流率(b),肝内輸送率(m)は,それぞれ(Mean±SD) 0.0294±0.0032, 0.0139±0.0021, 0.0145±0.0041で, 4時間停滞率は9±3%であった.慢性肝炎では正常対照群に比較して, mの減少と4時間停滞率の増加に有意差を認めた.溶血性貧血では移行率, 4時間停滞率ともほぼ正常であった.またGilbert症候群では, a,mの減少,bおよび4時間停滞率の著明な増加を示した.フェノバルビタールの投与で, Gilbert症候群の血漿ビリルビンクリアランスの改善効果を認めた.一方PCB中毒症ではビリルビン代謝の亢進が示唆された.

The purpose of this study was to compare the endoscopic findings based on the general rules for recording endoscopic findings on esophageal varices by the Japanese Research Society for Portal Hypertension with liver function tests including serum bile acids and bile acid clearance tests in 64 patients with liver cirrhosis. Cases of esophageal varices showed significantly higher serum bile acid levels and greater ICG retention than those without esophageal varices. The oral ursodeoxycholic acid tolerance test was significantly impaired in the group with esophageal varices (p less than 0.05). In cases with esophageal varices, there was no significant difference in serum bile acid levels between white and blue varix patients, while serum bile acid levels in the red-color sign-positive group were significantly higher than those in the negative group (p less than 0.01). Serum bile acid levels increased in parallel with the form of varices as reflected by the shape and size of varices and with the location of varices which reflects the longitudinal-extent of varices. These results indicate that the impaired clearance of serum bile acids in liver cirrhosis is closely related with the red-color sign on the variceal surface and with the form and location of esophageal varices, which may reflect the grade of portal-systemic shunting.

Plasma levels of pyridoxal-5'-phosphate (PLP) in cirrhotic patients were significantly lower than in control subjects. However, the plasma total pyridoxal level and urinary 4-pyridoxic acid excretion were not decreased in non-alcoholic patients but in alcoholic patients. In the latter, the percentage of apo alanine aminotransferase was not related to the plasma PLP level, but was significantly correlated with plasma total pyridoxal level and urinary 4-pyridoxic acid excretion. We conclude that alcoholic cirrhotic patients have vitamin B6 deficiency, which is at least responsible for low serum alanine aminotransferase activity.

Following overnight fasting, biliary levels of squalene, bile salts, cholesterol and phospholipid were estimated using human bile obtained with a duodenal double lumen catheter after administration of caerulein. While the squalene level in B-bile was 6.86 microM in the control group, it fell significantly in patients with parenchymal liver diseases, especially liver cirrhosis. There was no significant change in the level in patients with cholelithiasis. Biliary squalene concentration showed a significant correlation with concentrations of bile salts, cholesterol and phospholipid. These results substantiate the possibility that the biliary squalene level reflects sterol metabolism in the liver.

慢性肝炎活動型24例に約1年間副腎皮質ホルモン療法を行い,非投与群20例と対比検討した.副腎皮質ホルモン投与群は早期より種々の生化学検査の改善が認められ,とくにγグロブリンの改善が著明であった.副腎皮質ホルモンはガラクトースおよびビリルビン代謝能を有意に改善させたが,トルブタマイド代謝能には影響を及ぼさなかった.肝組織像は門脈域の細胞浸潤,肝細胞変性,Kupffer細胞動員に改善を認めたが,肝線維化は不変であった.副腎皮質ホルモン投与中に発症した糖尿病,消化性潰瘍は軽症であった.以上の成績は副腎皮質ホルモンによる肝間葉系反応の抑制と肝実質細胞の機能亢進にもとづくことが示唆された.

Fasting plasma caffeine concentrations, plasma levels of catecholamines and plasma renin activity were measured in patients with cirrhosis and control patients without hepatic dysfunction. A careful dietary history showed no significant difference in caffeine consumption (mean ± S.E.) among 46 cirrhotics (86 ± 7 mg per day) vs. 34 control patients (91 ± 8 mg per day). Fasting plasma caffeine concentrations, however, were significantly higher (7.68 ± 1.42 μg per ml) in cirrhotics than in controls (1.01 ± 0.20 μg per ml) (p < 0.01). Fasting plasma caffeine concentrations in cirrhotics varied significantly with Child's criteria, namely Child's A patients (2.06 ± 0.38 μg per ml); Child's B patients (6.92 ± 1.86 μg per ml), and Child's C patients (17.70 ± 3.65 μg per ml) (p < 0.001). In 44 cirrhotics, fasting plasma caffeine concentrations were compared with plasma levels of catecholamines and plasma renin activity. Plasma epinephrine concentrations were normal; however, plasma norepinephrine concentrations were increased in six cirrhotics, and plasma renin activities were increased in 28 cirrhotics. After a 3-day caffeine abstinence, plasma caffeine concentration and renin activity were significantly decreased (p < 0.01), and high plasma norepinephrine levels were also decreased in 12 cirrhotics. Plasma caffeine concentration, renin activity and norepinephrine level did not change in a control group of cirrhotics who continued to receive caffeine for 3 days (n = 6). After abstinence from caffeine, the decrease of fasting plasma caffeine concentration correlated well with the decrease of plasma renin activity (r = +0.746, p < 0.01). These results suggest that high levels of plasma renin activity and norepinephrine in cirrhosis are in part related to habitual intake of beverages with caffeine.

Investigation of granulocyte collagenase and cathepsin B activities in 53 patients with cancer of various digestive organs revealed that total collagenase, active collagenase and cathepsin B activities were found to be higher than normal. The mean total collagenase activity in patients with cancer of the stomach, pancreas or liver was significantly higher than control values. The mean active collagenase activity in patients with cancer of the colon or liver was also significantly higher than control values. The mean cathepsin B activity in patients with cancer of the esophagus, colon or pancreas was significantly higher than control values. Active collagenase activity increased in advanced stage cases. Cathepsin B activity correlated significantly with active collagenase activity, but not with total collagenase activity, supporting the hypothesis that collagenases might be activated by cathepsin B. These results suggest that granulocyte collagenolytic enzymes, stimulated by some factors released from tumor cells, facilitate the invasion of tumor cells.

Serum lysyl oxidase activity was examined in patients with various liver diseases. The activity of the enzyme was detected mainly in the serum fraction of the supernatant 80% saturated with (NH4)2SO4, and its molecular weight was estimated to be about 30,000 by Sephadex G-150 column filtration. Mean serum lysyl oxidase activity in 18 healthy controls was 129 +/- 50 (+/- SEM) cpm/ml and was significantly increased in patients with acute hepatitis, chronic active hepatitis, alcoholic liver disease and primary biliary cirrhosis, but not in those with chronic inactive hepatitis or liver cirrhosis. Serum lysyl oxidase activity was not correlated with the histological grade of hepatic fibrosis, but appeared to reflect active hepatic fibrogenesis in patients with liver diseases.