Five- and 10-year survival rates after surgery for biliary atresia: a report from the Japanese Biliary Atresia Registry

Purpose

The aim of this study was to elucidate the epidemiology and short- and long-term results of biliary atresia in Japan analyzing the data of the Japanese Biliary Atresia Registry (JBAR).

Methods

In 1989, the Japanese Biliary Atresia Society started a nationwide registry, JBAR, to investigate all aspects of biliary atresia. A total of 1,381 patients, 863 girls, 507 boys, and 11 unknown, were registered between 1989 and 1999. JBAR includes an initial and follow-up questionnaires. Using these patients’ data, the incidence, sex distribution, associated anomalies, the type of obstruction, the type of operation, and the surgical results were evaluated. The 5- and the 10-year results of 735 patients who were registered initially in or before 1994 also were analyzed.

Results

The incidence of biliary atresia was 1 in 9,640 live births. One hundred sixty-four patients (11.9%) had type I atresia of the common bile duct, 34 (2.5%) had type II atresia of the hepatic ducts, and 1,162 (84.1%) had type III atresia at the porta hepatis. Congenital associated anomalies were found in 19.6% of the patients including 33 cases associated with polysplenia. Impact of the age at operation on bile flow was not clear until 90 days of age, and after 90 days the bile flow rate worsened. The original Roux-en-Y procedure had been used in more than 50% of the patients since 1995. In 1999, 96% of the patients underwent the original Roux-en-Y procedure or the Roux-en-Y with an intestinal valve, and only 3 patients (3.5%) underwent other modifications. There were no significant differences in either the rate of disappearance of jaundice or the incidence of cholangitis among these 3 procedures. Of the 735 patients registered in or before 1994, 19 patients (2.6%) were lost to follow-up. The 5-year survival rates of patients registered in 1989, 1990, 1991, 1992, 1993, and 1994 were 62%, 64.5%, 61.3%, 59.0%, 58.7%, and 52.7% without liver transplantation (LTx), and 69.4%, 74.2%, 75.2%, 79.5%, 78%, and 78.3% with LTx, respectively. Although the overall 5-year survival rate changed from 69.4% to 78.3%, the difference was not statistically significant. According to the 10-year follow-up results of the 108 patients initially registered in 1989, 72 (66.7%) and 57 (52.8%) survived with and without the aid of LTx, respectively.

Conclusions

The overall 5- and 10-year survival rates were 75.3% (553 of 734) and 66.7% (72 of 108), respectively. In spite of the increasing number of survivors after LTx, there was no significant improvement in the 5-year survival rate. It was shown that the JBAR system was functioning well with only 19 patients lost to follow-up among the 743 patients registered from 1989 to 1994.     

A case of pseudo-Bartter's syndrome induced by long-term ingestion of furosemide delivered orally through health tea

A 32-year-old woman with a three-year history of muscle weakness and hypokalemia, was admitted to our hospital because of hypokalemic periodic paralysis. Clinical and laboratory findings were consistent with Bartter's syndrome. Although she denied any ingestion of diuretics substantial quantities of furosemide were detected in her urine. She had been drinking health tea which contained about 90 mg of furosemide per teabag daily for five years. Four years after discontinuation of drinking the tea, the hypokalemia was completely ameliorated, but poor renal concentration ability is still present. We conclude that is a case of pseudo-Bartter's syndrome that was caused by long-term ingestion of the health tea supplemented illegally with furosemide, and suspect that such cases may be observed more frequently than currently thought.     

Germinoma with syncytiotrophoblastic giant cells recurring 13 years after radiotherapy for a pineal germinoma--case report

A 28-year-old man presented with progressive mental deterioration. Thirteen years earlier he had undergone radiation therapy for a pineal germinoma. Neuroimaging showed a homogeneously enhanced mass lesion along the ventricular wall. The cerebrospinal fluid (CSF) level of human chorionic gonadotropin (HCG) was high. Endoscopic biopsy revealed that the tumor was a two-cell pattern germinoma. The diagnosis was germinoma with syncytiotrophoblastic giant cells (STGC). He first received three cycles of chemotherapy with carboplatin and etoposide and then two cycles with ifosfamide, cisplatin, and etoposide. Subsequently, the tumor size decreased markedly and the CSF level of HCG returned to normal. However, he died 22 months after the recurrence. Histological verification and measurement of tumor markers are necessary for the optimum treatment of germ cell tumors. Adequate initial chemotherapy and long-term follow up are essential for patients with germinoma with STGC.     

Quantification of the isomerization of Asp residue in recombinant human alpha A-crystallin by reversed-phase HPLC

A method for determining the isomerization of Asp residues in proteins is described and demonstrated by quantifying the isomerization of Asp(151) in recombinant human alphaA-crystallin. First, four types of dodecapeptide fragment ((146)IQTGLD(151)ATHAER(157)) in which the Asp residue was either L-Asp, D-Asp, L-isoAsp or D-isoAsp were synthesized, and RP-HPLC conditions were established for their separation. Next, the Asp(151)-containing peptide fragments isolated from the tryptic hydrolysate of recombinant alphaA-crystallin were analyzed under these conditions. New peaks, the retention times of which were the same as those of peptides containing D-Asp, L-isoAsp and D-isoAsp, were generated when alphaA-crystallin was incubated for 140 days at 37 degrees C. An amino acid composition, amino acid sequence, and enantiomeric analysis revealed that two peaks with retention times identical to those of peptides containing L-isoAsp and D-isoAsp represented dodecapeptide fragments containing L-isoAsp(151) and D-isoAsp(151), respectively. RP-HPLC analysis under other condition suggested that the peak with retention time identical to that of peptide containing D-Asp represented dodecapeptide fragments containing D-Asp(151). The present method does not require acid hydrolysis, which generates further isomerization products as artifacts, and thus make possible the sensitive quantification of each type of Asp isomer individually at a specific site in a protein. In our analysis of the Asp(151) residue in human alphaA-crystallin, the degree of isomerization from L-Asp to D-Asp can be determined to a level as low as 0.3%.     

Flow injection analysis of ascorbic acid using carriers modified with metal-porphine as oxidative solid catalyses

To investigate one of practical applications of the supports modified with metal–porphines as artificial solid-catalysts, columns into which the supports were packed were supplied to catalytic columns for a flow injection analysis (FIA) system for determination of ascorbic acid (AsA) by the following reactions:

AsA+O₂→dehydoroAsA+H₂O₂, H₂O₂+chromogen→2H₂O+Dye.

Among the columns tested, the column containing silica gels modified with Co–tetrakis(carboxyphenyl)porphine catalyzed most rapidly the oxidation reaction of AsA that is accompanied by the formation of hydrogen peroxide. The resulting hydrogen peroxide was determined by FIA system equipped with the column containing glass beads modified with Mn–tetrakis(carboxyphenyl)porphine, which gave a linear calibration curve and large peak-areas of the range corresponding to AsA concentration between 0.2 and 10 μmol/ml. The results indicated that some supports modified with metal–porphine would be applicable to the FIA for AsA as the solid catalyses which function as if the immobilized enzymes.     

Synthetic decarboxylated S-adenosyl-L-methionine as a substrate for aminopropyl transferases

Synthetic decarboxylated S-adenosyl-L-methionine (dcAdoMet), a mixture of the absolute configuration of S and R at the sulfonium center, was evaluated as a substrate for the measurement of spermidine synthase activity. The diastereomers were separated by HPLC with an isocratic elution, and the constant for racemization at the sulfur was determined to be 2.4x10(-6) s(-1) at 37 degrees C and pH 1.5 for the first-eluted biologically active isomer (S-dcAdoMet) and 2.0x10(-6) s(-1) for the second-eluted biologically inactive isomer (R-dcAdoMet). The peak area ratio of S-dcAdoMet to R-dcAdoMet of 48 to 52 in HPLC supported the different racemization constants. Similar substrate activity of dcAdoMet to that of S-dcAdoMet was demonstrated by enzymatic spermidine synthesis. It was shown from the result that the racemized [methyl-(14)C]dcAdoMet prepared in this report was useful for measuring spermidine synthase activity.     

Bioinformatics research on inter-racial difference in drug metabolism I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19

The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. In the present study, the frequencies of mutant alleles and PMs in each race were analyzed based on information from published studies, considering the genetic polymorphisms of CYP2D6 and CYP2C19 as the causal factors of racial and inter-individual differences in pharmacokinetics. As a result, it was shown that there were racial differences in the frequencies of each mutant allele and PMs. The frequencies of PMs on CYP2D6 are 1.9% of Asians and 7.7% of Caucasians, and those of PMs on CYP2C19 are 15.8% of Asians and 2.2% of Caucasians. Based on the results, it was suggested that there would be racial differences in the frequencies of PM subjects whose blood concentrations might be higher for drugs metabolized by these enzymes. Additionally, it was suggested that enzyme activities would vary according to the number of functional alleles even in subjects judged to be extensive metabolizers (EMs). In the bridging study, genetic information regarding CYP2D6 and CYP2C19 of the subjects will help extrapolate foreign clinical data to a domestic population.     

Novel nonsynonymous polymorphisms of the CYP1A1 gene in Japanese

We found five novel nonsynonymous polymorphisms of the human CYP1A1 gene from Japanese individuals. The five single nucleotide polymorphisms (SNP) in exon 7 (2346_2347 ins T, 2414T>A, 2461C>T, 2500C>T and 2546C>G causing premature stop codon, Ile(448)Asn, Arg(464)Cys, and Arg(477)Trp and Pro(492)Arg, respectively) were as follows:SNP, 030212Saito001; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-GTCAACCCATCT-/TGAGTTCCTACCT-3'.SNP, 030212Saito002; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-GTGAGAAGGTGAT/ATATCTTTGGCAT-3'.SNP, 030212Saito003; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-GAGACCGTTGCCC/TGCTGGGAGGTCT-3'.SNP, 030212Saito004; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-ATCCTGCTGCAAC/TGGGTGGAATTCA-3'.SNP, 030212Saito005; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-TGGACATGACCCC/GCATCTATGGGCT-3'.     

Molecular mechanisms for the activation of Ca2+-permeable nonselective cation channels by endothelin-1 in C6 glioma cells

We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channels (NSCC-1 and NSCC-2) in C6 glioma cells. It is possible to discriminate between these channels by using the Ca(2+) channel blockers SK&F 96365 (1-[beta-(3-[4-methoxyphenyl]propoxy)-4-methoxyphenethyl]-1H-imidazole hydrochloride) and LOE 908 [(R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide]. LOE 908 is a blocker for NSCC-1 and NSCC-2, whereas SK&F 96365 is an inhibitor for NSCC-2. The purpose of the present study was to identify the G-proteins that are involved in ET-1-activated Ca(2+) channels in C6 glioma cells. ET-1 activated only NSCC-1 in C6 glioma cells preincubated with U73122 (1-[6-[((17beta)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1H-pyrrole-2,5-dione), a phospholipase C (PLC) inhibitor. Microinjection of the dominant negative mutant of G(12)/G(13) (G(12)G228A/G(13)G225A) abolished activation of NSCC-1 and NSCC-2. In contrast, pertussis toxin did not affect any of the Ca(2+) channels in the ET-1-stimulated C6 glioma cells. These results indicate that G(12)/G(13) may couple with endothelin receptors and play an important role in the activation of NSCCs in C6 glioma cells. Moreover, the activation mechanisms of NSCC-1 and NSCC-2 by ET-1 were different. NSCC-1 activation depended upon a G(12)/G(13)-dependent cascade, whereas NSCC-2 activation depended upon both G(q)/PLC- and G(12)/G(13)-dependent cascades.