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Biomedical subjects

S Higuchi

Publications and source records attributed to S Higuchi.

At least 379 records · Page 21Linked to original sources
PubMed1992

Molecular and phylogenetic analysis of calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit genes.

In the mammalian brain, there are multiple catalytic subunits for the Ca(2+)- and calmodulin-dependent protein phosphatase [also called protein phosphatase 2B (PP-2B) and calcineurin] that are derived from two structural genes. The coding sequences of these two genes are distinguished by the absence (PP2B alpha 1) or the presence (PP2B alpha 2) of an amino terminus containing polyproline. Both of these genes can produce intragenic isoforms through alternative splicing. In the present study, a potential phylogenetic relationship of these genes was inferred from analysis of genomic DNA and from studies of mRNA and protein expression. Southern blot analysis showed unique restriction fragments for both genes in seven mammalian species; however, in organisms from two nonmammalian vertebrates (chicken and lizard), hybridization was observed only for PP2B alpha 1. In agreement with these results, Northern blots of mammalian brain RNA showed transcripts for both genes, with about two to three times more of the PP2B alpha 1 mRNAs, whereas in chicken and lizard, only PP2B alpha 1 transcripts were detected. An analysis of protein expression by two-dimensional electrophoresis was also consistent with these findings. For the purified mammalian brain protein, eight to ten variants were observed with isoelectric points of 5.2-5.8; immunoblot analysis using anti-peptide antibodies indicated that the majority of these were PP2B alpha 1 forms. In chicken brain, multiple isoforms were recognized by antibodies against the PP2B alpha 1 forms, but no reactivity was seen with those against the PP2B alpha 2 forms. Taken together, these findings suggest that: (i) in mammals, the predominant catalytic subunit isoforms in brain are PP2B alpha 1 products and (ii) the gene for the polyproline-containing catalytic subunit of calmodulin-dependent phosphatase (PP2B alpha 2) may have evolved after the avian/reptilian branching point, perhaps to carry out a role(s) of particular significance in mammals.

Animals↗
PubMed1992

Influence of age and co-medication on steady-state carbamazepine serum level-dose ratios in Japanese paediatric patients.

The effects of age and co-medication on steady-state carbamazepine (CBZ) level-dose (L/D) ratios were evaluated retrospectively in 370 paediatric patients. The CBZ L/D ratio increased significantly with age up to 15 years in patients on monotherapy (L/D = 0.051 x AGE + 0.334, n = 111, r = 0.593, P less than 0.001). Associated anti-epileptic therapy affected the CBZ L/D ratio, which was significantly reduced in patients on polytherapy as compared to patients on monotherapy. The study therefore suggests that routine monitoring of CBZ serum levels is extremely useful, especially in the paediatric age group, and in patients who require associated anti-epileptic medication.

Adolescent↗
PubMed1992

Influence of age and co-medication on steady-state phenobarbital serum level-dose ratios in Japanese paediatric patients.

The effects of age and co-medication on steady-state phenobarbital (PB) level-dose (L/D) ratios were evaluated retrospectively in 539 paediatric patients. The PB L/D ratio increased significantly with age up to 15 years. Associated anti-epileptic therapy affected the PB L/D ratio, which was significantly increased in patients on polypharmacy as compared to patients on monopharmacy. Therefore, routine monitoring of PB serum levels is extremely useful, particularly in the paediatric age group, and in patients who require associated anti-epileptic medication.

Adolescent↗
PubMed1992

Recombinant human granulocyte-colony-stimulating factor in the treatment of patients with chronic benign granulocytopenia and congenital agranulocytosis (Kostmann's syndrome).

Seven patients with chronic benign granulocytopenia and nine patients with congenital agranulocytosis, received consecutive seven-day courses of recombinant human granulocyte-colony stimulating factor at a starting dose of 50 micrograms/m2/day, subcutaneously. If there was no response the doses were increased to 300 micrograms/m2. All patients with chronic benign granulocytopenia responded rapidly at the minimum dose within 1-3 days after administration. By contrast, only three of the nine patients with congenital agranulocytosis responded within 1-7 days at this dose. Four patients with congenital agranulocytosis showed a response between days 7-19 at a dose of granulocyte-colony-stimulating factor 100-200 micrograms/m2 but in the remaining two cases no response was obtained. The administration of granulocyte-colony-stimulating factor was shown to be safe and effective also in reducing infectious episodes in these patients. Previously it was reported that granulocyte-colony-stimulating factor 10-30 micrograms/kg/day was effective for patients with congenital agranulocytosis. These results indicate that patients with congenital agranulocytosis may require much higher doses of recombinant human granulocyte-colony-stimulating factor than patients with chronic benign granulocytopenia and that the response to ordinary doses of recombinant human granulocyte-colony-stimulating factor may be useful in differentiating between chronic benign granulocytopenia and congenital agranulocytosis.

Adolescent↗
PubMed1992

Phenobarbitone population pharmacokinetics from routine clinical data: role of patient characteristics for estimating dosing regimens.

Routine clinical pharmacokinetic data collected from patients receiving phenobarbitone have been analysed to evaluate the role of patient characteristics for estimating dosing regimens. The data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The pharmacokinetic model of phenobarbitone was described using a one-compartment steady-state model. The effect of a variety of developmental and demographic factors on clearance was investigated. NONMEM estimates indicated a nonlinear function of total body weight as the optimum adjustment of phenobarbitone clearance. Concomitant administration of phenobarbitone and other antiepileptic drugs showed a decrease of phenobarbitone clearance in young children. The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the steady-state concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring.

Adolescent↗
PubMed1992

Digoxin population pharmacokinetics from routine clinical data: role of patient characteristics for estimating dosing regimens.

Routine clinical pharmacokinetic data collected from patients receiving digoxin have been analysed to evaluate the role of patient characteristics for estimating dosing regimens. The data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The pharmacokinetic model of digoxin was described using a one-compartment steady-state model. The effect of a variety of developmental and demographic factors on clearance was investigated. NONMEM estimates indicate that digoxin clearance was influenced by the demographic variables of age, total body weight, serum creatinine and sex. The interindividual variability in digoxin clearance was modelled with additive error with an estimated standard deviation of 46.15 L day-1 and the intraindividual variability, or residual error was 0.209 ng mL-1. The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the steady-state concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring.

Aged↗
PubMed1992

Clinical management of boric acid ingestion: pharmacokinetic assessment of efficacy of hemodialysis for treatment of acute boric acid poisoning.

Seven hours after suicidal ingestion of about 21 g of boric acid, a 26-year-old female admitted to our hospital in a state of slightly impaired consciousness, with frequent vomiting, shivering, fever and skin flush. Immediately, gastric lavage, followed by administration of activated charcoal and laxative (MgSO4), was performed. In order to ensure her urination, fluid infusion therapy was conducted with the aid of diuretics (furosemide). Since the serum concentrations of boric acid was very high, hemodialysis was carried out twice during the first 39 h. She responded well to the above mentioned treatment and was discharged 12 d post-admission without any sequelae. The concentrations of boric acid in serum and urine were measured in appropriate intervals with our modified Miyamoto's method, and the pharmacokinetics of boric acid were analyzed. The concentration of boric acid in serum and urine at the beginning of treatment was 465 micrograms/ml and 3.40 mg/ml, respectively. The half-life of boric acid in serum was 13.46 h, whereas it was shortened to 3.76 h during hemodialysis. The total body clearance was 0.99 l/h, while it increased to 3.53 l/h by hemodialysis. The additional removal of boric acid by hemodialysis was estimated to be about 5 g. It was concluded that the hemodialysis was very useful in the treatment of boric acid poisoning, because it accelerated the elimination of boric acid about four times faster than with conventional treatment.

Acute Disease↗
PubMed1992

Pharmacoepidemiological study on adverse reactions of antiepileptic drugs.

The relationship between the occurrence of side effects (SEs) and drug factors, such as antiepileptic drugs (AEDs), daily dose, duration of treatment, drug combination pattern, total and free serum concentrations, metabolite per parent level ratio as an index of metabolism ability, and co-medicated drugs except AEDs were evaluated in 227 outpatients with epilepsy. The possible influences of certain physiological and/or the pathophysiological factors were also evaluated. SEs with 19 clinical signs were observed in 66.1% of all patients. There was no definite dose- or serum concentration-dependent increase in the incidence of SEs. Stepwise discriminant function analysis revealed that benzodiazepines (BZN) polytherapy with AEDs produced a higher incidence of somnolence and general fatigue than did any other AED or drug combination. The effects of various drug combination patterns on the incidence of SEs were also evaluated on the basis of observed frequencies. The incidence of somnolence was significantly higher in patients taking phenytoin (PHT) plus carbamazepine (CBZ) therapy, and in patients taking BZN plus either PHT, phenobarbital (PB) or CBZ therapy compared with patients taking either PHT, PB or CBZ therapy. Other responsible drug combination patterns were PHT plus valproic acid (VPA) therapy for mental function impairment, acetazolamide (AZM) polytherapy with PB or PHT for dry mouth, and CBZ plus BZN therapy for constipation. In this study, the stratifying points (occurrence limits) of SEs were detected in various variables such as the number of prescribed drugs, daily dose and serum concentrations. Interestingly, these limits are within the commonly accepted "therapeutic range" or "usual daily dose," and some of these limits shifted down when another AED was co-medicated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

The relationship between low Km aldehyde dehydrogenase phenotype and drinking behavior in Japanese.

The relationship between the low Km aldehyde dehydrogenase (ALDH2) phenotype determined by the isoelectric focusing of hair root lysates, facial flushing and alcohol drinking patterns in Japanese (N = 282) was examined. Men who had inactive ALDH2 drank significantly less alcohol than those with active ALDH2. Although the effect was less noticeable, a similar relationship was detected in women. Two types of flushing responses were determined: one due to the inactive ALDH2, the other unrelated to this variant form of the isozyme. A striking difference between these flushing types, in terms of the inhibitory influence over drinking patterns, was noted. Nearly 86% of the subjects who reported always flushing in the face were shown to have inactive ALDH2, whereas infrequent flushing and absence of flushing were associated with active ALDH2. Thus, facial flushing may be used as an indicator of ALDH2 phenotype.

Adolescent↗
PubMed1992

The effect of acculturation on drinking attitudes among Japanese in Japan and Japanese Americans in Hawaii and California.

Data from a joint Japan-U.S. collaborative study were examined to determine the relationship of acculturation to drinking attitudes among Japanese in Japan and Japanese Americans in Hawaii and California. Drinking attitudes (i.e., self-reported acceptable or appropriate levels of drinking) among ethnic groups differed significantly for the nine situations studied: (1) at a bar with friends, (2) at a party at someone else's house, (3) as a parent, spending time with small children, (4) during working hours, (5) visiting in-laws, (6) with friends at home, (7) with friends after work, (8) with people at sports events and (9) before driving a car. Factor analysis was used to determine the differences in drinking attitudes among these ethnic groups. Japanese and Japanese Americans differentiated drinking situations into different categories. The major difference between the two groups was that the Japanese associated spending time with small children with a situation appropriate for drinking, such as being with friends at home, whereas Japanese Americans associated spending time with small children with a situation inappropriate for drinking, such as before driving.

Acculturation↗
PubMed1992

The relationship between three subtypes of the flushing response and DSM-III alcohol abuse in Japanese.

This study examined the relationship between the flushing response and drinking patterns and DSM-III alcohol abuse among Japanese using data collected in the joint U.S.-Japan collaborative study. The flushing response was classified into the following three subtypes: typical flushing (always flushed in the face after drinking), atypical flushing (sometimes) and nonflushing (never). This study of male current drinkers showed that typical flushers drank less alcohol than did atypical and nonflushers, but there was no observed difference between the drinking patterns of atypical flushers and nonflushers. Although the relationship was less pronounced, a similar association was found for female current drinkers. The 12-month prevalence of DSM-III alcohol abuse was estimated to be highest among atypical flushers and lowest among typical flushers, with nonflushers in between for both genders. When daily alcohol consumption and other pertinent sociodemographic variables were controlled, logistic regression analyses revealed that the risk for alcohol abuse by men was approximately 3.0 times higher among atypical flushers and 1.7 times higher among nonflushers than among typical flushers. The corresponding risks for abuse by women were 7.8 (atypical flushers) and 2.8 (nonflushers) times higher. Possible explanations for these differences in drinking patterns and the risk for alcohol abuse among the three flushing subtypes and between genders are discussed.

Adolescent↗
PubMed1992

Establishment of a human T-cell line constitutively producing several eosinophil chemotactic lymphokines and their functional heterogeneity on eosinophils.

We established a T-cell line, STO-2, by human T-cell lymphoma-leukemia virus-induced transformation of normal human T cells. Partial purification with isoelectric electrophoresis revealed that STO-2 liberated several eosinophil chemotactic factors (ECF) for eosinophils from healthy individuals with different isoelectric point of PI5, PI6, PI7, PI8, and PI9. Molecular weight of all the ECF was about 30,000 to 45,000. None of the ECF except ECF-PI5 was suppressed when they were incubated with monoclonal antibodies against IL-3, IL-5, and GM-CSF together, suggesting that ECF activity of ECF-PI5 is mainly comprised of IL-3, IL-5, and GM-CSF. ECF-PI5, PI6, and PI7 also exhibited enhancing activity on ex vivo eosinophil survival whereas ECF-PI8 and PI9 failed. Expression of Fc epsilon receptor II on eosinophils was potentiated by ECF-PI6 and ECF-PI7. In contrast, expression of Fc gamma receptor III was potentiated by ECF-PI7, ECF-PI8, and ECF-PI9. ECF-PI6 could also change an eosinophilic cell line, EOL-1, to eosinophilic granule-positive cells, whereas the rest of ECF failed. The above results suggested that eosinophils attracted by an ECF exhibit their biological functions, which differ from those of eosinophils attracted by other ECF. In further experiments, the chemotactic response of eosinophils from patients with eosinophilia was compared to that of eosinophils from healthy individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Line, Transformed↗
PubMed1992

[A case of diffuse large cell lymphoma treated with combination chemotherapy of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and BEMP (bleomycin, etoposide, mitoxantrone, procarbazine) with complete remission].

A 73-year-old man with diffuse large cell lymphoma was treated with noncross resistant alternating combination chemotherapy of CHOP and BEMP, consisting of cyclophosphamide (1,000 mg/body, i.v., day 1), doxorubicin (60 mg/body, i.v., day 1), vincristine (2 mg/body, i.v., day 1), prednisolone (100 mg/body, p.o., day 1-5), bleomycin (30 mg/body, i.v., day 22), etoposide (80 mg/body, i.v., day 22-24), mitoxantrone (6 mg/body, i.v., day 22), and procarbazine (100 mg/body, p.o., day 22-26). Following the three courses' administration of CHOP and BEMP, complete remission was obtained with a remission duration of over ten months. Leukocytopenia was a dose-limiting factor. It is concluded that noncross resistant alternating combination chemotherapy of CHOP and BEMP is effective for diffuse large cell lymphoma.

Administration, Oral↗
PubMed1991

Chromosomal mapping of the human genes for the calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit.

Multiple catalytic subunits of the Ca2+ and calmodulin (CaM)-dependent protein phosphatase (PrP) ("calcineurin" or PrP-2B) are derived from at least two structural genes, type 1 ("calcineurin A alpha") and type 2 ("calcineurin A beta "), each of which can produce alternatively spliced transcripts. To examine the possible linkage of these genes, we analyzed genomic DNA from human/hamster hybrid cell lines using probes of 122 base pairs that were designed to bind selectively to exon 3 of the open reading frame. In this region, the nucleotide sequence of the type 2 murine cDNA that we cloned was greater than 99% identical to the type 2 human cDNA but only 78% identical to the type 1 human cDNA. Hybridization to Southern blots containing DNA from all human chromosomes showed that gene 1 was found on chromosome 4, whereas gene 2 segregated to chromosome 10. These data suggest that expression of the two calcineurin genes is not physically linked.

Amino Acid Sequence↗
PubMed1991

Calmodulin-dependent protein phosphatase from Neurospora crassa. Molecular cloning and expression of recombinant catalytic subunit.

A cDNA for the catalytic subunit of a calmodulin (CaM)-dependent protein phosphatase was cloned from Neurospora crassa. The open reading frame of 1557 base pairs encoded a protein of Mr approximately 59,580 and was followed by a 3'-untranslated region of 363 base pairs including the poly(A) tail. Based on primer extension analysis, the mRNA transcript in vivo was 2403 base pairs. Expression of this CaM-protein phosphatase mRNA was developmentally regulated, being highest during early mycelial growth; production of the corresponding protein followed mRNA with a time lag of 8-12 h. Polymerase chain reaction amplification of genomic DNA revealed three small introns, the positions of which coincided with those in the mouse gene, indicating evolutionary conservation of these structures. The deduced sequence showed approximately 75% identity with the mammalian homologue, calcineurin, in aligned regions. A region of 40 amino acids preceding the CaM-binding domain was essentially unchanged, suggesting conservation of a crucial interaction site. Three small segments in the carboxyl half of the protein were unrelated to the mammalian gene and may constitute "variable regions" that confer substrate specificity to the enzyme. An active recombinant catalytic subunit was expressed in bacteria and purified by CaM-Sepharose chromatography. This preparation was stimulated 2- 3-fold by CaM and showed a p-nitrophenol phosphatase activity equal to that of the bovine brain holoenzyme, although its dephosphorylation of phosphoprotein substrates was markedly different. These findings demonstrate that the catalytic subunit of this phosphatase can exhibit high activity in the absence of its intrinsic Ca(2+)-binding subunit.

Amino Acid Sequence↗