Treatment with recombinant IL-2 for recurrent respiratory infection in a case of cartilage-hair hypoplasia with autoimmune hemolytic anemia.
Explore the source record for details and available documents.
Anemia, Hemolytic, Autoimmune↗
Biomedical subjects
M Shima
Publications and source records attributed to M Shima.
Mutation analysis of two Japanese patients with Fanconi-Bickel syndrome.
Fanconi-Bickel syndrome (FBS), or glycogen storage disease type XI, is a rare autosomal recessive disorder characterized by hepatorenal glycogen accumulation, Fanconi nephropathy, and impaired utilization of glucose and galactose. Recently, this disease was elucidated to link mutations in the glucose transporter 2 (GLUT2) gene. Only three mutations in three FBS families have been reported. Therefore, it is important to elucidate mutations in the GLUT2 gene in FBS by answering the question of whether the syndrome is a single gene disease. In this report, we describe two patients in two unrelated families clinically diagnosed with FBS. No mutation in the entire protein coding region of the GLUT2 gene was detected in patient 1, which suggested that no mutation existed in the GLUT2 gene, or that some mutations had affected the expression of the GLUT2 gene. In patient 2, a novel homozygous nonsense mutation (W420X, Trp at codon 420 to stop codon) was detected. These results support the correlation between GLUT2 gene mutation and FBS syndrome. However, many patients must be analyzed to determine whether other genes are involved in FBS.
Adult↗
Acquired haemophilia in recipients of depot thioxanthenes.
We present two cases in which the occurrence of acquired haemophilia is associated with the use of depot preparations of the thioxanthenes zuclopenthixol and flupenthixol. These drugs have not previously been implicated in the aetiology of acquired haemophilia.
Adult↗
Effect of outdoor and indoor nitrogen dioxide on respiratory symptoms in schoolchildren.
BACKGROUND: Nitrogen dioxide (NO(2)), an oxidant gas that contaminates both outdoor and indoor air, is considered to be a potential risk factor for asthma. We investigated concurrently the effects of outdoor and indoor NO(2) on the prevalence and incidence of respiratory symptoms among children. METHODS: A cohort study was carried out over 3 years on 842 schoolchildren living in seven different communities in Japan. Indoor NO(2) concentrations over 24 hours were measured in both winter and summer in the homes of the subjects, and a 3-year average of the outdoor NO(2) concentration was determined for each community. Respiratory symptoms were evaluated every year from responses to questionnaires. RESULTS: The prevalence of bronchitis, wheeze, and asthma significantly increased with increases of indoor NO(2) concentrations among girls, but not among boys. In neither boys nor girls were there significant differences in the prevalence of respiratory symptoms among urban, suburban, and rural districts. The incidence of asthma increased among children living in areas with high concentrations of outdoor NO(2). Multiple logistic regression analysis showed that a 10 parts per billion (ppb) increase of outdoor NO(2) concentration was associated with an increased incidence of wheeze and asthma (odds ratios [OR] = 1.76, 95% CI : 1.04-3.23 and OR = 2.10, 95% CI : 1.10-4.75, respectively), but that no such associations were found with indoor NO(2) concentration (OR = 0.73, 95% CI : 0.45-1.14 and OR = 0.87, 95% CI : 0.51-1.43, respectively). CONCLUSIONS: These findings suggest that outdoor NO(2) air pollution may be particularly important for the development of wheeze and asthma among children. Indoor NO(2) concentrations were associated with the prevalence of respiratory symptoms only among girls. Girls may be more susceptible to indoor air pollution than boys.
Air Pollutants↗
Mechanism for the development of ovarian cysts in patients with congenital lipoid adrenal hyperplasia.
OBJECTIVE: Although ovarian cysts commonly occur in patients with congenital lipoid adrenal hyperplasia (CLAH), the mechanism of development remains to be determined. To clarify the pathogenesis of the ovarian cysts, endocrinological examinations were performed in patients with CLAH. METHODS: The subjects were three Japanese CLAH patients. Basal body temperature, serum and urinary gonadotropin levels, serum and/or urinary ovarian hormones and mutations of the steroidogenic acute regulatory protein (StAR) gene were examined. RESULTS: The basal body temperature was not biphasic in any patient. Basal LH levels were high in all CLAH patients and markedly responded to LH-releasing hormone in two patients. Urinary gonadotropin analysis revealed repetitive LH surges in the menstrual cycles of the CLAH patients. No increase in the urinary pregnanediol suggested anovulation in all patients, and bilateral ovarian cysts were found in two of the subjects. Examination of the StAR gene revealed a frameshift mutation 840delA at codon 238, a nonsense mutation Q258X at codon 258, a homozygotic mutation at Q258X, and a compound heterozygotic mutation with 251insG and Q258X. CONCLUSIONS: We concluded that the development of ovarian cysts may be derived from continued anovulation in CLAH patients. Elevated LH levels may be explained by increased sensitivity of the anterior pituitary to circulating estrogen.
Adolescent↗
Pharmacokinetics, prophylactic effects, and safety of a new recombinant FVIII formulated with sucrose (BAY 14-2222) in Japanese patients with hemophilia A.
A clinical trial of BAY 14-2222, a recombinant factor VIII preparation (rFVIII) manufactured by new purification and formulation processes using sucrose as a stabilizer instead of human serum albumin, was performed in 5 previously treated Japanese patients with severe hemophilia A. In stage I, a single dose of BAY 14-2222 and Kogenate (a currently licensed rFVIII preparation) was administered alternately in the same patients to compare the pharmacokinetics of the 2 compounds using FVIII:C (FVIII clotting activity) as the measure of plasma drug levels. The normalized area under the curve (AUCnorm) and normalized maximal concentration (Cmax,norm) were slightly lower following the administration of BAY 14-2222 than those after the administration of Kogenate (ratio of BAY 14-2222/Kogenate:AUCnorm = 0.88, P = .050; and Cmax,norm = 0.87, P = .041). However, the biological half-life (t1/2) did not differ significantly between the 2 preparations (13.96 +/- 4.18 vs. 13.48 +/- 2.40 hours). The in vivo recovery of FVIII was 67.9 +/- 11.3% after the administration of BAY 14-2222 and 74.4 +/- 5.3% after the administration of Kogenate. In stage II, BAY 14-2222 was administered regularly to the 5 patients with hemophilia at single doses of 20 to 40 IU/kg 3 times weekly for 4 weeks, and its prophylactic effect on bleeding was evaluated. Results indicated that BAY 14-2222 has a good preventive effect on bleeding. Sixty-six infusions were performed in stages I and II of this trial, and no adverse reactions related to BAY 14-2222 were observed. In addition, there were no FVIII inhibitors or antibodies to foreign proteins detected. The trial confirmed that BAY 14-2222 is similar to Kogenate with respect to t1/2 and the in vivo recovery of FVIII:C and that periodic infusions for 4 weeks can be well tolerated. In addition, it was shown that BAY 14-2222 is effective in preventing bleeding. Thus it is expected that BAY 14-2222 will exhibit a hemostatic effect comparable to that of Kogenate in patients with hemophilia A.
Adolescent↗
An alloantibody recognizing the FVIII A1 domain in a patient with CRM reduced haemophilia A due to deletion of a large portion of the A1 domain DNA sequence.
We report the development of a FVIII inhibitor in a patient with severe, cross reacting material reduced (CRM(R)) haemophilia A. The level of Factor VIII antigen (FVIII:Ag) measured by ELISA using anti-C2 monoclonal and alloantibodies was 1.9 U/dl. This baseline FVIII:Ag level was increased to 8.3 U/dl after administration of DDAVP. The anti-FVIII inhibitor titer was 2.9 Bethesda U/ml. DNA analysis showed a large deletion of the FVIII gene from exon 4 to 7, corresponding to amino acid residues 111-317 included within the A1 domain. The size of the gene deletion was approximately 28 kb. 5' and 3' breakpoints were identified by sequencing in intron 3 and intron 7, respectively. FVIII mRNA was detected in the patient's peripheral lymphocytes and the deletion spanning exon 4 to 7 was confirmed at the RNA level. Immunoprecipitation experiments using 125I labeled A1, A2 and light chain demonstrated that the inhibitor reacted only with the 54 kDa A1 domain. The inhibitor activity was more than 95% neutralized by A1 domain polypeptide. Our findings suggest a close relationship between the inhibitor epitope and the specific gene deletion with regard to the pathogenesis of the inhibitor in this patient.
Adult↗
[Development of factor VIII inhibitor in three non-hemophiliac patients].
Infrequently, inhibitors against factor VIII can develop in non-hemophiliac patients and cause serious bleeding. In the last year, we have experienced 3 non-hemophiliac patients who developed factor VIII inhibitors. Here, we describe the clinical courses of the three patients and the characteristics of the inhibitors. Case 1: A 69-year-old man underwent a partial gastrectomy because of early gastric cancer, and one month later developed signs of a bleeding tendency such as hematemesis, tarry stools and intramuscular hemorrhage. Blood coagulation tests revealed prolongation of the activated partial thromboplastin time (aPTT), which had been normal on admission. Case 2: A 78-year-old woman with no previous disease history developed generalized subcutaneous purpura. Blood coagulation tests performed on admission revealed a prolonged aPTT. Case 3: A 30-year-old man was admitted to an emergency hospital because of left intrapleural hemorrhage and liver injury caused by a traffic accident. Two months later, a hematoma developed at the site of drainage in the left chest, and blood coagulation tests revealed prolongation of the aPTT, which had been normal on admission. Plasma factor VIII procoagulant activities in cases 1, 2 and 3 were 3%, 1% and 5%, respectively. The respective factor VIII inhibitor titers were 78, 870 and 0.5 Bethesda units/ml. The immunoglobulin class and subclass of the inhibitors examined by an ELISA method were: case 1, IgG1 and 4; case 2, IgG2 and 4 (dominant); case 3, IgG4. In cases 1 and 3, the patients recovered after glucocorticoid therapy, but in case 2 the patient died of intraperitoneal hemorrhage despite receiving two courses of methylprednisolone pulse therapy. The above clinical experience suggests that patients, who develop high titers of inhibitors may be refractory to ordinary immunosuppressive therapy, and therefore more aggressive therapy such as plasma exchange and/or bypass therapy using activated prothrombin complex concentrates or an activated factor VII preparation should be considered.
Adult↗
Transient factor VIII inhibitor in a hemophilia patient after staphylococcal septic shock syndrome.
We report a transient type I factor VIII inhibitor that arose in a 30-year-old hemophilia patient just after staphylococcal septicemia. This situation usually occurs early in the course of substitution therapy with factor VIII concentrate in hemophilia patients. Although disseminated intravascular coagulation and acute respiratory distress syndrome developed after septic shock, the patient recovered following intravenous administration of antibiotics (meropenem and gentamycin), an antithrombin preparation, high-dose methylprednisolone, and recombinant factor VIII concentrate (rFVIII). During this therapy, however, activated partial thromboplastin time gradually lengthened. On the seventh day of hospitalization, intracranial hemorrhage occurred with right hemiplegia, even though the substitution therapy had continued at the same dosage (30 U/kg per day) of rFVIII. At that point, 4 Bethesda units of the type I inhibitor against factor VIII were detected in the plasma. Increased amounts (46 U/kg per day) of rFVIII and prednisolone were administered, and hypothermic therapy was initiated. Following these treatments, the patient's general condition gradually improved, and within 25 days the inhibitor titer dropped to undetectable levels and did not recur during treatment. These clinical findings suggest that the staphylococcal septic shock may have acted as a trigger in the development of transient factor VIII inhibitor in this patient.
Adult↗
Role of factor VIII C2 domain in factor VIII binding to factor Xa.
Factor VIII (FVIII) is activated by proteolytic cleavages with thrombin and factor Xa (FXa) in the intrinsic blood coagulation pathway. The anti-C2 monoclonal antibody ESH8, which recognizes residues 2248-2285 and does not inhibit FVIII binding to von Willebrand factor or phospholipid, inhibited FVIII activation by FXa in a clotting assay. Furthermore, analysis by SDS-polyacrylamide gel electrophoresis showed that ESH8 inhibited FXa cleavage in the presence or absence of phospholipid. The light chain (LCh) fragments (both 80 and 72 kDa) and the recombinant C2 domain dose-dependently bound to immobilized anhydro-FXa, a catalytically inactive derivative of FXa in which dehydroalanine replaces the active-site serine. The affinity (K(d)) values for the 80- and 72-kDa LCh fragments and the C2 domain were 55, 51, and 560 nM, respectively. The heavy chain of FVIII did not bind to anhydro-FXa. Similarly, competitive assays using overlapping synthetic peptides corresponding to ESH8 epitopes (residues 2248-2285) demonstrated that a peptide designated EP-2 (residues 2253-2270; TSMYVKEFLISSSQDGHQ) inhibited the binding of the C2 domain or the 72-kDa LCh to anhydro-FXa by more than 95 and 84%, respectively. Our results provide the first evidence for a direct role of the C2 domain in the association between FVIII and FXa.
Amino Acid Sequence↗
Use of surface plasmon resonance for studies of protein-protein and protein-phospholipid membrane interactions. Application to the binding of factor VIII to von Willebrand factor and to phosphatidylserine-containing membranes.
The surface plasmon resonance phenomenon is used for real time measurements of protein-protein and protein-membrane interactions. In the present study two surface plasmon resonance-based binding assays permitting study of the interaction of coagulation factor VIII (fVIII) with von Willebrand factor (vWf) and phospholipid have been developed. These interactions of fVIII are required for maintenance of fVIII concentration in circulation and for the assembly of the functional factor Xase complex, respectively. With these binding assays, the role of the light chain (LCh) in fVIII binding to vWf and to immobilized phospholipid monolayers and intact vesicles containing 25% phosphatidylserine (PS) and 4% PS was examined. The finding that Kd of LCh binding to vWf (3.8 nM) is 9.5 times higher than that of fVIII (0.4 nM), indicates that the heavy chain (HCh) is required for the maximal affinity of fVIII for vWf. In contrast, affinities of LCh for 25/75 PS/phosphatidylcholine (PC) monolayers and 4/76/20 PSPC-phosphatidylethanolamine (PE) vesicles are similar to that of fVIII, indicating that LCh is solely responsible for these interactions. It was also examined how removal of the acidic region affects the binding affinity of the remaining part of LCh for vWf and phospholipid. It was demonstrated that the loss of the LCh acidic region upon thrombin cleavage leads to an 11 and 160-fold increase in the dissociation rate constant (k(off) value) and a 165 and 1500-fold increase in the Kd value of the binding of fVIII fragment A3-C1-C2 to vWf compared to that of LCh and fVIII, respectively. In contrast, the binding affinity of A3-C1-C2 for PS-containing membranes was 8-11-fold higher than that of LCh. Possible conformational change(s) in C2 domain upon removal of the acidic region were studied using anti-fVIII monoclonal antibody NMC-VIII/5 with an epitope within the C2 domain of LCh as a probe. The determined lower binding affinity of A3-C1-C2 for NMC-VIII/5 immobilized to a sensor chip than that of LCh, indicates that these conformational changes do occur.
Antibodies, Monoclonal↗
Mapping of the minimal domain encoding a conformational epitope by lambda phage surface display: factor VIII inhibitor antibodies from haemophilia A patients.
Haemophilia A patients who receive repeated transfusion of fVIII concentrates often develop inhibitor alloantibodies, resulting in reduced efficacy of the therapy. Determination of fVIII epitopes for the alloantibodies is essential for an understanding of their inhibitory effect on blood coagulation. Random fragments of fVIII displayed on lambda phage particles were selected using two patient plasmas immobilized onto the surface of a microtiter plate. A set of clones defined the minimal domain that consisted of 157 amino acid residues including cysteine at both boundaries. The minimal domain absorbed most of the binding activities of the plasmas to fVIII, suggesting that the domain contains a major determinant for the plasmas. Site-directed mutagenesis and chemical denaturation of the domain confirmed that a tertiary structure formed by the disulfide bridge was recognized by the antibodies. The epitope domain defined overlaps with fVIII binding sites to vWf and phospholipid, and may play an important role in blood coagulation. Thus, the bacteriophage lambda surface display may be useful for mapping the minimal folding domain of various protein antigens that contain a conformational epitope.
Absorption↗
Role of activation of the coagulation factor VIII in interaction with vWf, phospholipid, and functioning within the factor Xase complex.
Blood coagulation factor VIII (fVIII) in its nonactivated form circulates in plasma in a complex with von Willebrand factor (vWf). Upon activation by thrombin- or factor Xa-mediated site-specific proteolysis, activated fVIII (fVIIIa) serves as a cofactor for factor IXa. This protein complex assembled on a phospholipid surface (factor Xase) activates factor X. This complex plays the key role in the intrinsic pathway of blood coagulation. We reviewed the molecular events triggered by fVIII activation, which are required for the assembly and functioning of the Xase complex, including fVIIIa dissociation from vWf and a significant increase of fVIII affinity for binding to the phospholipid surface. Both events are mediated by activation-related cleavage within fVIII light chain (LCh), releasing the 40 amino-acid N-terminal LCh peptide, which is followed by a conformational change within the C2 domain. The conformational change within LCh is also required for the optimal fVIII cofactor functioning within the factor Xase complex, exerted via fVIIIa interactions with phospholipid, factor IXa, and factor X. Since factor IXa not only stabilizes but also proteolytically inactivates fVIIIa within the factor Xase complex, the stability of the membrane-bound fVIIIa in the presence and absence of factor IXa is discussed. In conclusion, we outline some new possible directions of the research. One of them arises from the recently demonstrated ability of plasma lipoproteins to provide a phospholipid surface for the assembly of the factor Xase complex in vitro. This finding raises a possibility that lipoproteins participate in factor Xase functioning in vivo and suggests a direct link between elevated levels of lipoproteins associated with atherosclerosis and increased thrombogenicity associated with this disease.
Cysteine Endopeptidases↗
Histocompatibility antigens and alleles in Japanese haemophilia A patients with or without factor VIII antibodies.
We carried out human leukocyte antigen (HLA)-A, B, Cw, DR and DQ serological typing and HLA-DQA1, DQB1, DRB1 and DPB1 genetic typing for 46 Japanese haemophilia A patients, including 20 who had developed an antibody to factor VIII. It appears that anti FVIII inhibitor formation is associated with the major histocompatibility complex in Japanese haemophilia A patients. Absence of HLA-A24 is a principal risk factor for inhibitor formation in Japanese haemophilia A patients. As supplemental risk factors, HLA-DR4.1, DQ4 and DQA1*0301=2 are positively associated with patients exhibiting inhibitor compared with normal subjects. This and previous studies show that the association between HLA antigens and the formation of inhibitor depends on race. Data of HLA typing may be useful for the recognition of groups at high risk for the possible formation of inhibitor among Japanese haemophilia A patients.
Alleles↗
Identification of a factor VIII peptide, residues 2315-2330, which neutralizes human factor VIII C2 inhibitor alloantibodies: requirement of Cys2326 and Glu2327 for maximum effect.
Factor VIII (FVIII) inhibitor alloantibodies react with combinations of the A2, C2 and A3-C1 domains of the FVIII molecule. Some inhibitors block binding of FVIII to both von Willebrand factor (VWF) and phospholipid, and recognize a C2 domain epitope which overlaps both binding sites. In order to determine the essential binding regions for alloantibodies inhibitory for FVIII activity, we have performed inhibitor neutralization assays and competitive inhibition assays using 10 overlapping synthetic peptides spanning the carboxy-terminal region of the C2 domain (residues 2288-2332). We found one peptide (2315-2330, L9) which neutralized the anti-FVIII activity of four out of five different C2 alloantibodies by 50%, 39%, 47% and 57%, respectively. Neutralization of these alloantibodies by recombinant C2 domain (residues 2173-2332) was 68%, 50%, 59%, 86% and >95%, respectively. The inhibitor which was not neutralized by L9 peptide and reacted by immunoblotting with peptide 2218-2307, did not prevent binding of FVIII to VWF and only partially inhibited binding of FVIII to phosphatidylserine. Mutants of the L9 peptide were prepared in which each residue from 2315-2330 was sequentially substituted by glycine. Inhibitor neutralization experiments using these peptides demonstrated that Arg2320 and Cys2326 or Glu2327 are important for the effect of L9 peptide, since their substitution by glycine reduced its neutralizing effect by 60% to >90%, suggesting that they are crucial for formation of the one of the C2 inhibitor epitopes.
Amino Acid Sequence↗
No enzyme activity of 25-hydroxyvitamin D3 1alpha-hydroxylase gene product in pseudovitamin D deficiency rickets, including that with mild clinical manifestation.
Pseudovitamin D deficiency rickets (PDDR) is an autosomal recessive disorder caused by defect in the activation of vitamin D. We recently isolated 25-hydroxyvitamin D3 1alpha-hydroxylase gene and identified four homozygous inactivating missense mutations in this gene by analysis of four typical cases of PDDR. This disease shows some phenotypic variation, and it has been suspected that patients with mild phenotypes have mutations that do not totally abolish the enzyme activity. To investigate the molecular defects associated with the phenotypic variation, we analyzed six additional unrelated PDDR patients: one with mild and five with typical clinical manifestation. By sequence analysis, all six patients were proven to have mutations in both alleles. The mutations varied, and we identified four novel missense mutations, a nonsense mutation, and a splicing mutation for the first time. The patient with mild clinical symptoms was compound heterozygous for T321R and a splicing mutation. The splice site mutation caused intron retention. Enzyme activity of the T321R mutant was analyzed by overexpressing the mutant 1alpha-hydroxylase in Escherichia coli cells to detect the subtle residual enzyme activity. No residual enzyme activity was detected in T321R mutant or in the other mutants. These results indicate that all of the patients, including those of mild phenotype, are caused by 1alpha-hydroxylase gene mutations that totally abolish the enzyme activity.
25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
Analysis of the treatment of acute myocardial infarction using ambulance records in Japanese cities.
By means of ambulance records, the current state of medical services for the treatment of acute myocardial infarction (AMI) was investigated in Chiba City and Ichihara City, Japan. From all patients transported by ambulance personnel in 1992 (n=31,191), 388 patients who were admitted within 2 weeks after the onset were studied. Types of admitting institution, diagnoses, medical treatments and prognoses were investigated. According to medical records, 168 patients fulfilled the criteria of definite AMI and were admitted alive. Percutaneous transluminal coronary angioplasty (PTCA) and recanalization (PTCR) were performed on 54 and 6 patients, respectively. The hospital case-fatality rates were lower in the patients who underwent emergency PTCA or PTCR than in the others. Emergency PTCA or PTCR, and admission to coronary care units (CCU) or institutions equipped with coronary angiography, decreased the fatality risk, even after considering age, sex, and disease severity. These results show the importance of the selection of institutions for AMI patients. Because 40% of definite AMI patients were sent to institutions without CCU, it is essential that enough CCU are available through an improvement in cooperation between the various types of institutions, and in the proper transfer of AMI patients to CCU
Adult↗
[Present situation of medical care for foreigners at medical facilities in Chiba City].
OBJECTIVE: The number of foreigners residing in Japan has increased during the past decade. The aim of this survey was to clarify the present situation and the disadvantages in the medical care for foreigners. METHODS: In October 1997, we mailed a questionnaire to all clinics and hospitals in Chiba City. The questionnaire included questions regarding the number of foreign patients who visited during the past three months, the proportion of patients who have any health insurance, procedures for handling foreign patients, and the disadvantages in medical care for them. RESULTS: Of the 210 respondents (183 clinics and 27 hospitals), 133 facilities (63.3%) provided medical care for foreign patients during the past three months, and 187 (89.0%) during the past year. In 102 facilities (76.7%), the number of foreign patients was fewer than 10 during the past three months. The mean number of foreign patients was 13.8 per facility (12.2 per clinic, and 23.5 per hospital). Of these foreign patients, 68.6% had any health insurance. In 172 facilities (81.9%), foreign patients were accepted in the same way as the Japanese. The main disadvantages in medical care for foreigners were difficulty in understanding because of communication problems, and default in payment of medical expenses for the foreigners with no health insurance. In 154 facilities (73.3%), no special preparation to communicate with foreign patients was provided, and few facilities could understand foreign languages except for English. In 20 facilities, fees for medical care had been left unpaid by foreign patients during the past year, and the total outstanding amount was about 23,800,000 yen. CONCLUSION: In Chiba City, many medical facilities provide medical care for foreign patients. This study suggests that support for communication with foreigners and compensation for default in medical expenses are necessary.
Communication↗