Hiroko Tsuda

Anticardiolipin Antibody-Induced Sudden Profound Sensorineural Hearing Loss

INTRODUCTION A link between sensorineural hearing loss (SNHL) and autoimmune disease is postulated. The association of SNHL in a patient with systemic lupus erythematosus is reported. METHODS An adolescent female with left lateral medullary syndrome and right internuclear ophthalmoplegia was diagnosed with systemic lupus erythematosus. Treatment with prednisolone markedly improved her symptoms. Two years later, profound SNHL developed in the right ear. Extensive serologic testing was undertaken. RESULTS Serologic tests for syphilis were false-positive. Enzyme-linked immunosorbent assay to the immunoglobulin (Ig)G anticardiolipin antibody was positive. The anticardiolipin antibody is strongly correlated with episodes of recurrent venous or arterial thrombosis. CONCLUSIONS It appears that the anticardiolipin antibody may be associated with sudden profound sensorineural hearing loss in patients with autoimmune disease.

Patient preferences and experiences of CPAP and oral appliances for the treatment of obstructive sleep apnea: a qualitative analysis

ObjectivesThe aim of this study is to better understand patients’ perspectives and preferences about treatment with continuous positive airway pressure (CPAP) and oral appliance (OA) devices for obstructive sleep apnea.MethodsThe current study used qualitative analysis of four focus group sessions with current CPAP and OA users. Twenty-two participants with OSA who currently use either CPAP or OA participated in the sessions at the University of British Columbia.ResultsFive topics from the focus group sessions were descriptively analyzed using NVivo software: goals and expectations of treatment, benefits of treatment for bed partners, side effects and inconveniences of CPAP, side effects and inconveniences of OA, and factors impacting treatment choice. In order of most to least frequently mentioned, patients expressed six expectations of treatment: improved health, apnea elimination, improved sleep, reduced fatigue, reduced snoring, and bed-partner benefits. The most to least mentioned factors impacting treatment choice were device effectiveness, transportability, embarrassment, and cost.ConclusionsThis qualitative study showed that many factors impact patients’ experience with their treatment device and that their treatment needs are not only physical but also relate to their lifestyle. This preliminary study provides treatment characteristics and attributes necessary to develop a quantitative questionnaire study, to assist in the selection of therapy, weighing the relative importance of patient and OSA treatment characteristics on treatment preference and adherence. Matching therapy to patient preferences may help identify the most appropriate treatment, and this may achieve greater likelihood of adherence.

Screening for Aetiology of Thrombophilia: A High Prevalence of Protein S Abnormality

We systematically screened for the aetiology of thrombophilia in 115 patients with venous, arterial and small vessel thromboses. Forty-one patients (36% of those we examined) suffering from a variety of thromboses, including deep vein thrombosis, pulmonary embolism, arterial occlusion, cerebral infarction, Moyamoya disease and ulcerative colitis, were characterized either with positive lupus anticoagulants or with decreased activities of protein S, protein C, antithrombin III and/or plasminogen. Eight mutation sites were confirmed in 11 thrombotic patients using gene analysis. Decreased protein S activity was found with a high incidence (23 out of 115) in Japanese patients who suffered from not only venous thrombosis but also arterial and small vessel thrombosis. We emphasize here the important role of protein S in the pathogenesis of thrombosis in the Japanese population.

Deficiency of coagulation factor XIII A subunit caused by the dinucleotide deletion at the 5' end of exon III.

A congenital deficiency of the coagulation Factor XIII A subunit (F XIII A) is a rare autosomal recessive disorder that is characterized by a life-long bleeding tendency complicated by a difficulty in healing. Thus far, no molecular genetic analysis of this disorder has been reported. In this study, we demonstrate the molecular abnormalities in a family with this disorder. We performed Northern blot analysis of peripheral blood monocytes obtained from the propositus and found a 4-kb single band of F XIII A mRNA whose size was identical with that of normal subjects. Exons II-XV, which encode all the amino acids, were individually amplified by a polymerase chain reaction (PCR). All PCR products from the propositus had lengths indistinguishable from those of the wild type on agarose gel, suggesting that this defect results from either a point mutation or a short deletion/insertion. The sequencing of F XIII A cDNA from the propositus revealed a deletion of the dinucleotide AG within the AGAG repeat at the position of 210 to 213. Concerning the genomic sequence, a deletion of dinucleotide AG was also demonstrated in the intron B-exon III boundary. This deletion appeared to cause a frameshift mutation making a new stop codon shortly thereafter, and leading to a deficiency of plasma F XIII A. The heterozygosity of the F XIII A deficiency in the patients offspring was documented by the nucleotide sequences of their exon III.

Four missense mutations identified in the protein S gene of thrombosis patients with protein S deficiency: Effects on secretion and anticoagulant activity of protein S

Four missense mutations, G54R, T589I, K155E, and Y595C, were identified in the protein S (PS) gene of the patients with PS deficiency and venous thrombosis. Three patients were heterozygous for the novel mutations, G54R, T589I, and Y595C, while a remaining one patient was homozygous for the K155E mutation, which is known to be a polymorphism in the Japanese population. A family study revealed that the Y595C mutation was associated with a Type I PS deficiency and the K155E mutation with a Type II PS deficiency, while no family study was performed for the patients with the G54R and T589I mutations. To determine whether these four mutations play a causative role in PS deficiency, the four PS mutants and wild-type PS were stably expressed in human embryo kidney (HEK) 293 cells. Pulse-chase experiments showed intracellular degradation and decreased secretion of the Y595C mutant. In the activated protein C (APC) cofactor assays, the specific activity of the K155E mutant decreased to 58% of that of wild-type PS. The APC cofactor activity of the three mutants, G54R, K155E, and T589I, were inhibited by C4b-binding protein (C4BP) with a dose dependency similar to that of wild-type PS. These results indicate that the Y595C and the K155E mutations are responsible for a secretion defect and a decreased anticoagulant activity of PS, respectively. The remaining two mutations, G54R and T589I, however, did not produce any definite abnormality leading to a low plasma PS activity.

Effects of magnetic fields on fibrinolysis

In this study, we investigated the possible effects of magnetic fields on the fibrinolytic process. Fibrin dissolution was observed and the fibrinolytic activities were evaluated. First, fibrinolytic processes in magnetic fields were investigated by the fibrin plate method. We gathered solutions from the dissolved fibrin, and measured mean levels of fibrin degradation products (FDPs) in solutions. Mean levels of FDPs exposed to 8 T magnetic fields were higher than those not exposed to fields. Second, we carried out an experiment to understand how fibrin oriented in a magnetic field dissolves. FDPs in solutions of dissolved fibrins in fibrin plates were assayed. The result was that fibrin gels formed in a magnetic field at 8 T were more soluble than those not formed in a magnetic field. A model based on the diamagnetic properties of macromolecules was explained, and changes of protein concentrations in a solution in gradient magnetic fields were predicted.

Thrombophilia found in patients with moyamoya disease.

Sixteen patients with Moyamoya disease and four with quasi-Moyamoya disease were investigated in order to elucidate the presence of thrombophilia. The assay system for diagnosing thrombophilia consisted of assessing both the activity and antigen levels of antithrombin III, protein C, protein S, fibrinogen and plasminogen as well as detecting lupus anticoagulants. The analysis revealed that one third (four definite cases and three quasi-cases) of the examined patients demonstrated either congenital or acquired thrombotic tendency. Protein C deficiency was found in two definite cases and in two quasi-cases among whom one quasi-case was identified to have a hereditary type I Protein C deficiency. Protein S deficiency was found in one definite case and in one quasi-case. Type II plasminogen deficiency was found in one quasi-case, and lupus anticoagulant was present in one quasi-case. Based on these findings, an evaluation of thrombophilia should thus be performed when both diagnosing and treating suspected cases of Moyamoya disease.

A Novel Splice Acceptor Site Mutation of Protein S Gene in Affected Individuals with Type I Protein S Deficiency: Allelic Exclusion of the Mutant Gene

Sequencing studies of the protein S gene (PROS1) in a Japanese patient suffering from recurrent thrombosis revealed the following. The proband and his first daughter, but not the second daughter, were having the type I protein S (PS) deficiency due to a novel point mutation from A to G at the intronic acceptor splice site in intron 13 of the PROS1. In the affected daughter, exclusion of the aberrant allele was assessed by the BstX1 dimorphism of PROS1 at Pro626 (CCG/CCA). The reduced PS activities in the proband and his first daughter were apparently due to defective production of mRNA from the mutant allele.

Diamagnetic properties of fibrin and fibrinogen

The authors have observed that the fibrinolytic process in strong magnetic fields up to 8 T was enhanced. Here they focused on the mechanism of this phenomenon. First, they observed that gradient magnetic fields eroded a fibrin gel in a specific direction. Next the authors carried out an experiment to measure concentrations of fibrin in magnetic fields up to 8 T. They measured levels of fibrin degradation products by colorimetric determination and concluded that changes in concentrations of fibrin polymers occurred in gradient magnetic fields up to 8 T. Also, by measuring transmittance at 500 nm of fibrin gels, the authors investigated the effects of magnetically formed structures of fibrin polymers on the dissolution of fibrin gels. The magnetic orientation of fibrin remained in the fibrinolytic process after coagulating in an 8 T magnetic field. >

New quantitative total protein S-assay system for diagnosing protein S type II deficiency: clinical application of the screening system for protein S type II deficiency.

Venous thromboembolism (VTE) incidence is rising rapidly in Japan with lifestyle westernization and aging. Deficiency of protein S, an important blood coagulation regulator, is a risk factor for VTE. Protein S deficiency prevalence in Asians is approximately 10 times that in Caucasians and that of protein S type II deficiency, associated with the protein S Tokushima mutation (K155E), is quite high in Japan. However, currently available methods for measuring protein S are not precise enough for detection of this deficiency. We developed a novel assay system for precise simultaneous determinations of total protein S activity and total protein S antigen level, using a general-purpose automated analyzer, allowing protein S-specific activity (ratio of total protein S activity to total protein S antigen level) to be calculated. Mean specific activity was 0.99 for samples from healthy individuals but 0.69 or less (mean-3SD) in protein S type II-deficient and warfarin-treated samples, but was 1.0 in an estrogen-treated sample with significantly decreased protein S antigen. Protein S gene analyses in healthy individuals with specific activity 0.69 or less revealed the K155E mutation in all three. These results show our new assay system to be an effective screening tool for protein S type II deficiency. This system can also be used in an automated analyzer, facilitating numerous sample measurements, and is, thus, applicable to regular medical checkups and diagnosing VTE. Such applications would potentially contribute to early detection of protein S type II deficiency, and, thereby, to thrombosis prevention.