We studied the polymorphism of alpha1-antichymotrypsin (ACT), very low density lipoprotein receptor (VLDLR) and apolipoprotein E (ApoE) genes in 200 control subjects and 65 patients with Alzheimer's disease (AD) in Japanese. The subjects consisted of 30 patients with early onset familial Alzheimer's disease (FAD), a patient with late onset FAD, 29 patients with an early onset isolated form of AD, and 5 patients with late onset AD. ApoE genotypes were significantly different between controls and FAD (p < 0.0005) or AD (p < 0.05), and patients carrying at least one ApoE epsilon4 allele were found in 44% of FAD and 34.3% of AD; both were significantly different (p < 0.001) from the controls (12.5%). ACT genotypes and allele frequencies were not different among these groups except for genotypes between ApoE epsilon4 FAD and ApoE epsilon4 controls (p = 0.019). There was a slight but significant increase of the 5 repeat allele of VLDLR in AD (p = 0.014), but the difference was rather diminished in the presence of an ApoE epsilon4 allele. None of combinations of ACT and VLDLR genotypes in the presence or absence of an ApoE epsilon4 allele gave significant difference. Thus, we conclude that among the reported genetic risk factors, ApoE epsilon4 is the only definite risk factor for both FAD and AD, and the VLDLR polymorphism might be associated with AD cases in Japanese.

Alleles↗

PubMedDate not supplied

Production and characterization of a novel tissue-type plasminogen activator derivative in Escherichia coli.

We have created a novel thrombolytic agent by the combination of mutation with partial deletion of tissue-type plasminogen activator (t-PA). We constructed Escherichia coli expression vectors for (i) native t-PA (nt-PA) and its derivatives; (ii) K1K2P, consisting of kringle 1 (K1), kringle 2 (K2), and protease (P) domains; (iii) K2P, consisting of K2 and P domains; (iv) D-nt-PA; (v) D-K1K2P; and (vi) D-K2P. The latter three are point mutants of nt-PA, K1K2P, and K2P, respectively, in which Arg275 (number corresponds to that of nt-PA) has been mutated to Asp. The production of nt-PA and its derivatives was remarkably improved by (i) removal of the 3' noncoding region of nt-PA cDNA from expression vectors and (ii) expression in mutant E. coli derived from E. coli HB101, which is insensitive to heat-shock inductions. The proteins produced were precipitated as insoluble aggregates in the cells and were renatured to active forms by extraction with 8 M urea followed by dialysis against a redox buffer containing GSH and GSSG. The renaturation yield depended on the pH of the buffer and the number of disulfide bonds of the proteins (nt-PA << K1K2P < K2P). The mutation of Arg275 (the plasmin cleavage site) caused an increase in the catalytic enhancement by fibrin and a decrease of the interaction with plasminogen activator inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

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A prospective 5-year follow-up study on the behavioral disturbances of community-dwelling elderly people with Alzheimer disease.

The aim of the present study was to determine the longitudinal course of behavioral disturbances and to examine whether these disturbances are stage dependent during the course of Alzheimer disease (AD). One hundred seven community-dwelling patients with probable AD were assessed up to six times annually by using a validated and reliable rating scale, the Troublesome Behavior Scale, for assessing the frequencies of behavioral disturbances. The subjects were divided into three groups according to their baseline global function as assessed by the Clinical Dementia Rating (CDR; 1 = mild, 2 = moderate, 3 = severe). At the end of the 5-year observation period, 31 subjects were still active participants, 52 had died, 20 lived in institutions, and 4 had stopped participating. The patterns of their behavioral disturbance changes depended to a considerable extent on the baseline severity of the illness. The behavioral disturbance frequencies generally peaked at the CDR 2 stage and followed a downward trend thereafter. Considerable individual variations in the disturbance frequencies during the course of the illness were observed. Knowing the behavioral course of AD will enable clinicians to better counsel families and appraise the results of treatments for behavioral symptoms.

Aged↗

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Analysis of behavioral disturbances among community-dwelling elderly with Alzheimer disease.

One hundred seven community-dwelling elderly patients with Alzheimer disease were enrolled in a study to evaluate the characteristics specific to the patients' and caregivers' situations that are associated with behavioral disturbances and to examine how these disturbances are related to caregiving stress. The frequencies of the disturbance were assessed by using the Troublesome Behavior Scale according to its three categories, agitation, hyperactivity, and miscellaneous. The patients' characteristics found to contribute most to their own behavioral disturbances were visual and speech function, activities of daily living, years of education, cognitive function, and sex, whereas the caregivers' characteristics contributing to these disturbances were duration of caregiving, age of caregiver, and relationship to the patient. In addition, a mutual relation among the three categories was found. Among the three categories, agitation was most strongly related to the caregivers' psychologic health status rated by use of the General Health Questionnaire. Behavioral disturbance as a whole was the only predictor of the patient's institutionalization within 2 years after baseline examination. Thus, behavioral disturbances were found to be influenced by the personal characteristics and situational circumstances of both the patient and caregiver, influencing, in turn, the caregivers' psychologic health status.

Activities of Daily Living↗

PubMedDate not supplied

Recent progress in the development of Terumo implantable left ventricular assist system.

The research group of the Terumo Corporation, the NTN Corporation, and Setsunan University (T. Akamatsu) has been developing an implantable left ventricular assist system (ILVAS) featuring a centrifugal blood pump with a magnetically suspended impeller (MSCP). The impeller of the MSCP is suspended by a magnetic bearing, providing contact-free rotation of the impeller inside the pump housing. Thus the MSCP is expected to provide years of long-term durability. Ex vivo chronic sheep experiments using the extracorporeal model (Model I) demonstrated long-term durability, nonthrombogenicity, and a low hemolysis rate (plasma free Hb <6 mg/dl) for more than 2 years. The prototype implantable model (Model II; 196 ml, 400 g) was evaluated ex vivo in 2 sheep and intrathoracically implanted in a small sheep (45 kg). These experiments were terminated at 70, 79, and 17 days, respectively, because of blood leakage through the connector system within the housing of Model II. There was no thrombus formation on the retrieved pump surfaces. A new connector system was introduced to the Model II pump (modified Model II), and the pump was intrathoracically implanted in a sheep. Pump flow rate was maintained at 3-7 L/min at 1700-1800 rpm. The temperature elevation on the surfaces of the motor and the electromagnet inside the pump casing was kept less than 6 degrees C. The temperature of the tissue adjacent to the pump casing became normal 10 days postoperatively. The sheep survived for more than 5 months without any sign of mechanical failure or thromboembolic complication. In vitro real-time endurance tests of motor bearings made of stainless steel and silicone nitride have been conducted for more than 1 year without any sign of bearing wear. The next prototype system (Model III), with an implantable controller and a new MSCP with reduced input power, has been developed with a view toward a totally implantable LVAS.

Alanine Transaminase↗

PubMedDate not supplied

Terumo implantable left ventricular assist system: results of long-term animal study.

The research group of Terumo Corporation, NTN Corporation, and the Setsunan University have been developing an implantable left ventricular assist system (T-ILVAS) featuring a centrifugal blood pump with a magnetically suspended impeller (MSCP). The present study describes results of chronic animal experiments using the MSCP. The MSCP has been tested ex vivo and in vivo in 6 sheep as a left heart bypass between the left ventricular apex and descending aorta. Ex vivo chronic sheep experiments using Model I demonstrated long-term durability, nonthrombogenicity, low hemolysis (<6 mg/dl), and excellent stability of the magnetic bearing with long-term survival for up to 864 days. Average pump flow rate was 4 L/min at a fixed rotational speed of 2000 rpm. Power spectral analyses of heart rate, aortic pressure, and blood temperature maintained normal 1/f fluctuation during the study. The retrieved pump was completely free from thrombus formation and there was no evidence of infarct in major organs. The implantable Model II was evaluated ex vivo in two sheep and intra-thoracically implanted in a sheep. These experiments were terminated at 70, 79, and 17 days due to blood leakage through the connector system within the housing. No thrombus formation was observed in any of the retrieved pumps. A modified Model II with a new connector system was subsequently intra-thoracically implanted in a sheep. The sheep survived for 482 days without any sign of thromboembolic complication or hemolysis at a fixed rotational speed of 1700 rpm and an average pump flow rate of 5 L/min. There was no intra-device thrombus formation or infarct in major organs. The Model III system, consisting of an implantable controller and a new MSCP with a reduced input power of 13 W, has been developed and implanted in a chronic sheep model. The MSCP was implanted in the left pleural space and the controller in the abdominal wall. The experiment is still in progress for more than 30 days without any significant complication to date. These animal studies strongly suggest the feasibility of the MSCP for use as long-term circulatory assist.

Animals↗

PubMedDate not supplied

Genetic analysis in patients with familial and sporadic frontotemporal dementia: two tau mutations in only familial cases and no association with apolipoprotein epsilon4.

We screened for tau gene mutations among 24 Japanese (6 familial and 18 sporadic cases) and 4 Polish patients with frontotemporal dementia (FTD) using PCR-SSCP analysis followed by DNA sequencing. We identified 2 missense mutations in exon 10: N279K and P301L in 2 Japanese patients with familial FTD. Additionally 3 DNA polymorphisms: 2 known (3' exon 3 + 9, A --> G and exon 7, codon 176, G --> A) and 1 new (exon 8, codon 185, T --> C) were identified in 1 Polish patient. Tau mutations were not found in subjects with a negative family history suggesting that tau mutations do not account for most sporadic cases of FTD. We also found no association of apolipoprotein E4 allele with FTD.

Aged↗

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Distribution of apolipoprotein E gene polymorphisms in Japanese patients with Alzheimer's disease and in Japanese centenarians.

We have demonstrated an association between apolipoprotein E (apoE) gene polymorphisms and Alzheimer's disease (AD) in 163 Japanese patients by means of PCR. We found a significant increase in risk of nonfamilial AD for apoE allele epsilon4 in these individuals; this trend decreases with the increase in onset age. In centenarians, the distribution of apoE gene alleles is similar to that in the general population. The protective effect of allele epsilon2 against the development of AD is not statistically significant in our analysis. This indicates that apoE polymorphism is associated with AD regardless of race and that the age of onset is related to the apoE gene in the development of AD.

Aged↗

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Predictors of success in bypass to the distal segment of completely occluded coronary arteries.

Suitability for grafting and efficacy of aortocoronary bypass to the completely occluded coronary artery were studied in 25 patients in whom bypasses were attempted to the segments distal to the complete occlusion. We concluded that even when a coronary artery is occluded completely, if the distal coronary artery has a suitable lumen and viable muscle remains, bypass to the segment distal to the occlusion is worthwhile. Bypasses on the left anterior descending arteries were successfully constructed in 80% of grade 3 patients where distal segments of occlusion were severely compromised. Thallium-201 stress-myocardial scintigraphy is reliable in confirming myocardial viability beyond the area of complete coronary artery occlusion.

Cardiac Output↗