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Biomedical subjects

T Funahashi

Publications and source records attributed to T Funahashi.

At least 109 records · Page 6Linked to original sources
PubMed1992

Low-density lipoproteins in hyperalphalipoproteinemic heavy alcohol drinkers have reduced affinity for the low-density lipoprotein receptor.

Heavy alcohol intake causes a marked inhibition of cholesteryl ester transfer protein (CETP) activity resulting in cholesterol ester enrichment of HDL. In this study we have characterized LDL of 35 chronic heavy alcohol drinkers with hyperalphalipoproteinemia to clarify the effect of alcohol on the metabolism of LDL. Serum concentrations of LDL-cholesterol and apolipoprotein B were normal, while the chemical composition of LDL was characterized by depletion of cholesteryl ester and enrichment of triglyceride. The LDL particles of the drinkers were significantly smaller in size than those of controls and had reduced affinity for LDL receptors of normal human fibroblasts. After cessation of alcohol, these abnormal characteristics returned toward normal along with elevation of CETP activity. These results suggest that heavy alcohol intake alters the compositions and particle size of LDL, consequently reducing their affinity for LDL receptors. This may be attributed, at least in part, to the reduction of CETP activity.

Adult↗
PubMed1992

Non-macrophage-related accumulation of cholesterol during probucol treatment in familial hypercholesterolemia: report of two cases.

Two patients receiving long-term (3-4 years) treatment with probucol for familial hypercholesterolemia (FH) developed diffuse yellow lesions over the upper eyelids suggesting lipid storage in those tissues (diffuse lipid-storage lesions). Interestingly, each patient had shown a substantial reduction in their cholesterol levels together with a marked regression of their tendon xanthomas or typical xanthelasmas during treatment. To evaluate the role of probucol in this unusual finding we conducted histological and immunochemical evaluations of the lesions (removed surgically) and compared them with those of a non-probucol-treated subject with FH and typical audinal xanthelasma. In both probucol-treated patients the lesions were filled with foam cells and contained large amounts of cholesteryl ester. However, immunochemical analysis of the lesions of one patient using anti-monocyte monoclonal antibody (HAM56) demonstrated that they were not composed of macrophage-derived foam cells in contrast to those of the non-probucol-treated subject which stained clearly with anti-monocyte monoclonal antibody. In each case the foam cells did not react with muscle-actin-specific monoclonal antibody (HHF35). It appears that non-macrophage-related diffuse lipid-storage lesions may occur even during treatment with probucol despite the reduction in cholesterol levels and the regression of xanthomas, suggesting that probucol may alter the distribution of cholesterol from the macrophage to other cells.

Adult↗
PubMed1992

Polydisperse low-density lipoproteins in hyperalphalipoproteinemic chronic alcohol drinkers in association with marked reduction of cholesteryl ester transfer protein activity.

Long-term heavy alcohol intake is well known to increase serum high-density lipoprotein (HDL) cholesterol concentrations. Epidemiologic studies have shown that the protective effect of alcohol intake against coronary heart disease (CHD) is observed in moderate alcohol drinkers, but not in heavy ones. To clarify whether heavy alcohol intake may cause abnormalities in lipoprotein metabolism, we analyzed the plasma lipoproteins in eight male chronic heavy alcohol drinkers with marked hyperalphalipoproteinemia. Although their serum HDL cholesterol levels were remarkably high, ranging from 2.67 to 3.58 mmol/L, three patients had CHD and corneal arcus was present in seven patients. Cholesteryl ester transfer protein (CETP) activity was reduced in all subjects (7.3% +/- 4.2%/10 microL/18 h in alcohol drinkers v 20.5% +/- 2.4%/10 microL/18 h in control; mean +/- SD, P < .001). The CETP mass levels were also markedly reduced in these subjects. The analysis of low-density lipoprotein (LDL) on nondenaturing polyacrylamide gradient gel electrophoresis revealed that four subjects with severely low CETP activity (< 25% of control) had polydisperse LDLs, similar to those observed in genetic CETP deficiency. The other four subjects with approximately half the normal CETP activity had homogeneous but smaller-sized LDLs, as compared with control subjects. Particle size of HDL was larger than that of normal control HDL in all subjects. After cessation of alcohol intake, plasma HDL cholesterol levels were decreased and LDLs became more homogeneous and normal in size, in parallel with elevation of CETP activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Left atrial myxoma metastasizing to the aorta, with intraluminal growth causing renovascular hypertension.

The first case of 'a metastatic intraluminal myxoma of the aorta' is reported. The patient was a 48-year-old man who had already developed metastases to his skin and brain from a left atrial myxoma. Then, his myxoma grew in his leg and intraluminally in the aorta and caused renovascular hypertension. Surgical removal of the tumor could relieve his hypertension, but he finally died 6 months after surgery. The findings at autopsy were described and previous reports on metastasizing left atrial myxomas were also reviewed.

Aorta, Abdominal↗
PubMed1990

Hypocholesterolaemic factor from gallbladder cancer cells.

A patient is reported with drug-resistant familial hypercholesterolaemia in whom serum cholesterol fell after the onset of gallbladder cancer with intraperitoneal invasion. Cancer cells were obtained from ascitic fluid and a cultured cell line established. Incubation of the culture medium of these cells with skin fibroblasts from the patient and from normal subjects increased low-density lipoprotein (LDL) receptor activity in a dose-dependent manner. These results show that gallbladder cancer cells from this patient secrete a substance that stimulates LDL receptor activity. This substance may have contributed towards reduction of serum cholesterol.

Adenocarcinoma↗
PubMed1990

Adsorption of anti-dsDNA antibodies by immobilized polyanionic compounds.

Antibodies to dsDNA are characteristically present in serum from patients with systemic lupus erythematosus (SLE), and have been shown to have the capacity to react with various molecules bearing repeating negative charges. After a number of polymeric or monomeric molecules with differently charged groups and hydrophobic molecules had been coupled covalently as ligands on cellulose gel, the adsorption capacities of the ligands for anti-dsDNA antibodies were evaluated. It was found that gels coupled with polyanionic dextran sulphate (DXS) and polyacrylic acid (PA) and monoanionic sulphanilic acid (SA) absorbed anti-dsDNA antibodies effectively. DXS gel also adsorbed antibodies to ssDNA and heparan sulphate, antigens with repeating negatively charged moieties, while no ligand was able to adsorb anti-nRNP antibodies. The finding that DXS gels adsorbed anti-dsDNA antibody in proportion to their charge density, and that the interaction between anti-dsDNA and DXS gel is broken readily by an increase in ionic strength, indicated that the binding is ionic in nature. Moreover, virtually all F(ab')2 anti-dsDNA became adsorbed onto the DXS gels, suggesting that the binding occurred via specific antigen-binding sites on the antibody molecule. Binding of these polyanion-binding autoantibodies with anionic sites in the glomerular basement membrane may therefore cause the tissue damage observed in SLE.

Adsorption↗
PubMed1989

Analysis of a recycling-impaired mutant of low density lipoprotein receptor in familial hypercholesterolemia.

A mutant low density lipoprotein (LDL) receptor with abnormal ligand binding and recycling abilities was found in a patient with familial hypercholesterolemia. The molecular weights of the precursor and the mature form of the receptor were 72,000 and 115,000, respectively, which were about 45,000 smaller than those of the normal receptor. The mutant receptor was concluded to be present on the cell surface because the mature form was susceptible to Pronase digestion, and specific monoclonal antibody against the LDL receptor (IgG-C7) could bind to the cell surface. This mutant receptor could not bind LDL, but could bind other ligands for the LDL receptor, beta-migrating very low density lipoprotein, and the apolipoprotein E-lipid complex. After the receptor bound to the ligand, it disappeared from the cell surface of the mutant cells faster than that of normal cells, showing that, in the mutant cells, the receptor was not efficiently recycled back to the cell surface. Southern blotting of the genomic DNA from the patient showed a large deletion of about 12 kilobases around the epidermal growth factor precursor homology domain. For further characterization of the mutant, we cloned a 9.4-kilobase EcoRI/XbaI fragment, which was expected to contain the deletion joint. Mapping and sequencing analyses of the receptor gene showed that exons 7-14 were deleted. The nucleotide sequence suggested that this mutation may have occurred by recombination between repetitive Alu sequences in introns 6 and 14 of the receptor gene. The recombination brought about a complete deletion of the gene coding the epidermal growth factor precursor homology domain. The characteristics of the receptor protein produced by this mutation were similar to those of an artificial mutation constructed by Davis et al. (Davis, C. G., Goldstein, J. L., Südhof, T. C., Anderson, R. G. W., Russell, D. W., and Brown, M. S. (1987) Nature 326, 760-765) in which the whole gene coding this domain was deleted. The clinical phenotype of the patient having this mutation was similar to that of so-called "receptor-defective" type familial hypercholesterolemia, in which cells show detectable, but markedly reduced activity of the LDL receptor.

Base Sequence↗
PubMed1989

Association of apolipoprotein E with the low density lipoprotein receptor: demonstration of its co-operativity on lipid microemulsion particles.

When human apolipoprotein E (apoE), which forms a self-associated tetramer in an aqueous solution, bound to the surface of triolein/phosphatidylcholine microemulsion with a particle diameter of 26 nm, it became monomeric on the lipid particle surface without strong evidence for its accumulation on a particular particle that might be expected from its tetramer formation in the aqueous phase. ApoE in the form of the self-associated tetramer did not inhibit binding of human low density lipoprotein (LDL) to its receptor on cultured human skin fibroblast. LDL binding was inhibited only when apoE was bound to the lipid particle surface. The affinity of the apoE-containing lipid particle to the LDL receptor was of the same order as that of LDL on the basis of particle molarity when the surface of the particle was covered with apoE up to 40 to 50% of the saturation level. When the particle was covered more with apoE, the affinity increased by some 20 times. Since the surface of the lipid particle was saturated with 7 apoE molecules, the particle seemed to require to have at least 4 apoE molecules on its surface in order to obtain high binding affinity to LDL receptor.

Adsorption↗
PubMed1989

Selective removal of anti-double-stranded DNA antibodies by immunoadsorption with dextran sulphate in a patient with systemic lupus erythematosus.

A dextran sulphate gel column removed anti-double-stranded DNA antibodies (anti-dsDNA) selectively, efficiently, and safely from the circulation of a patient with systemic lupus erythematosus (SLE). The mechanism of the removal is thought to be due to cross reactivity of anti-dsDNA with dextran sulphate, which has negatively charged units. Selective removal of anti-dsDNA is expected to contribute not only to the treatment but also to elucidation of the pathogenesis of SLE.

Adult↗
PubMed1988

Selective reduction of cholesterol in HDL2 fraction by probucol in familial hypercholesterolemia and hyperHDL2 cholesterolemia with abnormal cholesteryl ester transfer.

Long-term treatment with probucol induced marked regression of xanthoma in patients with both homozygous and heterozygous familial hypercholesterolemia despite a substantial accompanying decrease in high-density lipoprotein (HDL) cholesterol. Furthermore, a close correlation was found between the extent of the regression and the reduction of HDL cholesterol, which suggests that the probucol-induced decrease in HDL may not be an atherogenic change, but may reflect a favorable change for lipoprotein metabolism. The present study also evaluated the effects of probucol on HDL metabolism in patients with familial hyperHDL2 cholesterolemia who had extremely high levels of HDL cholesterol ranging from 130 to 280 mg/dl. Premature corneal opacities were present in 2 patients, 1 of whom also had coronary artery disease despite high HDL cholesterol levels. In the 2 cases, the net transfer of cholesteryl ester from HDL to very low density lipoprotein and LDL was impaired, and low hepatic triglyceride lipase activity was observed, but cholesteryl ester transfer protein was not deficient. Administration of probucol to these patients caused a marked reduction of serum cholesterol, which was accounted for exclusively by a reduction in the HDL2 fraction. The size of the HDL2 particles, which had been much larger, decreased to normal, and the net transfer rate of cholesteryl ester was normalized. In the other 3 cases of hyperHDL2 cholesterolemia, the cholesteryl ester transfer activity was completely deficient. Unlike its effect in the first 2 cases, probucol did not cause any change in lipid and apoprotein in the 3 patients with complete deficiency of cholesteryl ester transfer activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Carrier Proteins↗
PubMed1988

Mutations of the low density lipoprotein receptor in Japanese kindreds with familial hypercholesterolemia.

Mutations of the low density lipoprotein (LDL) receptor in 16 Japanese kindreds with homozygous familial hypercholesterolemia (FH) were studied using an anti-LDL receptor antibody. The LDL receptor mutations in Japanese FH were heterogeneous and included defects in synthesis, post-translational processing, ligand-binding activity, and internalization of the LDL receptor. Of the 16 kindreds, 10 were receptor-negative and 5, receptor-defective types and 1 was an internalization-defective type with respect to LDL binding. The receptor-negative group was further subdivided into four groups: those with cells producing (i) no immunodetectable receptor (five kindreds); (ii) 160-kd mature receptors, which were quite scarce (two kindreds); (iii) receptors that could not be processed to the mature receptor properly (two kindreds); and (iv) receptors with an apparent molecular weight smaller than normal (one kindred). The last kindred synthesized an about 155-kd mature receptor that was rapidly degraded. This finding is compatible with the low concentration of the cell surface LDL receptors and decreased binding activity for LDL in the cells of this kindred. The receptor-defective group, which could produce a residual amount of functional receptors, exhibited a lower tendency to coronary artery disease than the receptor-negative group.

Homozygote↗
PubMed1988

A novel system of LDL apheresis combining a centrifugal plasma separator with a specific LDL adsorption column.

A novel system of low density lipoprotein (LDL) apheresis for familial hypercholesterolemia (FH) was developed, combining a centrifugal plasma separator (IBM-2997) with a new adsorption column specific to lipoproteins containing apolipoprotein B (apo-B), and its operation was compared to previous methods. The present system selectively removed LDL without the substantial reduction of high density lipoprotein that was seen with other methods using membrane filters. The capacity for LDL removal was slightly more reduced with the adsorption column than with the membrane filters when a single column was used. Since the ability to obtain plasma in the centrifugal system was much higher than in the system using membrane filters for plasma separation, efficient apheresis could be performed in a much shorter time, without making an arterio-venous shunt. Remixing of blood cells, such as platelets, with the separated plasma sometimes raises the pressure within the plasma component separator, but the problem could be avoided by withdrawing the buffy coat fraction, using the WBC pump of the IBM separator. In conclusion, the novel system, combining the centrifugal plasma separator with the adsorption column, has proved, in our hands, to be a more useful and more convenient method than those previously used for the treatment of severe FH.

Adsorption↗
PubMed1988

Characterization of low-density lipoproteins from patients with recessive X-linked ichthyosis.

We investigated lipoprotein metabolism in 14 patients with recessive X-linked ichthyosis (RXLI), a metabolic disease characterized by scaly skin, corneal opacity and steroid sulfatase deficiency. Plasma total cholesterol (TC) levels ranged from normal to slightly low (mean +/- SD: 156 +/- 28 mg/dl). Four patients showed a mild or moderate elevation of plasma triglyceride (TG) levels ranging from 150 to 365 mg/dl. The apoprotein B (apo B) to TC ratio was higher than in normal controls (0.63 +/- 0.11 vs. 0.52 +/- 0.07, P less than 0.01), while plasma apoB levels were within the normal range (99 +/- 17 mg/dl). Polyacrylamide gel electrophoretic mobility of low-density lipoprotein (LDL) was markedly increased in all patients, and further analyses showed that this finding was not due to a change in the particle size of the LDL but to an increased content of cholesterol sulfate (1.0-2.3% of the LDL-cholesterol content). In addition to the alteration of electrophoretic mobility, marked changes in the lipid and apoprotein compositions of the LDL fraction were observed; cholesterol ester content in LDL (LDL-CE) was significantly lower than that of control subjects (37 +/- 4% vs. 41 +/- 2% of total lipids, P less than 0.01), while the triglyceride content (LDL-TG) and apo B to cholesterol ratios in LDL were significantly higher than those of controls (18 +/- 7 vs. 10 +/- 2, P less than 0.001; 1.21 +/- 0.19 vs. 0.73 +/- 0.05, P less than 0.001, respectively). This anionized LDL, in which cholesterol sulfate was increased, was shown to bind to the LDL receptor of fibroblasts to much the same extent as normal LDL. In conclusion, the increase in cholesterol sulfate in LDL fraction not only alters the electrophoretic moiety but also the relative contents of apoB, cholesterol, and triglyceride in the lipoprotein. It does not change the affinity of LDL for the LDL receptor.

Adolescent↗
PubMed1988

[A case of neurogenic bladder complicated by an acute rash syndrome (measles?)].

A 24-year-old female patient was was admitted because of urinary retention, four days after the development of rash with fever to be diagnosed as measles by a doctor. Neurological examinations showed hyperesthesia in lower thoracic regions and increased deep tendon reflexes in lower extremities. Cystometric findings revealed an areflexic bladder with normal sensation. Cerebrospinal fluid examination showed mononuclear pleocytosis and slightly elevated levels of protein. There was no significant increase in serum measles antibody titer. She regained normal voiding by conservative treatment with an indwelling catheter for four days. The bladder motor paralysis was probably due to non-transverse myelitis in sacral spinal region. Neurological complications of measles are briefly discussed.

Adult↗
PubMed1987

Cells of an internalization-defective familial hypercholesterolemia mutant secrete low density lipoprotein receptors.

Familial hypercholesterolemia (FH) is a congenital disorder of plasma low density lipoprotein (LDL) metabolism resulting from the defect or malfunction of LDL receptors on the cell surface. In most cases of FH, LDL binding to the cell surface is disrupted, while in some special cases LDL binding to the receptors occurs normally but the internalization of the bound LDL is inhibited (internalization-defective type). We studied the biosynthesis and transport of the LDL receptor in cultured fibroblasts obtained from one of the internalization-defective mutants by using [35S]methionine labeling and detection with anti-LDL receptor antibody. The mutant cells synthesized LDL receptors with a molecular weight slightly smaller than normal as shown in SDS-polyacrylamide gel electrophoresis. A large portion of the synthesized receptors was secreted into the medium while the other portion was associated with the cells. The apparent molecular weight of the receptors secreted into the medium was about 10 kDa smaller than that of the cell-associated receptors. The cell-associated form was converted into the secreted form following a prolonged incubation of the cells, showing the precursor-product relationship between the cell-associated and the secreted forms.

Antibodies, Monoclonal↗