Biomedical subjects

F M Yatsu

Publications and source records attributed to F M Yatsu.

At least 19 recordsLinked to original sources

PubMed1995

Sodium butyrate inhibits platelet-derived growth factor-induced proliferation of vascular smooth muscle cells.

Sodium butyrate (SB), a naturally occurring short-chain fatty acid, was investigated for its therapeutic value as an antiproliferative agent for vascular smooth muscle cells (SMCs). At 5-mmol/L concentration, SB had no significant effect on rat SMC proliferation. However, at the same concentration, SB inhibited platelet-derived growth factor (PDGF)-AA-, -AB-, and -BB-induced proliferation of SMCs. Exposure of SMCs to PDGF-BB resulted in activation of receptor intrinsic tyrosine kinase activity and autophosphorylation of beta-PDGF-receptor (beta-PDGFR). The activated beta-PDGFR physically associated and phosphorylated signaling molecules such as ras-GTPase activating protein (GAP) and phospholipase C gamma (PLC gamma). SB, in the absence of PDGF-BB, caused neither beta-PDGFR tyrosine phosphorylation nor phosphorylation and association of GAP and PLC gamma with beta-PDGFR. PDGF-BB-enhanced activation of receptor intrinsic tyrosine kinase activity and autophosphorylation of tyrosine residues of beta-PDGFR were unaffected by SB irrespective of whether SMCs were preincubated with SB before exposure to PDGF-BB plus SB or incubated concomitantly with PDGF-BB plus SB. Likewise, phosphorylation and association of GAP and PLC gamma with PDGF-BB-activated beta-PDGFR were unaffected. In addition, SB did not block PDGF-BB-stimulated, PLC gamma-mediated production of inositol triphosphate. Similarly, PDGF-BB-induced beta-PDGFR degradation was unaffected when SMCs were exposed to PDGF-BB plus SB, and SB by itself had no influence on beta-PDGFR degradation. Unlike beta-PDGFR kinase activity, mitogen-activated protein kinase (MAP-kinase) activity was stimulated by SB by about 2.7-fold. Exposure of SMCs to PDGF-BB caused an approximately 11.4-fold increase in MAP-kinase activity and this increase in activity was not significantly affected when cells were coincubated with PDGF-BB and SB (10.3-fold). However, pretreatment of SMCs with SB for 30 minutes and subsequent incubation in PDGF-BB plus SB abolished most of the PDGF-BB-induced MAP-kinase activity (4.6-fold). Transcription of growth response genes such as c-fos, c-jun, and c-myc were induced by PDGF-BB, and their induction was suppressed, particularly c-myc, by incubating SMCs with PDGF-BB plus SB. Similarly, preincubation of cells with SB for 30 minutes and subsequent incubation in PDGF-BB plus SB diminished PDGF-BB-induced transcription of c-fos, c-jun, and c-myc. However, SB by itself had no significant effect on c-fos, c-jun, and c-myc transcription.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Molecular biological studies in atherothrombotic brain infarction.

Strokes due to atherosclerosis are the most prominent neurological disease affecting adults, and efforts to reduce stroke occurrence, in addition to stroke-risk reduction, will require insights into molecular mechanisms. Our studies showing abnormal metabolism of low and high density lipoproteins (LDL and HDL) in vivo and of RFLP in apoprotein AI, the major protein of HDL, in stroke-prone subjects suggest that greater exploration of fundamental mechanisms of atherothrombotic brain infarction (ABI) should yield preventative strategies, the ultimate treatment for strokes.

Apolipoprotein A-I↗

PubMed1992

Restriction fragment length polymorphism of the apoprotein A-I-C-III gene cluster in control and stroke-prone white and black subjects: racial differences.

BACKGROUND AND PURPOSE: The presence of known restriction fragment length polymorphisms in the apoprotein A-I-C-III gene cluster, which encodes their respective apoproteins, was investigated using the restriction enzymes Sac I and Pst I to determine the potential role of genetic variations for stroke risk in an American population. METHODS: Ninety-eight subjects (70 white, 28 black subjects), both normal controls with no carotid stenosis and those with carotid stenosis believed at risk for stroke, defined as showing stenosis focally or diffusely at that site, composed the study population. RESULTS: Sac I polymorphic S2 allele frequency was higher in stroke-risk groups, whereas Pst I polymorphic P2 allele frequency was similar in control and stroke-risk groups. Significantly higher levels of serum cholesterol, triglycerides, and low density lipoprotein (p less than 0.05) and significantly lower levels of high density lipoprotein (p less than 0.05) were observed in stroke-risk groups with diffuse stenosis. Results of our study with the two racial groups show the following: the frequency of Sac I polymorphism was significantly higher in American black compared with American white subjects (chi 2 = 3.92, p less than 0.05). Among serum lipids, triglycerides were significantly higher in white compared with black subjects (p less than 0.05). In white subjects, carotid artery stenosis was associated with significantly elevated total cholesterol and low density lipoprotein (p less than 0.01) but not with Sac I polymorphism. In black subjects the converse was observed, namely, the Sac I polymorphic S2 allele seemed to be associated with carotid bifurcation stenosis but did not reach statistical significance because of the small number of subjects. In addition, Sac I polymorphism did not correlate with any lipid profile. Pst I polymorphism was not associated with any lipid profile or carotid artery stenosis abnormalities. CONCLUSIONS: Our results indicate that carotid artery stenosis identifies white subjects with increased plasma total cholesterol and low density lipoprotein, an atherogenic profile, but not with Sac I polymorphism. These findings suggest that carotid bifurcation stenosis in white subjects is associated with an atherogenic lipid profile but not with apoprotein A-I-C-III restriction fragment length polymorphisms. In black subjects, Sac I polymorphism seems to identify those individuals with significant carotid stenosis, a necessary precursor to atherothrombotic brain infarction, but not those with elevated total cholesterol, elevated low density lipoprotein, and/or reduced high density lipoprotein. These results suggest that Sac I polymorphism may identify black subjects at increased risk for atherothrombotic brain infarctions.

Aged↗

PubMed1992

Low and high density lipoprotein metabolism in atherothrombotic brain infarction.

BACKGROUND AND PURPOSE: Elevated low density lipoprotein and reduced high density lipoprotein cholesterol may increase the risk of atherothrombotic brain infarction, but the metabolic mechanisms accounting for this relation are poorly understood. METHODS: The kinetic parameters of low density and high density lipoprotein were studied in nine subjects with atherothrombotic brain infarction or identifiable (by noninvasive testing) extracranial occlusive disease and in 12 control subjects. Autologous iodine-125-labeled lipoproteins were injected intravenously. Blood samples were drawn 10 minutes after injection and periodically thereafter for 10 days. Kinetic parameters were calculated from the decay curves. RESULTS: The stroke-risk group showed significantly higher triglyceride (p less than 0.05), total cholesterol (p less than 0.02), and low density lipoprotein cholesterol (p less than 0.01). The fractional catabolic rate of low density lipoprotein was significantly lower (p less than 0.001) and the high density lipoprotein rate higher (p less than 0.02) in the stroke-risk group than in the control group. Regression analysis (using all subjects) of serum lipoproteins and their respective fractional catabolic rates correlated significantly (for low density lipoprotein, r = 0.684, p less than 0.001; for high density lipoprotein, r = 0.595, p less than 0.002). Mean percent stenosis showed a significant relation with triglyceride level (r = 0.678, p less than 0.01) and low density lipoprotein cholesterol (r = 0.535, p less than 0.02) but not with high density lipoprotein cholesterol. Mean percent stenosis also showed correlation with both fractional catabolic rate of low density lipoprotein (r = 0.667, p less than 0.002) and with serum high density lipoprotein levels (r = 0.504, p less than 0.02). CONCLUSIONS: Our study provides insights into the role of altered low and high density lipoprotein metabolism in the pathogenesis of carotid stenosis. The statistically significant association of serum lipoprotein metabolic rates with carotid stenosis, rather than their respective serum concentrations, implies that metabolic parameters may be more important in predicting stroke risk.

Carotid Stenosis↗

PubMed1992

A critical appraisal of ticlopidine, a new antiplatelet agent. Effectiveness and clinical indications for prophylaxis of atherosclerotic events.

BACKGROUND: Recommendations are broadening for the prophylaxis of atherosclerotic disorders, but aspirin is the only widely used agent. Ticlopidine hydrochloride, a new antiplatelet medication, has recently been approved for prescription in North America. We reviewed the major clinical trials of ticlopidine and derived guidelines for its use. METHODS: Studies of ticlopidine were sought through MEDLINE for 1980 to 1990 and through bibliographies of retrieved articles. All published, randomized trials of ticlopidine were appraised if they reported major morbidity and mortality as primary end points. All eligible studies were formally reviewed by an expert panel according to published principles for critical appraisal of the medical literature. Both benefits and risks were quantified. RESULTS: Four randomized trials reported major clinical end points. In these, ticlopidine was more effective than placebo for preventing recurrences after completed stroke; was more effective than aspirin for patients with transient ischemic attacks and partial strokes; and reduced vascular death and nonfatal myocardial infarction in an open trial among patients with unstable angina. For patients with intermittent claudication ticlopidine, was not significantly better than placebo for preventing myocardial infarction or stroke. Side effects were more common with ticlopidine than with aspirin or placebo. CONCLUSIONS: Ticlopidine should be prescribed in place of aspirin for stroke prophylaxis or unstable angina if the patient is unable to tolerate aspirin. Ticlopidine may also benefit patients who experience new ischemic events while taking aspirin or, probably, patients with peripheral vascular disease. A complete blood cell count should be performed every 2 weeks during the first 3 months of therapy to check for leukopenia.

Arteriosclerosis↗

PubMed1991

The community hospital-based stroke programs in North Carolina, Oregon and New York--V. Stroke diagnosis: factors influencing the diagnostic evaluation of patients following acute stroke.

Among the 4129 patients of the Community Hospital-based Stroke Program, 30% had an unspecified stroke diagnosis. Since specific diagnosis and, perhaps, eventual treatment, derives in part from diagnostic testing, we examined the effect of clinical condition, geographic and demographic factors on the incidence of certain diagnostic tests after acute stroke. In this multivariable analysis, race, sex, history of hypertension and history of diabetes did not influence the chance of having any test, but older age strongly reduced the chances of receiving extensive evaluation. When CT scanning was available, the utilization of a CT as well as other diagnostic studies including cerebral angiography, radionuclide brain scan, EEG and EKG was increased. The odds of receiving a CT scan increased if the patient was married, and decreased with a history of previous stroke. A history of previous TIA increased the chance of having a cerebral angiogram while a history of cardiac disease decreased the chance. There were striking regional geographic differences in the use of CT, radionuclide brain scanning and cerebral angiography which may, in part, reflect differences between the availability of these technologies in urban and rural hospitals. These results indicate that evaluation of stroke patients remains heterogenous.

Aged↗

PubMed1991

Strokes in Asians and Pacific-Islanders, Hispanics, and Native Americans.

Stroke in Asian and Pacific-Islander populations remains the principal cause of death among adults, but its incidence in the United States approximates that of Caucasians. Although controversial, uncontrolled hypertension in certain population groups (e.g., northern Japanese) and high dietary saturated fat in others (e.g, Pacific-Islanders) are believed to be responsible for the high stroke incidence rates. The recent reduction in stroke frequency rates in these areas is thought to be the result of better hypertension control. In the Ni-Hon-San Study, the level of hypertension and its frequency were similar in Hawaii and Japan, but ischemic infarction and intracerebral hemorrhage were less frequent in Hawaii. Reduced meat and fat intake may contribute to small vessel disease in Japan. Stroke is the third major cause of death among Hispanic-Americans and Native Americans, yet there is a paucity of information, especially about stroke, in subgroups of these populations. There is also considerable ignorance and controversy about risk factors for stroke in these populations. The need for additional research is urgent.

Asian↗

PubMed1990

Community hospital-based stroke programs in North Carolina, Oregon, and New York. IV. Stroke diagnosis and its relation to demographics, risk factors, and clinical status after stroke.

The use of diagnostic tests, the accuracy of stroke type diagnosis, and their relationship to outcome are important from the standpoint of patient management and health care costs. To address this issue, we examined the differences between stroke types in terms of demographics, risk factors, diagnostic tests, and clinical outcome in the 4,129 patients who comprise the Community Hospital-Based Stroke Program. Previous transient ischemic attacks were equally frequent among patients with embolic and those with thrombotic stroke. For all stroke types, previous stroke was as frequent as previous transient ischemic attacks. Hypertension and cardiac disease were the most common risk factors, but 10% of all stroke patients had no recognized risk factors. Intracerebral hemorrhage was most often associated with death (45%). There was a strong direct relation between in-hospital mortality and a decreased level of consciousness at admission. Overall, 30% of patients did not receive a specific stroke type diagnosis; these patients were elderly, usually nonwhite, and often had an altered level of consciousness at admission but had a risk factor profile similar to that of patients who received a specific stroke type diagnosis. In summary, our findings suggest the continued need for physician education about and refinement of stroke type diagnosis.

Aged↗

PubMed1990

Molecular biology of atherothrombotic brain infarction.

Because reduced high density lipoproteins may contribute to atherothrombotic brain infarction, we performed molecular biologic and metabolic studies to characterize high density lipoprotein metabolism with respect to its role in reverse cholesterol transport, to clone the high density lipoprotein receptor, and to determine gene polymorphism for apolipoprotein A-I, the major protein of high density lipoprotein, because altered structure may impair reverse cholesterol transport. For high density lipoprotein metabolism measurements, high density lipoprotein 3 was isolated, purified, and labeled with iodine-125. The radiolabeled high density lipoprotein 3 was reinjected, and daily blood samples were taken for 10 days. Synthesis rates and fractional catabolic rates were determined from the specific activities and daily decrements. Preliminary data indicate that stroke-prone individuals' fractional catabolic rates for high density lipoprotein 3 are twice those of normal individuals. Also, the conversion of high density lipoprotein 3 to high density lipoprotein 2 is reduced in these individuals, suggesting that high density lipoprotein may be abnormally processed in individuals prone to atherothrombic brain infarctions. We surveyed more than 100 patients with carotid stenosis using a 2.2-kb probe for the apolipoprotein A-I gene. A subset of these patients displays polymorphism with restriction enzymes SacI or PstI. These preliminary findings suggest that gene polymorphism for apolipoprotein A-I may provide a molecular clue of atherothrombic brain infarction.

Arteriosclerosis↗

PubMed1990

Pilot study of nicardipine for acute ischemic stroke.

The author performed a pilot study of nicardipine (NC), a Ca(+)+ channel blocker, to study its dosing, toxicity, and possible efficacy for hemispheric cerebral infarction within 12 hours (mean 6.9 hr) of onset to determine the advisability of proceeding with a multi-centered controlled trial. NC was administered IV (3 to 7 mg/hr) X 72 hours by titrating dose to mean arterial blood pressure (MABP not less than 10% of baseline), then orally X 30 days. Forty-three patients have been entered; mean age 63 (range 34-89), 25 male and 18 female. Only 3 had CT evidence of infarct on entry. Results have shown improvement in a 100-point (pt) graded exam (40 pts at entry, 68 pts at 3 months). Of 20 patients completing 3 months' evaluation, 17 improved and none worsened. Sixteen out of 20 were at home and 8 had minimal or no impairment. Mean Barthel's index was 72. Mean maximal serum NC level was 75 ng/mL. MABP decreased from 103 (entry) to 83 (72 hours). A larger controlled study is warranted to determine the efficacy of NC for acute cerebral infarct.

Acute Disease↗

PubMed1989

Receptor-mediated uptake and 'retroendocytosis' of high-density lipoproteins by cholesterol-loaded human monocyte-derived macrophages: possible role in enhancing reverse cholesterol transport.

Human monocyte-derived macrophages (MDM) are cholesterol-loaded, and the rates of uptake, degradation and resecretion of high-density lipoproteins are measured and compared to the rates in control cells. Results show the binding activity of these lipoproteins is upregulated in cholesterol-loaded cells; the bound and internalized lipoproteins are not degraded to any appreciable extent but primarily resecreted as a larger particle. The enhancement of binding activity for high-density lipoproteins is arrested when cycloheximide is added to the medium, suggesting that protein synthesis is involved. Preliminary evidence also indicates that HDL3 (without apoE) after internalisation is converted intracellularly to a larger apoE-containing HDL2-like particles. Thus, MDM appears to possess specific receptors for HDL3 without apoE that may function to facilitate HDL-mediated removal of excess cholesterol from cells.

Biological Transport↗

PubMed1989

Atherosclerosis: current concepts on pathogenesis and interventional therapies.

Atherosclerosis, the primary pathological condition accounting for most stroke syndromes, has been the intense focus of epidemiological, basic, and clinical investigations. Since these studies have direct bearing on the prevention of atherothrombotic brain infarction, this review emphasizes those advances in treatment resulting from their findings. The two most prominent theories on the pathogenesis of atherosclerosis relate to aberrations in lipoprotein metabolism and to enhanced proliferation of smooth muscle cells; likely, the theories are complementary. As a practical guideline for preventive therapy, the importance of using the total cholesterol level is stressed, although finer distinctions must rely on the low-density and high-density lipoprotein concentrations and their normalization. Since prevention of stroke may ultimately be its most effective therapy, consideration of cholesterol level, akin to strategies for preventing coronary heart disease, and efforts to avert platelet adhesion or aggregation and coagulation are warranted.

Arteriosclerosis↗

PubMed1989

Prediction of carotid stenosis progression by lipid and hematologic measurements.

We followed 19 men and 19 women with asymptomatic carotid stenosis up to 30 months to determine whether hematologic or lipid abnormalities could identify those individuals developing progressing carotid atherosclerosis (defined as an increase in mean percent stenosis greater than or equal to 19% or an increase in a single region of greater than or equal to 23%) on B-mode carotid ultrasonography performed at 2- to 6-month intervals. Our patients demonstrated increased beta-thromboglobulin, platelet factor 4, and fibrinogen compared with age-matched controls. Eight patients developed progression of carotid stenosis, and this group had higher baseline low-density lipoprotein (LDL) and fibrinogen than the 30 nonprogressing patients. Multiple regression analyses of age, sex, smoking, coronary artery disease, peripheral vascular disease, diabetes, hypertension, and baseline high-density lipoprotein (HDL), HDL2, HDL3, LDL, beta-thromboglobulin, platelet factor 4, and fibrinogen identified coronary artery disease and elevated LDL and fibrinogen as the only independent variables significantly associated with the progressing group. We conclude that, in patients with carotid atherosclerosis, a combination of coronary artery disease and elevated LDL and fibrinogen will predict with 88% accuracy whether the patient will have progressing carotid stenosis.

Aged↗

PubMed1988

Pentoxifylline in acute nonhemorrhagic stroke. A randomized, placebo-controlled double-blind trial.

The efficacy and safety of pentoxifylline were assessed in 297 adult patients with ischemic stroke in a multicenter, double-blind, randomized and placebo-controlled trial. Treatment was started within 12 hours after the stroke onset. Study medication was administered intravenously continuously (16 mg/kg/day, maximum 1,200 mg/day) for 3 days and per os (400 mg t.i.d.) for the remainder of 28 days. Demographic data were comparable, and functional impairment and mortality (pentoxifylline 12%, placebo 10%) were not different between the two groups. Neurologic deficit scores improved from baseline admission scores during the 4-week study in both groups but did not differ between groups at admission or throughout the study except during the first few days when the consciousness level (Days 1 and 2), motor function (Days 1 and 2), cranial nerve function (Days 1-4), and total neurologic deficit scores (Days 1 and 2) were better in the pentoxifylline group than in the placebo group, especially in a subset of patients with severe deficits at admission. Laboratory values and side effects were also comparable between groups. Our study indicates that pentoxifylline can be given safely in patients with acute ischemic stroke. Although pharmacologic effects were present during the first few days, the clinical benefits were small and not sustained.

Acute Disease↗

PubMed1988