Role of genetic factors (CETP gene Taq I B polymorphism and Apo A-I gene Msp I polymorphism) in serum HDL-C levels in women.

BACKGROUND AND AIM: Plasma high density lipoprotein cholesterol (HDL-C) levels are determined by a variety of environmental and genetic factors. The cholesteryl ester transfer protein (CETP) and apolipoprotein A-I (Apo A-I) are considered to be associated with HDL-C metabolism. The aim of this study was to investigate the relationship between the CETP gene Taq I B and Apo A-I gene Msp I polymorphisms and plasma lipid levels taking into account environmental factors, and to determine the combined effects of these polymorphisms on HDL-C levels in Japanese women. METHODS AND RESULTS: The study involved 270 Japanese women aged 30-69 years. We found a significant association between the CETP genotypes and HDL-C levels (p=0.0020), which were also associated with the Apo A-I gene (M1) polymorphism. Stepwise multiple regression analysis revealed that both the CETP Taq I B and Apo A-I gene (M1) genotypes were independent predictive variables. The strength of the association between the Apo A-I (M1) subgroup and HDL-C levels was reduced in the subjects with a high Body Mass Index (BMI). The combination of genotypes provided more detailed information about HDL-C levels. The "high risk" combination of the M1+ (M1+/+) and B1B1 genotypes was associated with the lowest HDL-C level (1.52+/-0.36 mmol/L), and the "low risk" combination of the M1- (M1+/- or M1-/-) and B2B2 genotypes was associated with the highest HDL-C levels (2.06+/-0.34 mmol/L). CONCLUSIONS: Our results suggest that the combination of the two polymorphisms influences HDL-C levels in women, and that the association between genetic factors and HDL-C levels is altered by environmental factors. They may also help to detect individuals with low HDL-C levels at high risk for coronary artery syndrome.

Experimental concept for examination of biological effects of magnetic field concealed by gravity.

Space is not only a place to study biological effects of gravity, but also provides unique opportunities to examine other environmental factors, where the biological actions are masked by gravity on the ground. Even the earth's magnetic field is steadily acting on living systems, and is known to influence many biological processes. A systematic survey and assessment of its action are difficult to conduct in the presence of dominant factors, such as gravity. Investigation of responses of biological systems against the combined environment of zero-gravity and zero-magnetic field might establish the baseline for the analysis of biological effects of magnetic factors. We propose, in this paper, an experimental concept in this context, together with a practical approach of the experiments, both in orbit and on the ground, with a thin magnetic shielding film. Plant epicotyl growth was taken as an exemplar index to evaluate technical and scientific feasibility of the proposed system concept.

Comparative biochemical studies of carotenoids in catfishes.

The carotenoids of 12 species of Siluriformes fishes (eight families) were investigated from a comparative biochemical point of view. The patterns of carotenoids in catfishes belonging to the family Siluridae were quite different from those of the other seven families of catfishes (Bagridae, Amblycipitidae, Clariidae, Plotosidae, Ictaluridae, Callichthyidae and Malapteruridae). 7, 8-Dihydro-beta-carotene; 7, 8, 7', 8'- and 7, 8, 9, 10-tetrahydro-beta-carotene; (3R)-7', 8'-dihydro-beta-cryptoxanthin; 7, 8-dihydrolutein A; 7, 8-dihydrolutein B; parasiloxanthin; 7', 8'-dihydroparasiloxanthin; and 4 or 4'-hydroxyparasiloxanthin were characteristic carotenoids found in only one family, Siluridae, and these carotenoids accounted for 24-60% of total carotenoids. In catfishes belonging to the other seven families except Siluridae, the carotenoid patterns were very similar and the most predominant carotenoid was zeaxanthins (23-56%).

Apheresis technology for prevention and regression of atherosclerosis.

Familial hypercholesterolemia (FH) is a congenital disorder of cholesterol metabolism, which is due to a deficiency in low-density lipoprotein (LDL) receptors. The homozygous form of FH is especially liable to coronary artery disease (CAD) in youth because of the very high LDL-cholesterol levels. It is resistant to drug therapy, and LDL-apheresis is the only practical way of treatment for these patients. Some patients with heterozygous FH also have high LDL-cholesterol levels that cannot be brought down into the optimum range by any combination drug therapy. We have treated or are treating 10 homozygous and 28 heterozygous FH patients in our hospital or in affiliated hospitals expert in blood purification. Among the 10 homozygous patients, 2 died of myocardial infarction. Only one young female patient is still free of symptoms, and the other patients have been suffering from regurgitation through the aortic valve although they have not experienced myocardial infarction. Rapid rebound of LDL-cholesterol after each apheresis treatment limits the period during which LDL-cholesterol is in the optimum range. The use of atorvastatin at a high dose (40 mg/day) was attempted to suppress this rebound. In contrast with good results in receptor-defective-type patients, receptor-negative-type patients did not show a response in LDL-cholesterol levels to the statin therapy although there was a slight increase in high-density lipoprotein (HDL)-cholesterol with a decrease in very-low-density lipoprotein-triglyceride and -cholesterol. Follow-up study of the patients with heterozygous FH revealed that LDL-apheresis was effective in lengthening the life expectancy of the patients with pre-existing CAD, especially those who had received intervention coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA). It was also shown that the use of probucol in combination with LDL-apheresis was effective in reducing coronary events as shown by the necessity of CABG or PTCA. Clinical data on the effect of LDL-apheresis, recently reported from some other institutions in Japan, will also be reviewed.

Structures of carotenoids with 5,6-dihydro-beta-end groups from the spindle shell Fusinus perplexus.

A series of pirardixanthin derivatives, 1, 2, 3, 4, and 5, possessing the 5,6-dihydro-beta-end group were isolated from the spindle shell Fusinus perplexus.(1,2) Their structures and absolute configurations were determined by modern spectroscopic analysis to be (4S,5S,6S,4'S,5'S,6'S)-5,6,5',6'-tetrahydro-beta,beta-carotene-4,4'-diol (1), (3S,4R,5S,6S,4'S,5'S,6'S)-5,6,5',6'-tetrahydro-beta,beta-carotene-3,4,4'-triol (2), (3S,4R,5S,6S,3'S,4'R,5'S,6'S)-5,6,5',6'-tetrahydro-beta,beta-carotene-3,4,3',4'-tetrol (3), (5S,6S,4'S,5'S,6'S)-4'-hydroxy-5,6,5',6'-tetrahydro-beta,beta-caroten-4-one (4), and (4'S,5'S,6'S)-4'-hydroxy-5',6'-dihydro-beta,beta-caroten-4-one (5).

Salmoxanthin, deepoxysalmoxanthin, and 7,8-didehydrodeepoxysalmoxanthin from the Salmon Oncorhynchus keta.

The absolute configuration of salmoxanthin (5,6-epoxy-5,6-dihydro-beta,epsilon-carotene-3,3',6'-triol) (1) first isolated from the salmon Oncorhynchus keta was determined to be 3S, 5R, 6S, 3'S, 6'R. Furthermore, two minor carotenoids, deepoxysalmoxanthin (2) and 7,8-didehydrodeepoxysalmoxanthin (3), were isolated, and their structures were determined to be (3R,3'S,6'R)-beta,epsilon-carotene-3,3',6'-triol and (3R,3'S,6'R)-7,8-didehydro-beta,epsilon-carotene-3,3',6'-triol by (1)H NMR and CD spectroscopy.

Parental pediatric corticosteroid preferences.

Corticosteroids are often prescribed in the acute care management of asthma. Prednisolone can be administered intramuscularly (IM) or orally in 2 different concentrations. This study evaluated parental preference for three prednisolone preparations based on the route of administration, taste, and volume required. Accompanying adults (AAs) of pediatric patients were interviewed about their preferences based on the 3 factors. Those AAs who passed the health screen (51 of 214) were asked to taste 2 oral prednisolone preparations and reinterviewed about their corticosteroid preferences. Of the 214 AAs, 96% were parents. Of the group, 43% preferred IM corticosteroids whereas 40% preferred oral corticosteroids. Without considering taste as a factor for oral corticosteroids, 94% preferred the more concentrated syrup compared with the less concentrated one. When told that the less concentrated syrup tasted better, 58% preferred the less concentrated/better tasting syrup. After the 51 taste test subcohort subjects tasted the syrups, 96% preferred the less concentrated/ better tasting syrup over the more concentrated/poorer tasting syrup. Taste is more important than volume of administration for this particular corticosteroid comparison. Simply asking parents about their IM/oral and syrup formulation preferences may be the easiest way of optimizing their treatment plan.

Isolation of stereoisomeric epoxy carotenoids and new acetylenic carotenoid from the common freshwater goby Rhinogobius brunneus.

Stereoisomeric epoxy carotenoids with 3,5-cis configuration, diadinoxanthin B [(3S,5S,6R,3'R)-diadinoxanthin] (1) and antheraxanthin B [(3S,5S,6R,3'R)-antheraxanthin] (2), along with diadinoxanthin A [(3S,5R,6S,3'R)-diadinoxanthin] and antheraxanthin A [(3S,5R,6S,3'R)-antheraxanthin], were isolated from the common freshwater goby Rhinogobius brunneus. This is the first example in nature of 3,5-cis carotenoid epoxides. Furthermore, a new acetylenic triol carotenoid, gobiusxanthin (3), was obtained, and its structure was determined to be 7,8-didehydro-beta, epsilon-carotene-3,3', 6'-triol by chemical and spectral data.

Association of insulin resistance with salt sensitivity and nocturnal fall of blood pressure.

Insulin resistance was demonstrated in hypertensive patients and in salt-sensitive subjects. It was recently reported that the salt-sensitive state was related to a reduced fall in blood pressure during the night in essential hypertension. In the present study, the relationship among insulin sensitivity, blood pressure response to salt intake, and nocturnal fall in blood pressure was examined in 20 subjects with nondiabetic and nonobese essential hypertension during a low-salt and a high-salt diet. The subjects were maintained on a low-salt diet (50 mmol/d) and a high-salt diet (255 mmol/d) for 1 week each, in random order. On the sixth day of each diet, blood pressure was measured every hour for 24 hours with an automatic device. Insulin sensitivity was measured according to the steady-state plasma glucose (SSPG) method on the seventh day of each diet. Salt-induced increase in blood pressure, which we defined as the change in 24-hour mean arterial pressure between the low and the high dietary salt intakes, was significantly correlated with SSPG (r=0.60, P<0.01) during the high-salt period. There was a significant negative correlation (r=-0.61, P<0.01) between SSPG and a nocturnal fall in mean arterial pressure during the high-salt period. Salt-induced increase in blood pressure was inversely correlated with a nocturnal fall in mean arterial pressure (r=-0.52, P<0.02) with the high-salt diet. These results suggest that insulin resistance, salt sensitivity, and failed nocturnal fall in blood pressure are associated with each other in subjects with essential hypertension.

Intravascular free tissue factor pathway inhibitor is inversely correlated with HDL cholesterol and postheparin lipoprotein lipase but proportional to apolipoprotein A-II.

To elucidate the distribution and clinical implications of tissue factor pathway inhibitor (TFPI) concentrations, we measured TFPI levels consisting of preheparin free, lipoprotein-bound (Lp-bound), and endothelial cell-anchor pools in 156 patients with coronary artery disease (average age, 61.2+/-9.1 years; range, 32 to 78 years) by heparin infusion (50 IU/kg) and compared them with the preheparin TFPI levels of 229 healthy subjects (average age, 59. 6+/-9.4 years; range, 41 to 80 years). The patients had lower preheparin free TFPI and lower HDL cholesterol (HDL-C) levels than the healthy subjects with equivalent Lp-bound forms (free TFPI, 15. 9+/-6.5 versus 19.2+/-8.1 ng/mL). In a partial correlation analysis, the preheparin free TFPI levels were shown to be inversely correlated with the HDL-C concentrations in both the patients (r=-0. 454, P<0.001) and the healthy subjects (r=-0.136, P<0.05). As determined by comparison of preheparin and postheparin plasma, the patients generally showed preheparin free TFPI <10%, Lp-bound TFPI at 30%, and endothelial cell-anchor TFPI at 60%. When the patients were divided into 4 categories by their LDL cholesterol (LDL-C, 130 mg/dL) and HDL-C (40 mg/dL) levels to specify their coronary risks, the low-HDL-C groups had significantly increased preheparin and postheparin free TFPI levels and decreased postheparin LPL levels, whereas the high-LDL-C groups showed increased levels of Lp-bound TFPI. In a partial correlation analysis, we found a proportional relation between postheparin free TFPI and apolipoprotein A-II (r=0. 5327) and between HDL-C and LPL (r=0.4906), whereas postheparin free TFPI was inversely correlated with HDL-C (r=-0.4280) and postheparin LPL (r=-0.4791). The inverse relationship between TFPI and LPL suggests that increased free TFPI concentrations as a compensatory response of the endothelium to prevent atherothrombotic processes compete with and displace LPL on endothelial surface, resulting in reduced LPL and low HDL-C.

Dynamic SPECT evaluation of renal plasma flow using technetium-99m MAG3 in kidney transplant patients.

OBJECTIVE: The purpose of this study was to evaluate Patlak's graphic analysis method to determine renal plasma flow (RPF) in kidney transplants. METHODS: Dynamic SPECT was performed with 99mTc MAG3 in 12 patients. RPF was determined by both Patlak's graphic analysis method and Russell's method. Ventral, central and dorsal tomographic images of the transplanted kidney were reconstructed to estimate intrarenal distribution of renal plasma flow. RESULTS: The renal influx constant (Ku) calculated by Patlak's graphic analysis method was reproducible and correlated with both serum creatinine (r = -0.88, P < 0.001) and blood urea nitorogen levels (r = -0.82, P < 0.002). However, a significant difference was noted between the RPF values derived from Patlak's graphic analysis method and Russell's method. Ku was corrected by a factor calculated from raw and reconstructed data, and the resulting values were in fair agreement with those determined by Russell's method. CONCLUSION: These methods are useful in evaluating the function of transplanted kidneys.

Effect of carbohydrate intake on serum 3,5,3'-triiodothyronine-response to glucose ingestion and its relation to glucose tolerance in lean non-insulin-dependent diabetic patients.

This study was conducted to know the effect of carbohydrate intake on serum 3,5,3'-triiodothyronine (CAS 6893-02-3, T3)-response to glucose ingestion and its relation to glucose tolerance in lean non-insulin-dependent diabetes mellitus (NIDDM) patients. Ten patients, body mass index: 21.8 +/- 2.2 (mean +/- SD) kg/m2, were given a control diet (2012 kcal/day(d); carbohydrate (CHO): 299 g/d) on admission. Several days later, they were given a low-calorie and low-CHO diet (Low-CHO) (1156 kcal/d; CHO: 139 g/d) and 2 weeks later, they received a low-calorie and high-CHO diet (High-CHO) (1154 kcal/d; CHO: 176 g/d) and another 2 weeks later, they were given Low-CHO again for 2 weeks. They received oral 75 g glucose tolerance tests after completion of each diet. sigma dGlucose (mmol/l) decreased from 54.3 +/- 11.9 (control) to 42.5 +/- 7.5 after Low-CHO and reached 34.5 +/- 10.4 after High-CHO but increased to 36.4 +/- 11.1 after the 2nd Low-CHO (F = 7.46, p = 0.0005). sigma dT3 (nmol/l) increased from -0.18 +/- 0.52 (control) to 0.12 +/- 0.67 after Low-CHO and reached 0.92 +/- 0.59 after High-CHO but decreased to 0.36 +/- 0.65 after the 2nd Low-CHO (F = 5.92, p = 0.0022). Serum insulin and body weight remained unchanged throughout the study. Negative correlation between sigma dT3 and sigma dGlucose (r = -0.493, n = 40, p = 0.0012) was found throughout the diet modification. Carbohydrate intake affected serum T3-response to glucose ingestion and the response was closely related to glucose tolerance in lean NIDDM patients.

Characteristic cardiovascular manifestation in homozygous and heterozygous familial hypercholesterolemia.

BACKGROUND: The aortic valve dysfunction of patients with homozygous familial hypercholesterolemia (FH) suggests that hypercholesterolemia affects not only coronary arteries but also the aortic valve. We studied the aortic root of patients with homozygous FH and those of patients with heterozygous FH to characterize the premature atherosclerotic lesions by using histopathologic specimens. METHODS AND RESULTS: The aortic roots of 10 patients with homozygous FH, age 9 to 58 years, were studied by cardiac catheterization with several angiographies. The aortic roots of 39 patients with heterozygous FH under age 60 years were also examined for aortic and mitral valvular functions by color Doppler echocardiography, and 30 normocholesterolemic patients with coronary artery disease were examined as control subjects. In addition, in 22 patients with FH and 20 control subjects, the internal diameter of the aortic annulus and the aortic ridge in cardiac cycles were measured. Of the 10 homozygotes with FH, 8 patients had aortic regurgitation demonstrated by aortography; 3 of them showed significant transvalvular pressure gradients. Stenotic changes of coronary ostia were observed in 8 of the 10 homozygotes with moderate coronary atherosclerosis. Of the 39 heterozygotes with FH, 10 patients had aortic regurgitation shown by Doppler echocardiography, as did only 1 of the 30 control subjects (P <.05). The average diameter and distensibility of the ascending aorta were significantly reduced in the heterozygotes compared with the control subjects. The surgically resected cusp specimens of aortic valves obtained from 1 homozygous and 1 heterozygous patient showed significant thickening of the cusp with foam cell infiltration. CONCLUSIONS: Premature atherosclerosis in FH had a characteristic distribution, affecting the aortic root dominantly. The involvement of the aortic valve indicating "hypercholesterolemic valvulopathy" was a peculiar feature of FH, especially its homozygous form, but was reminiscent of ubiquitous processes caused by hypercholesterolemia.

Growth of pea epicotyl in low magnetic field: implication for space research.

A magnetic field is an inescapable environmental factor for plants on the earth. However, its impact on plant growth is not well understood. In order to survey how magnetic fields affect plant, Alaska pea seedlings were incubated under low magnetic field (LMF) and also in the normal geo-magnetic environment. Two-day-old etiolated seedlings were incubated in a magnetic shield box and in a control box. Sedimentation of amyloplasts was examined in the epicotyls of seedlings grown under these two conditions. The elongation of epicotyls was promoted by LMF. Elongation was most prominent in the middle part of the epicotyls. Cell elongation and increased osmotic pressure of cell sap were found in the epidermal cells exposed to LMF. When the gravitational environment was 1G, the epicotyls incubated under both LMF and normal geomagnetic field grew straight upward and amyloplasts sedimented similarly. However, under simulated microgravity (clinostat), epicotyl and cell elongation was promoted. Furthermore, the epicotyls bent and amyloplasts were dispersed in the cells in simulated microgravity. The dispersion of amyloplasts may relate to the posture control in epicotyl growth under simulated microgravity generated by 3D clinorotation, since it was not observed under LMF in 1G. Since enhanced elongation of cells was commonly seen both at LMF and in simulated microgravity, all elongation on the 3D-clinostat could result from pseudo-low magnetic field, as a by-product of clinorotation. (i.e., clinostat results could be based on randomization of magnetic field together with randomization of gravity vector.) Our results point to the possible use of space for studies in magnetic biology. With space experiments, the effects of dominant environmental factors, such as gravity on plants, could be neutralized or controlled for to reveal magnetic effects more clearly.

Novel cephalosporin derivatives possessing a bicyclic heterocycle at the 3-position. Part II: Synthesis and antibacterial activity of 3-(5-methylthiazolo[4,5-c]pyridinium-2-yl)-thiomethylcephalosporin derivatives and related compounds.

A series of cephalosporin derivatives with a thiazolopyridinium group at the 3-position was synthesized and evaluated for antibacterial activity. Some of these cephalosporin derivatives having a (5-alkylthiazolo[4,5-c]pyridinium-2-yl)thiomethyl group at the 3-position showed strong activity against Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa. Among them, 5a showed a good antibacterial spectrum in vitro, and also showed a similar or slightly superior activity to that of ceftazidime in vivo against P. aeruginosa.

Novel cephalosporin derivatives possessing a bicyclic heterocycle at the 3-position. Part I: Synthesis and biological activities of 3-(benzothiazol-2-yl)thiocephalosporin derivatives, CP0467 and related compounds.

A series of cephalosporin derivatives with various bicyclic heterocycles at the C-3 position was synthesized and evaluated for antibacterial activity. Among them CP0467 (3a) showed excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) (MIC90 = 6.25 microg/mL), and extremely high affinity for the penicillin binding protein 2' of MRSA (I50 = 0.49 microg/mL). Furthermore, 3a showed a long-acting pharmacokinetic profile in mice (AUC(infinity) = 482.3 microg/h/mL and T(1/2) = 1.9 h).

Development of approximate formula for LDL-chol, LDL-apo B and LDL-chol/LDL-apo B as indices of hyperapobetalipoproteinemia and small dense LDL.

Estimation of LDL-chol and LDL-apo B is useful for the diagnosis of hyperapobetalipoproteinemia (normal LDL-chol with increased LDL-apo B), which is one of the most commonly occurring lipoprotein disorders associated with atherosclerotic cardiovascular diseases. The LDL-chol/LDL-apo B ratio reflects the level of small dense LDL, which is an important risk factor for IHD, CVD and ASO. In order to estimate LDL-apo B and LDL-chol/LDL-apo B ratio from blood chol, TG, HDL-chol and apo B values, we developed a formula for LDL-chol ¿0.94Chol- 0.94HDL-chol - 0.19TG¿, LDL-apo B ¿apo B - 0.09Chol + 0.09HDL-chol-0.08TG¿, and LDL-chol/LDL-apo B [¿0.94Chol-0.94HDL-chol - 0.19TG¿/¿apo B - 0.09Chol + 0.09HDL-chol-0.08TG¿] using ultracentrifugal data from 2179 subjects. These were calculated by the least squares method on the assumption that a certain compositional relationship exists between Chol, TG and apo B in VLDL, IDL and LDL. Friedewald's formula for LDL-chol (Chol - HDL-chol - 0.2TG) includes IDL-chol, but the present new formula theoretically excludes IDL-chol. It suggests a better estimation for the correct LDL-chol. Estimated LDL-apo B is useful for the diagnosis of hyperapobetalipoproteinemia and detection of small dense LDL. Without performing ultracentrifuge, additional information is obtained for the quantitative and qualitative alteration of LDL, such as small dense LDL. The above formulae and a new classification of lipoproteinemia including apo B were applied to the analyses of lipoprotein profiles of subjects with cardiovascular diseases, which were compared with those in the general population. Hyperapobetalipoproteinemia with high TG was observed 2-3 times more frequently in subjects with CAD, MI and ASO than in the Suita population. Lower ratios of LDL-chol/LDL-apo B, reflecting preponderance of small dense LDL, were observed in the above three groups. Type IIb and combined low HDL-chol were also frequent phenotypes in CAD, A-Th and ASO. The present formulae are useful for the detailed analyses of lipoprotein disorders in both qualitative as well as quantitative aspects.