FH Group Research Articles

Influencia de las mutaciones HF Valencia 1 y 2 del gen del receptor de LDL sobre la respuesta terapéutica a simvastatina en sujetos con hipercolesterolemia familiar heterocigota caracterizada molecularmente

To analyse whether the molecular diagnosis in FH patients is useful to predict the response to treatment with simvastatin in a south European population. A randomised clinical trial with no control group, with 20 mg/day of simvastatin was conducted in 27 genetically diagnosed FH subjects (11 male) from 8 FH families, randomly selected from 30 FH families with a molecular diagnosis. Clinical features and lipid parameters at baseline and after simvastatin treatment were compared between subjects classified as null mutations (FH Valencia 1 and 2; n = 11) and defective mutations (n = 16). FH with null mutations (FH Valencia 1 and 2) have a poor response to simvastatin treatment. The mean reduction of plasma LDLc levels in subjects with null mutations were significantly lower (32.6% [9.5] vs 42.8% [12.2]; p = 0.03) than in subjects with defective mutations. Baseline and after treatment plasma HDLc values were also significantly lower in FH group with null mutations. No statistically significant differences were found at baseline, after treatment and in the response to treatment between males and females. FH subjects with null alleles (FH Valencia 1 and 2) showed a poor response to simvastatin treatment. The type of LDL receptor gene mutation could predict the response to simvastatin in our south European FH population.

Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline.

In patients with cystic fibrosis, CF-related diabetes mellitus (CFRD) has been associated with increased morbidity and mortality. Whether glucose intolerance is also associated with poor outcomes is unclear. To better define these relationships we prospectively followed a group of 152 patients with CF without diabetes for 4 yr. Patients were classified as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or CFRD without fasting hyperglycemia (CFRD-No FH). FEV(1), FVC, and body mass index (BMI) were measured at baseline and quarterly. At baseline 45% of the patients had NGT, 38.8% had IGT, and 15.8% had CFRD-No FH. FEV(1), FVC, and BMI at baseline were comparable among these groups (all p > 0.1). After 4 yr an overall decline in FEV(1) and FVC occurred, with no change in BMI. The rates of decline for FEV(1) and FVC correlated with the glucose tolerance groups, with the highest rates of decline occurring among the CFRD-No FH group. In addition, patients in the lowest quartile for insulin production at baseline experienced the highest rates of pulmonary function decline over time, suggesting a relationship between insulin deficiency and clinical deterioration. We conclude that the degree of glucose intolerance is a strong determinant of future lung function decline in patients with CF.

Effects of fasting and insulin-induced hypoglycemia on brain cell membrane function and energy metabolism during hypoxia–ischemia in newborn piglets

This study was done to determine the effects of 12 h fasting-induced mild hypoglycemia (blood glucose 60 mg/dl) and insulin-induced moderate hypoglycemia (blood glucose 35 mg/dl) on brain cell membrane function and energy metabolism during hypoxia–ischemia in newborn piglets. Sixty-three ventilated piglets were divided into six groups; normoglycemic control (NC, n=8), fasting-induced mildly hypoglycemic control (FC, n=10), insulin-induced moderately hypoglycemic control (IC, n=10), normoglycemic/hypoxic–ischemic (NH, n=11), fasting-induced mildly hypoglycemic/hypoxic–ischemic (FH, n=12) and insulin-induced moderately hypoglycemic/hypoxic–ischemic (IH, n=12) group. Cerebral hypoxia–ischemia was induced by occlusion of bilateral common carotid arteries and simultaneous breathing with 8% oxygen for 30 min. The brain lactate level was elevated in NH group and this change was attenuated in FH and IH groups. The extent of cerebral lactic acidosis during hypoxic–ischemic insult showed significant positive correlation with blood glucose level ( r=0.55, p<0.001). Cerebral Na +, K +-ATPase activity and concentrations of high-energy phosphate compounds were reduced in NH group and these changes were not ameliorated in FH or IH group. Cortical levels of conjugated dienes, measured as an index of lipid peroxidation of brain cell membrane, were significantly elevated in NH, FH and IH groups compared with NC, FC and IC groups and these increases were more profound in FH and IH with respect to NH. Blood glucose concentration showed significant inverse correlation with levels of conjugated dienes ( r=−0.35, p<0.05). These findings suggest that, unlike in adults, mild or moderate hypoglycemia, regardless of methods of induction such as fasting or insulin-induced, during cerebral hypoxia–ischemia is not beneficial and may even be harmful in neonates.

VALIDITY OF TWO FIELD TESTS AS PREDICTORS OF AEROBIC CAPACITY IN COMPETITIVE ATHLETES.

1367 The purpose of this study was to compare the efficiency of Yo-Yo Endurance Test (YY) and 12-minute run (Cooper test) (CT) to determine the maximal oxygen uptake (VO2 max.) in elite athletes. We tested 31 competitive sport participants (CSP): 11 male (MH) and 12 female (FH) elite grass hockey players, and 8 male (VP) volley players of International level from the Argentine National Team. It included anthropometric measurements (somatotype), Anaerobic Threshold (Conconi Test)(A.T.), and YY and CT as predictors of aerobic capacity. All this athletes were developing regular training three times a week for the last eight months. Data showed the following results: TableTableStatistical analysis (t-test) showed: no significant difference in VO2 max. determinded with CT and YY in VP group (p=0.473); FH group(p=0.079) and low significant in MH group (p=0.048) (95% confidence interval). We conclude that YO-YO Endurance test not only give an accurately prediction of VO2 max., in competitive sport participants, but also is very useful because it lets determine the different speeds of each stage, specially A.T. level, and is an effective method for regulating exercise intensity for training sessions.

Human chorionic gonadotropin or human recombinant follicle-stimulating hormone (FSH)-induced ovulation and subsequent fertilization and early embryo development in hypophysectomized FSH-primed mice.

Adult hypophysectomized FSH-primed mice were used to study ovulation, fertilization, and preimplantation embryo development. Twelve days after hypophysectomy, animals were injected sc with oFSH (4 micrograms/day) twice a day for 3 days. This resulted in large preovulatory follicles that did not secrete estrogen. Concurrent with the last FSH injection, either hCG (5 IU) or human recombinant FSH (10 IU) was injected sc to induce ovulation. Animals were mated or not and killed 1-4 days later. The ovulation rate was similar for both the hCG-induced group (FH) and the FSH-induced group (FF), 97% and 90%, respectively. About 45% of the FH mice mated successfully with 56% of the eggs fertilized compared to only 25% of the FF mice with 45% of the eggs fertilized. However, only 5% of ovulated eggs developed to four-cell stages in vivo by day 3 for the FH animals and none in the FF group. To determine the reasons for the in vivo retarded embryo development, embryos at the one- or two-cell stage were collected on day 2 from the FH group. After 96 h of culture, 22% of two-cell embryos were converted to blastocysts, and 11% of one-cell eggs divided to the four-cell stage. In contrast, 80% of two-cell embryos from normal mice develop into blastocysts by 72 h of culture. The ovarian incubation medium and serum were used to measure progesterone (P4), androstenedione (A), and estradiol (E2). The patterns of serum and in vitro production of steroids were parallel. In FH mice, P4 increased immediately on the day after hCG injection (day 1) and decreased progressively on days 2 and 3; A and E2 levels increased on day 2, A decreased on day 3, and E2 decreased on day 4. When human recombinant FSH was used to induce ovulation, there were no significant changes in serum P4 and A; E2 levels were about 4 times higher on day 1 than in the FSH-primed control, then dropped to baseline levels on days 2 and 3. However, on day 3 in both the FH and FF groups, FSH receptors were still present on the granulosa cells of antral follicles, and LH/hCG receptors were present on the granulosa cells of large antral follicles and newly formed corpora lutea.(ABSTRACT TRUNCATED AT 400 WORDS)

A Gender Difference in the Association Between Salt Sensitivity and Family History of Hypertension

We examined 174 subjects (82 men and 92 women) with essential hypertension to determine whether gender played an important role in the association of blood pressure (BP) familial disposition, and hypertension. To evaluate the salt sensitivity of BP, we measured changes in blood pressure after restricting salt intake from about 15 g/day to less than 3 g/day. The familial disposition to hypertension was categorized into four groups according to the presence or absence of hypertension in the father, mother, and siblings. If none, one, two, or three family members had hypertension, they were assigned the FH(-), FH(+), FH(++), and FH( ) groups, respectively. Only in women did the FH(-) group show a significantly smaller blood pressure reduction than that of the other groups. The mean BP reduction in the four groups was 4.1 +/- 1.9, 8.5 +/- 1.1, 10.1 +/- 1.5, and 11.2 +/- 2.8 mm Hg (mean +/- SEM), respectively. This difference in BP reduction was not observed in men. Multiple regression analysis, using percent changes in mean BP as the dependent variable and other factors as independent variables, also showed a significant partial correlation coefficient for familial disposition to hypertension only in women. Thus, the relationship between salt sensitivity and familial disposition to hypertension differed according to gender. This difference may provide an important insight into the hereditary nature of hypertension.

Influence of apo E polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia

In a group of 120 patients with heterozygous familial hypercholesterolemia (1711) the influence of the apolipoprotein E (apoE) polymorphism on pre-treatment plasma lipid levels and on the response to treatment with simvastatin was studied. The apoE phenotype distribution did not differ significantly between the FH group and a sample group of the Dutch population. Differences in pre-treatment lipid levels were not related to the apoE polymorphism in this FH population. After 12 weeks use of a daily dose of 40 mg simvastatin, the plasma total cholesterol, low density lipoprotein (LDL)-cholesterol and plasma triglyceride levels were reduced on average by 33%, 38% and 19% respectively. At the same time high density lipoprotein (HDL)-cholesterol concentration increased on average by 7%. In the combined FH patient group (males and females) a considerable interindividual variation in response to simvastatin was observed, but was not related to the apoE polymorphism. However, considering males and females separately, we found that female FH patients with the apoE3E3 phenotype responded better on simvastatin treatment with respect to LDL-cholesterol than male FH patients with the apoE3E3 phenotype.

Relation of Serum and Erythrocyte Magnesium Levels to Blood Pressure and a Family History of Hypertension A Follow‐up Study in Japanese Children, 12‐14 Years Old

Serum and erythrocyte magnesium concentrations (S-Mg, E-Mg) were measured in 122 junior high school students followed up for two years from 12 to 14 years of age, and the relationship to blood pressure and a family history of hypertension were investigated. The subjects who had high S-Mg and E-Mg levels at the first examination two years prior tended to show high levels after this follow-up. There were significant positive correlations between two intraindividual values of S-Mg and E-Mg. A similar tendency was found for blood pressure. Tracking phenomena were observed with these measures. The subjects who had high E-Mg levels at the first examination showed no blood pressure elevation during the two-year period. The subjects with a family history of hypertension [FH(+)] showed a higher degree of blood pressure rise during two years than those with no family history [FH(-)], with a significant difference in systolic blood pressure at the age of 14. E-Mg tended to be lower in the FH(+) group than in the FH(-) group with a significant difference in 14-year-old girls. These results suggest that a hereditary predisposition to hypertension is related to magnesium metabolism and that intracellular magnesium deficiency may influence blood pressure elevation in the FH(+) children.

動脈硬化性疾患における非侵襲的動脈硬化診断法の意義

Arteriosclerosis was classified by the pathological study, but not due to the clinical examination. The purpose of the study is to develop the noninvasive methods for the clinical diagnosis of arteriosclerosis and to evaluate the relation of arteriosclerosis diagnosed by these methods to the arteriosclerotic vascular diseases such as coronary heart disease (CHD), cerebrovascular disease (CVD) and atherosclerosis obliterans (ASO).The 291 in- and out-patients of both sexes aged 21 to 88 years inclusive of 83 CHD, 48 CVD, 41 ASO and 30 familiar hypercholesterolemic patients (FH), who were visited NCVC-Hospital, were investigated the severity of arteriosclerosis. The calcification index (C. I.) and the wall thickening and stenosis index (S. I.) were calculated from the computed tomography (CT) of the abdominal aorta (AA) and the common iliac artery (CIA) before and after the enhancement with 76% urographine. The C. I. and the S. I. of the AA were highly correlated with those of the lower part of the abdominal aorta (LAA) defined as the upper part within 4 cm of the aorto-iliac bifurcation, (r=0.957, n=54 and r=0.945, n=48) respectively. The C. I. of the LAA was also correlated with that of the CIA. (r=0.721, n=111)The pulse wave velocity of the aorta (PWV) and ocular fundi were examined in a majority of patients on the same opportunity. Significant correlations between the C. I. and the S. I. of the LAA, (r=0.557, n=224) the C. I. of the LAA and the PWV (r=0.435, n=202) and the S. I, of the LAA and the PWV (r=0.224, n=177) were seen, but the grade of retinal arteriosclerosis was not correlated with the C. I., the S. I. or the PWV. Among the same age group, the most obvious personal variation and the remarkable difference between the arterioscleritic vascular disease (ASVD) and the non-vascular disease (NVD) groups appeared in the S. I. of the LAA, while no significant difference between the ASVD and the NVD groups was observed, in the PWV. Fifty-two per cent in the ASVD group, 25% in the male NVD group and 18% in the female NVD group showed higher value over 40 score of S. I., on the contrary, all CVD patients with 0 score of the S. I. had the retinal arteriosclerosis, as well as 5 of 7 vasospastic CHD patients got O score of the S. I. and the relative higher value of the C. I. compared with that of the S. I. In the FH group, high score of 52.7 of the S. I. but the normal PWV of 678 cm/sec were observed.In conclusion, (1) the severity of atherosclerosis was diagnosed by the S. I. of the LAA, which might be the best predictable sign for the atherosclerotic vascular disease. (2) The C. I. would be useful for the diagnosis of Monckeberg's sclerosis or atherosclerosis when compared with the S. I. (3) Arteriolosclerosis could be assessed partly by the retinal findings. (4) The PWV would appear the change of the connective tissue of arteries due to the aging, the chronic inflammation and the other causes, but not the index of atherosclerosis.

Studies on regulatory functions of malic enzymes. VII. Structural and functional characteristics of sulfhydryl groups in NADP-linked malic enzyme from Escherichia coli W.

NADP-linked malic enzyme from Escherichia coli W contains 7 cysteinyl residues per enzyme subunit. The reactivity of sulfhydryl (SH) groups of the enzyme was examined using several SH reagents, including 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) and N-ethylmaleimide (NEM). 1. Two SH groups in the native enzyme subunit reacted with DTNB (or NEM) with different reaction rates, accompanied by a complete loss of the enzyme activity. The second-order modification rate constant of the "fast SH group" with DTNB coincided with the second-order inactivation rate constant of the enzyme by the reagent, suggesting that modification of the "fast SH group" is responsible for the inactivation. When the enzyme was denatured in 4 M guanidine HCl, all the SH groups reacted with the two reagents. 2. Althoug the inactivation rate constant was increased by the addition of Mg2+, an essential cofactor in the enzyme reaction, the modification rate constant of the "fast SH group" was unaffected. The relationship between the number of SH groups modified with DTNB or NEM and the residual enzyme activity in the absence of Mg2+ was linear, whereas that in the presence of Mg2+ was concave-upwards. These results suggest that the Mg2+-dependent increase in the inactivation rate constant is not the result of an increase in the rate constant of the "fast FH group" modification. 3. The absorption spectrum of the enzyme in the ultraviolet region was changed by addition of Mg2+. The dissociation constant of the Mg2+-enzyme complex obtained from the Mg2+- dependent increment of the difference absorption coincided with that obtained from the Mg2+- dependent enhancement of NEM inactivation. 4. Both the inactivation rate constant and the modification rate constant of the "fast SH group" were decreased by the addition of NADP+. The protective effect of NADP+ was increased by the addition of Mg2+. Based on the above results, the effects of Mg2+ on the SH-group modification are discussed from the viewpoint of conformational alteration of the enzyme.

Nychthemeral and seasonal patterns of thermoregulation in cattle

1. The nychthemeral (24 hr) and seasonal cycles in thermoregulation at high (Fh) and standard (Fs) levels of feeding were studied in Holstein heifers during spring (mean daily air temperature 18.2°C) and late summer (mean daily air temp. 27.5°). 2. In the two seasons the percentage respiratory evaporative cooling (% RC) and rectal temperature (Tr) displayed marked nychthemeral cycles in both feeding groups, while heat production (Hp) cycles were evident in the Fh group only. 3. In both seasons the effect of the 22.4% larger Hp in the Fhgroup was to prolong the duration of higher % RC; Tr was relatively increased in the summer only. 4. The seasonal changes were: a 20% reduction in Hp in both groups; a larger amplitude of Hp cycling (19% of the mean in summer and 12.9% in spring) in the Fh group; a higher Tr (+ 0.40°C in the Fs group and + 0.63° in the Fh group), cycling with a larger amplitude (0.33° v. 0.52°); a 21° depression in feed intake in the Fh group and 9° in the Fs group. 5. Within each season Tr and the rate of change in Tr were significantly correlated with Hp in the Fh group only. On a between-season basis Hp and Tr were significantly correlated in both feeding groups. These suggest that the relationship between body temperature and heat production follows different patterns in nychthemeral cycles from those in seasonal changes. 6. The nychthemeral patterns of respiratory, %RC, Tr, and Hp responses indicated that the animals were acclimatized to the seasonal change in Tr, possible through a shift in the set-point for temperature control. The depression in heat production and feed intake did not prevent the maintenance of a normal rate of growth.