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PubMed2006

Monoamine and motor responses to cocaine are co-deficient in the Fawn-Hooded depressed animal model.

The Fawn-Hooded (FH) genetic animal model of depression continues to be of interest because the FH model has limited biochemical and immune function. The FH animal has an inherited trait, platelet storage pool deficiency (PSPD), an hemorrhagic disorder that is also a component of Chediak-Higashi syndrome (CHS). CHS is a pyrogenic infectious childhood disease; few patients live past the age of 20. Our hypothesis was that FH animals may exhibit different monoamine and motor responses to cocaine versus the Sprague-Dawley (SD) "normal" animal strain, which does not have the FH trait. Therefore, selective neuromolecular imaging (NMI) of the monoamines, dopamine (DA) and 5-HT within nucleus accumbens (NAcc) of behaving male FH versus SD rats was performed in vivo with BRODERICK PROBE sensors and a semiderivative voltammetric circuit. Each animal was placed in a faraday chamber and electrochemical signals were detected via a mercury commutator and flexible cable. Baseline values for neurotransmitters and behavior were derived during the last half-hour of habituation behavior. Release of DA and 5-HT was detected selectively, at separate oxidation potentials, within seconds, before and after intraperitoneal administration of the psychostimulant, cocaine (10 mg/kg). At the same time, frequencies of ambulations and central ambulations were separately monitored with infrared photobeams, which surrounded the faraday chamber. Data were compared by ANOVA analysis followed by Tukey's post hoc test. The data showed that (1) DA release in NAcc of behaving FH animals did not respond to cocaine; neither first hour nor second hour values significantly differed from baseline (both hours, p>0.05), whereas SD animals exhibited a significant increase in cocaine-induced DA release in NAcc (both hours, p<0.001). The ability for acute cocaine to increase DA release in NAcc was significantly greater in SD than in FH animals (p<0.001). (2) 5-HT release in NAcc of behaving FH animals was not significantly increased by cocaine (both hours, p>0.05), whereas 5-HT release in NAcc of SD animals was significantly increased after cocaine (both hours, p<0.001). The ability for acute cocaine to increase 5-HT release was significantly greater in SD than in FH animals (p<0.001). (3) Ambulations in the FH strain were modestly, yet significantly, enhanced after cocaine during both hours of study (p<0.05, p<0.001, respectively) as were ambulations in the SD strain. Nonetheless, the ability for acute cocaine to increase ambulations was significantly greater in SD than in FH animals in the first hour (p<0.001). (4) Central ambulations in the FH strain was not affected by cocaine (both hours, p>0.05), whereas SD animals showed a significant increase in central ambulatory activity in both hours of the cocaine study (p<0.001). The ability for acute cocaine to increase central ambulations was significantly greater in SD than in FH animals (p<0.001). Thus, this is the first study to determine in vivo the neurochemical response to acute cocaine in the behaving FH animal. Moreover, this is the first study to determine in vivo and simultaneously the neurochemical and behavioral response to acute cocaine in the FH strain in comparison with SD animals, a "normal" strain. Remarkable deficiencies in the ability for acute cocaine to alter neurochemistry and behavior in animals with the FH trait are shown. These studies emphasize the need to look differentially at cocaine effects in biochemically and immune-compromised subjects versus "normal" subjects.

Animals↗

PubMed1997

Comparison of the effect of two low-density lipoprotein receptor class mutations on coronary heart disease among French-Canadian patients heterozygous for familial hypercholesterolaemia.

The aim of this study was to compare the age at first elective coronary angiogram and the age at first revascularization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) in 102 patients without familial hypercholesterolaemia (FH), who were matched for age and sex with 76 heterozygous FH patients carrying a defective allele at the low-density lipoprotein (LDL) receptor gene (LDL-R) and 26 heterozygous FH patients bearing a null mutation at the LDL-R. The prevalence of diabetes was significantly higher in the non-FH group than in the two FH groups (P < 0.05). Furthermore, mean body mass index (BMI) and waist circumference values were also higher in the non-FH group than in the two FH heterozygous groups (P < 0.005). However, FH patients who were null allele carriers had the highest plasma total and LDL-cholesterol levels and the highest cholesterol/HDL-cholesterol ratio, whereas the defective allele carriers group had intermediate levels between null allele carriers and non-FH patients. Comparison of the age at first coronary angiography revealed that the null allele carriers group were younger at first angiogram than the non-FH patients (P < 0.005). In addition, a trend was observed for a younger age at first angiogram in FH heterozygotes bearing a null allele than in carriers of a defective allele (P = 0.06). Moreover, null allele carriers were younger at first revascularization than defective allele carriers (P < 0.005) or non-FH patients (P < 0.005). Finally, the mean number of diseased vessels with > 50% stenosis was higher in null allele carriers than in non-FH patients and tended to be higher than among defective allele carriers (P < 0.01). Although no difference in plasma Lp(a) levels were noted between null allele carrier and non-FH patients, plasma Lp(a) concentrations were higher in the defective allele group than in the other two groups. In summary, the development of coronary artery disease as estimated by the age at first elective coronary angiography or at first revascularization is premature in FH patients carrying a null mutation compared with defective allele carriers or with non-FH patients. Moreover, the higher number of stenosed vessels among null allele carriers suggests that coronary artery disease was more severe in FH subjects with a null allele at the LDL-R locus.

Adult↗

PubMed1999

Discrimination of two different clinical entities, acute-type and subacute-type, human fulminant hepatitis by peripheral blood lymphocyte subsets.

Human fulminant hepatitis tends to be classified into two groups: acute type (A-FH) and subacute type (S-FH). In order to define these two clinical entities more precisely, we examined and compared peripheral blood lymphocyte subsets in A-FH and S-FH patients. We found that S-FH patients had a higher prevalence of CD19+ B cells (31.1 +/- 7.6% in S-FH vs 12.7 +/- 3.7% in A-FH) and also a lower prevalence of CD3+T cells (50.2 +/- 8.7% in S-FH vs 65.6 +/- 10.5% in A-FH). Furthermore, by examining the absolute cell numbers of these subsets, we determined that their imbalance in S-FH was mainly due to a decrease in CD3+ T cells. Among several T cell subsets, the CD8+CD11b-T cell subset was elevated in A-FH and decreased in S-FH (6.1 +/- 2.1% in S-FH, 24.4 +/- 5.8% in A-FH, and 14.8 +/- 7.8% in control). Serial studies of two S-FH patients revealed that the imbalance of these lymphocyte subsets returned to their proper ratio together with the improvement of their liver injury. These results indicate that there might be a different immunological background between A-FH and S-FH.

B-Lymphocyte Subsets↗

PubMed2002

Positive family history for coronary heart disease and 'midband lipoproteins' are potential risk factors of carotid atherosclerosis in familial hypercholesterolemia.

Patients with heterozygous familial hypercholesterolemia (FH) were examined with B-mode ultrasound in order to determine intima-media thickness (IMT) in the common carotid artery, and to uncover potential risk factors responsible for the development of IMT. Ninety seven FH subjects and 132 non FH type IIa hyperlipidemic subjects were involved in the present study. Age was found to correlate positively with IMT in both FH and non FH groups. FH individuals showed a higher IMT, along with elevated low density lipoprotein (LDL) cholesterol levels, compared with age-matched non FH individuals. To clarify potential factors contributing to the formation and development of carotid atherosclerosis, we divided the FH subjects into two subgroups, namely FH with high IMT group (HIG), and those with low IMT group (LIG). We investigated those two subgroups on the presence of angiographically documented coronary heart disease (CHD), of family history of CHD and of 'midband lipoproteins' by polyacrylamide gel electrophoresis (PAGE) analysis, by matching for age and LDL-cholesterol (LDL-C) level. Fifty percent of FH men in HIG was found to have CHD, whereas only 14% of those in LIG had CHD (P<0.05). Thirty-three percent of FH women in HIG was found to have CHD, whereas only 12% of those in LIG had CHD (P<0.05). Fifty percent of FH men in HIG was found to have 'midband lipoproteins', whereas only 7% of those in LIG had 'midband lipoproteins' (P<0.01). Seventy-three percent of FH women in HIG had 'midband lipoproteins', whereas only 21% of those in LIG had 'midband lipoproteins' (P<0.0005). Fifty-five percent of FH men in HIG was had positive family history for CHD, whereas only 14% of those in LIG had positive family history for CHD (P<0.05). Sixty-three percent of FH women in HIG was found to have positive family history for CHD, whereas only 29% of those in LIG had positive family history for CHD (P<0.05). Based on these findings, we propose that, besides age and elevated levels of LDL-C, positive family history for CHD and 'midband lipoproteins' are important determinants for the development of carotid atherosclerosis in FH individuals in Japanese population.

Carotid Artery Diseases↗

PubMed2002

Cholesterol metabolism in normal and heterozygous familial hypercholesterolemic newborns.

In heterozygous familial hypercholesterolemia (FH), serum low-density lipoprotein (LDL) cholesterol levels are frequently increased in utero. A unique Finnish FH population, FH-North Karelia (FH-NK), has been identified, providing an excellent opportunity to study the diagnostic significance of cholesterol metabolism in FH. For that purpose, we investigated lipoprotein lipids, cholesterol precursors (squalene, methyl, and demethyl sterols), cholestanol, and plant sterols in FH-NK newborns (n = 5), non-FH siblings (n = 7), and controls (n = 20) at birth and after 1-year follow-up in 8 FH-NK and 5 non-FH children. The sum of concentrations (micrograms per deciliter) of methyl sterol (8-monomethylsterol, methostenol, 8-dimethylsterol, 8,24-dimethylsterol, and lanosterol) and squalene was higher in FH newborns than in non-FH siblings but overlapped with one control case. Cord-blood total or LDL cholesterol values could not be used for diagnostic purposes, whereas 1-year LDL cholesterol values were highly superior to those measured at birth. The methyl sterol ratio in cord blood was 29 to 193 10(2) mmol/mol cholesterol and was undetectable in serum at the age of 1 year; those of the demethyl precursor sterols were 1.5 to 8 times higher in cord blood than in serum at the age of 1 year, suggesting that cholesterol synthesis was markedly increased at birth. Plant sterols, not synthesized in human beings, were already present in serum of all the groups at birth, indicating their transfer, apparently with cholesterol, from mother to fetus. Babies born to FH mothers showed a greater tendency toward accelerated cholesterol synthesis than did those born to FH fathers. Despite signs of markedly high but similar synthesis of cholesterol at birth in FH and non-FH newborns, the diagnosis of FH was questionable by measurement of cholesterol precursors or LDL cholesterol in cord blood. The latter measurement, at the 1-year mark, is superior for diagnostic purposes.

Cholesterol↗

PubMed2000

Primary aldosteronism: learning from the study of familial varieties.

Primary aldosteronism (PAL) has been traditionally regarded as a rare cause of hypertension and not worth looking for in the absence of hypokalemia. However, the availability of the aldosterone/renin ratio as a screening test and its application to a wider population of hypertensives has resulted in a marked increase in detection rate, suggesting that PAL is common, with most patients being normokalemic. The spectrum of PAL has been expanded further by the study of familial varieties, in which family screening efforts have permitted the recognition of earlier, sometimes even pre-clinical, stages of disease. Familial hyperaldosteronism type I(FH-I) In FH-I, inheritance of a 'hybrid' 11beta-hydroxylase/aldosterone synthase gene causes adrenocorticotrophic hormone (ACTH)-regulated aldosterone and 'hybrid steroid' (18hydroxy-cortisol and 18-oxo-cortisol) overproduction. Genetic testing, by Southern blot or polymerase chain reaction-based techniques, has greatly facilitated detection, being more convenient and more reliable than dexamethasone suppression testing, and has led to a fuller appreciation of the marked phenotypic variability in this disorder. The demonstration of excessive, abnormally regulated aldosterone production in normotensive subjects with FH-I suggests that absence of hypertension in such individuals cannot merely be attributed to lack of expression of the hybrid gene. Determinants of hypertension severity may include patient gender, gender of affected parent, degree of hybrid gene expression, and interactions with other genetic and environmental factors. Detailed biochemical studies, including analyses of aldosterone/PRA/cortisol 'day-curve' levels, have led to a fuller understanding of aldosterone regulation both before and in response to glucocorticoid treatment in this condition, and prompted a re-examination of current approaches to treatment Unless ACTH is completely suppressed by glucocorticoid treatment, the hybrid gene dominates over the wild-type aldosterone synthase genes in terms of aldosterone production, both in untreated and treated FH-I. This may in part be due to an abnormality affecting the functional expression of the 'wild-type' genes. Demonstration of persisting hybrid gene expression in patients rendered normotensive by very low doses of glucocorticoids suggests that currently recommended doses, aimed at normalizing aldosterone regulation (rather than blood pressure), may be too high, and may therefore place patients at unnecessary risk of developing Cushingoid side effects. Familial hyperaldosteronism type II (FH-II) Like FH-I, FH-II is associated with hyperaldosteronism and probable autosomal dominant inheritance. Unlike FH-I, hyperaldosteronism in FH-II is not dexamethasone suppressible, and is not associated with the hybrid gene mutation. Detection of adrenal mass lesions, which are frequently (17 of 57 patients in the Greenslopes Hospital series) responsible for PAL in FH-II, does not help to differentiate FH-II from FH-I, since mass lesions may also be common in that condition (detected in seven of 21 patients). Biochemically and morphologically, FH-II is indistinguishable from apparently non-familial PAL, and demonstrates similar variability even among individuals of the same family. In one informative family available for linkage analysis, FH-II does not segregate with either the AT1 gene or the CYP11B2 gene, or any other genetic defect in the chromosome 8q21-8qtel region. A genome-wide search is in progress. As has already occurred in FH-I, the elucidation of underlying genetic mutations in FH-II is likely to facilitate early detection, thereby helping to broaden its spectrum and to permit close follow-up and appropriately timed institution of specific therapy, and wider detection among patients with hypertension of potentially curable or specifically treatable forms.

Family Health↗

PubMed2000

Continuous measurements of instantaneous heart rate and its fluctuations before and after hatching in chickens.

There has been considerable interest in heart rate (fh) fluctuations in relation to cardiovascular control systems and foetal conditions during pregnancy in mammals. Prominent fluctuations in fh also occur in avian embryos, which are an important experimental model for studying developmental physiology. The present study determined the instantaneous fh of seven chick embryos continuously from the last stage of prenatal development (day 18), throughout the pipping (perinatal) period (days 19-21) until hatching and, subsequently, of newly hatched chicks (up to day 2). The distinctive patterns of instantaneous fh fluctuations took the form of specific changes within a broad mean fh baseline. Cyclic oscillations (ultradian rhythm) occurred until an early stage of the perinatal period, when the fh baseline started rising. Subsequently, the baseline dropped and respiratory arrhythmia began to appear concomitant with external pipping. During the final stage of external pipping, when the fh baseline rose again prior to hatching, three unique patterns of instantaneous fh fluctuations were evident: relatively long-lasting cyclic small accelerations, irregular intermittent large accelerations and short-term repeated large accelerations. Furthermore, repeated alternate occurrences of the latter two types of acceleration formed an additional oscillating pattern with a period of 10-15 min. During the early period after hatching, when the fh baseline reached its maximum, instantaneous fh changed relatively slowly accompanied by transient rapid decelerations, probably due to augmented vagal tone. Subsequently, the mean fh baseline dropped to its minimum, and a circadian rhythm and three types of previously reported fh fluctuations (types I-III) appeared. Developmental patterns of mean fh and the appearance of distinctive patterns of instantaneous fluctuations in fh and circadian rhythms were not influenced by an ultimate failure of hatching after a normal development. The demonstration of complex, repeatable patterns of fh fluctuation that change during development suggests that the avian embryo model should be useful in studying the phenomenon of fh fluctuation and its underlying causes.

Animals↗

PubMed1993

Restriction fragment length polymorphisms of the human renin gene: association study with a family history of essential hypertension.

The aim of this study was to elucidate whether human renin gene restriction fragment length polymorphism (RFLP) is associated with essential hypertension. We sampled randomly 45 inpatients at our hospital and divided them into two groups according to a family history of essential hypertension, FH(-) and FH(+) groups. The FH(+) group was further divided into two subgroups based on the level of BP, FH(+) x HT(-) and FH(+) x HT(+) groups. The frequencies of renin gene RFLP patterns were compared among three groups: FH(-), FH(+) x HT(-) and FH(+) x HT(-). Among 18 restriction endonucleases tested, renin gene RFLPs were detected by three restriction endonucleases, Mbo I, Bg I and Hind III, digestion. There was a significant difference in the distribution of renin gene Mbo I genotypes among the three groups (chi 2 = 13.284, P < 0.01). The distribution of Mbo I genotypes in the FH(-) group was different from FH(+) x HT(-) group (chi 2 = 5.990, P < 0.05) and FH(+) x HT(+) group (chi = 9.210, P < 0.01), but there was no significant difference between the FH(+) x HT(-) and FH(+) x HT(+) groups. The distribution of renin gene Bgl I and Hind III genotypes were similar in the three groups, FH(-), FH(+) x HT(-) and FH(+) x HT(+). These results indicate that human renin gene Mbo I RFLP is significantly associated with a family history of essential hypertension.

Adolescent↗

PubMed2001

Folded-back solution structure of monomeric factor H of human complement by synchrotron X-ray and neutron scattering, analytical ultracentrifugation and constrained molecular modelling.

Factor H (FH) is a regulatory cofactor for the protease factor I in the breakdown of C3b in the complement system of immune defence, and binds to heparin and other polyanionic substrates. FH is composed of 20 short consensus/complement repeat (SCR) domains, for which the overall arrangement in solution is unknown. As previous studies had shown that FH can form monomeric or dimeric structures, X-ray and neutron scattering was accordingly performed with FH in the concentration range between 0.7 and 14 mg ml(-1). The radius of gyration of FH was determined to be 11.1-11.3 nm by both methods, and the radii of gyration of the cross-section were 4.4 nm and 1.7 nm. The distance distribution function P(r) showed that the overall length of FH was 38 nm. The neutron data showed that FH was monomeric with a molecular mass of 165,000(+/-17,000) Da. Analytical ultracentrifugation data confirmed this, where sedimentation equilibrium curve fits gave a mean molecular mass of 155,000(+/-3,000) Da. Sedimentation velocity experiments using the g*(s) derivative method showed that FH was monodisperse and had a sedimentation coefficient of 5.3(+/-0.1) S. In order to construct a full model of FH for scattering curve and sedimentation coefficient fits, homology models were constructed for 17 of the 20 SCR domains using knowledge of the NMR structures for FH SCR-5, SCR-15 and SCR-16, and vaccinia coat protein SCR-3 and SCR-4. Molecular dynamics simulations were used to generate a large conformational library for each of the 19 SCR-SCR linker peptides. Peptides from these libraries were combined with the 20 SCR structures in order to generate stereochemically complete models for the FH structure. Using an automated constrained fit procedure, the analysis of 16,752 possible FH models showed that only those models in which the 20 SCR domains were bent back upon themselves were able to account for the scattering and sedimentation data. The best-fit models showed that FH had an overall length of 38 nm and is flexible. This length is significantly less than a predicted length of 73 nm if the 20 SCR structures had been arranged in an extended arrangement. This outcome is attributed to several long linker sequences. These bent-back domain structures may correspond to conformational flexibility in FH and enable the multiple FH binding sites for C3 and heparin to come into close proximity.

Amino Acid Sequence↗

PubMed1987

Coronary angiographic characteristics in Japanese patients with heterozygous familial hypercholesterolemia.

Coronary angiographic findings were analyzed in 51 consecutive patients (36 males and 15 females) with heterozygous familial hypercholesterolemia (FH) and 279 consecutive patients (216 males and 63 females) without FH (non-FH). The coronary stenosis index and over 75% stenosis vessel subset were almost three times as high in the FH group. The incidence of myocardial infarction was almost twice as high in the FH group. Levels of total cholesterol and its lipoprotein fractions, except HDL-cholesterol, were almost twice as high in the FH group. In the FH group aged under 50 years, the two parameters of coronary angiogram and the incidence of myocardial infarction were significantly higher in males than in females. However, in the group aged over 50 years, all three parameters were not significantly different between those in males and females. The level of HDL-cholesterol was significantly lower in males than in females. A significantly higher incidence (18%) of coronary ectasia was observed in the FH group compared with the incidence (2%) in non-FH. All patients with coronary ectasia were males, except one female with FH. On comparison of the males among the FH patients with those among the non-FH patients matched for total cholesterol, age and other risk factors, the FH patients were associated with a significantly higher degree of coronary atherosclerosis and lower level of HDL-cholesterol. Seven FH patients with a normal coronary angiogram were observed. However, any factors as regards age, total cholesterol, HDL-cholesterol and Achilles tendon thickness failed to distinguish between the FH patients with a normal coronary angiogram and those without.(ABSTRACT TRUNCATED AT 250 WORDS)

Achilles Tendon↗

PubMed1995

Heterozygous familial hypercholesterolaemia: the influence of the mutation type of the low-density-lipoprotein receptor gene and PvuII polymorphism of the normal allele on serum lipid levels and response to lovastatin treatment.

OBJECTIVES: To study whether (i) the low-density-lipoprotein (LDL)-receptor gene mutation type itself or (ii) the PvuII restriction-fragment-length polymorphism (RFLP) of the intact LDL-receptor gene affects serum lipid levels and their responses to lovastatin treatment in heterozygous familial hypercholesterolaemia (FH). DESIGN: Comparison of serum lipid levels in 149 heterozygous FH patients, including 79 patients with the FH Helsinki gene and 70 patients with the FH North Karelia gene, grouped according to the PvuII RFLP status of their nonmutated LDL-receptor allele; studies of lovastatin responses in 23 FH patients with different mutation types. SUBJECTS: Molecularly defined heterozygous FH patients. INTERVENTIONS: DNA analysis by polymerase chain-reaction assay (PCR) and Southern blotting, fasting serum lipid measurements in all patients, and administration of lovastatin 40-80 mg daily to 16 FH Helsinki patients and seven FH North Karelia patients. MAIN OUTCOME MEASURES: Baseline and post-treatment serum cholesterol. LDL cholesterol, high-density-lipoprotein (HDL) cholesterol and triglyceride levels. RESULTS: There were no significant differences in serum total or LDL-cholesterol levels in FH patients with the FH Helsinki gene compared with those carrying the FH North Karelia gene. Regardless of the mutation type, patients without the PvuII site in the normal LDL-receptor gene (P--subjects) tended to have 6-8% higher serum and LDL-cholesterol levels than patients possessing this restriction site (P+ subjects). Although not statistically significant, this difference is qualitatively and quantitatively similar to that reported in three different non-FH populations. Treatment with lovastatin brought about similar hypolipidaemic responses in FH patients with either mutation type (FH Helsinki or FH North Karelia) or PvuII RFLP status (P+ or P-). CONCLUSIONS: Two LDL-receptor gene mutations with dissimilar phenotypic characteristics are associated with similar serum lipid levels and response to statin treatment. Our data also support the previous assumption that the PvuII RFLP of the LDL-receptor gene locus is associated with variation of serum cholesterol levels.

Alleles↗

PubMed2004

Family history of coronary artery disease and prognosis after first acute myocardial infarction in a national survey.

A positive family history (FH) of coronary artery disease (CAD) is considered an independent risk factor for developing CAD. However, the natural history, coronary angiographic findings and prognosis of patients with a positive FH developing first acute myocardial infarction (AMI) are not well defined. A cohort of 2,690 consecutive patients with first AMI from two prospective nationwide surveys conducted during 1996 and 1998 in all coronary care units operating in Israel was studied. Baseline characteristics, hospital course, management and outcome of 405 patients with first AMI and a positive FH were compared with 2,285 controls without a positive FH. Coronary angiograms of patients with and without a positive FH were reviewed and compared. Patients with a positive FH were younger (53 vs. 64 years), more often male, current smokers and patients with hyperlipidemia, but less often patients with diabetes or hypertension than patients without a positive FH. Patients with a positive FH developed heart failure during hospital stay less frequently. Thrombolytic therapy was similarly administered to both groups. During the hospital stay, coronary angiography, percutaneous coronary intervention or coronary artery bypass grafting were more frequently performed in patients with a positive FH. The coronary anatomy and the extent of the CAD were similar in patients with and without a positive FH. Crude and covariate-adjusted mortality rates were significantly lower in patients with a positive FH than in patients without a positive FH on day 30 (2.2 vs. 9.6%, p < 0.001; odds ratio 0.50, 95% confidence interval 0.22-0.99) and at 1 year (3.5 vs. 14%, p < 0.001; hazard ratio 0.58, 95% confidence interval 0.42-0.80). Patients with a positive FH developed their first AMI more than 1 decade earlier in comparison to those without such a history. The extent of their coronary disease is similar to the older patients without a positive FH. The better prognosis of patients with a positive FH is mostly explained by their younger age.

Adult↗

PubMed1996

Lp(a) levels and atherosclerotic vascular disease in a sample of patients with familial hypercholesterolemia sharing the same gene defect.

There is considerable variation in the severity of cardiovascular disease among patients with familial hypercholesterolemia (FH). Some reports have suggested that plasma lipoprotein(a) [Lp(a)] levels may explain such variation and that FH subjects deficient in LDL receptors, especially those with coronary heart disease, tend to have elevated Lp(a) levels. We have investigated the possible role of the LDL receptor in determining plasma Lp(a) levels in genetically homogeneous FH population and the contribution of Lp(a) to cardiovascular risk. A total of 98 FH subjects and 66 healthy first- and second-degree relatives from 30 families with FH due to the French-Canadian > 10-kilobase deletion of the LDL receptor gene were studied. A reference group of 392 normolipidemic French-Canadian participants in a Heart Health Survey was used for comparison. FH subjects were subdivided into subsets of 63 individuals free from atherosclerotic vascular disease (AVD) and 35 individuals with AVD. A complete cardiovascular evaluation was performed, and plasma lipid, lipoprotein, and Lp(a) levels were measured in all subjects in the absence of medication. Apolipoprotein (a) [apo(a)] phenotype was determined in 112 of FH and non-FH subjects. The log-transformed values for plasma Lp(a) were not significantly different among the three groups: 0.98 +/- 0.54 (mean +/- SD) in FH subjects with AVD, 0.89 +/- 0.51 in FH subjects without AVD, and 0.82 +/- 0.64 in their relatives. The distribution of the apo(a) phenotypes did not differ between the FH and non-FH groups. Comparison of two age- and sex-matched subgroups of FH subjects, with and without AVD, failed to show any differences in Lp(a) level. However, mean Lp(a) log values in the reference group (n = 392) were significantly lower than values obtained for the total FH group (0.79 +/- 0.57 versus 0.92 +/- 0.52, respectively; P < .05) but were not different from those of the unaffected family members. Thus, in our sample, the LDL receptor appears not to influence plasma Lp(a) levels; rather, these levels reflect shared apo(a) genes. The cardiovascular risk in this group of subjects with FH was related to age, male sex, total and LDL cholesterol, and higher apoB but not Lp(a) levels.

Adolescent↗

PubMed2004

Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome.

Several studies have demonstrated genetic predisposition in non-shigatoxin-associated hemolytic uremic syndrome (HUS), involving regulatory proteins of the complement alternative pathway: Factor H (FH) and membrane co-factor protein (CD46). Regarding the observations of thrombotic thrombocytopenic purpura patients, in whom a von Willebrand factor protease (ADAMST-13) deficiency may be inherited or acquired secondary to IgG antibodies, it was speculated that HUS might occur in a context of an autoimmune disease with the development of anti-FH antibodies leading to an acquired FH deficiency. The presence of FH autoantibodies was investigated by an ELISA method using coated purified human FH in a series of 48 children who presented with atypical HUS and were recruited from French university hospitals. Anti-FH IgG antibodies were detected in the plasma of three children who presented with recurrent HUS. The anti-FH specificity was conserved by the Fab'2 fraction. The plasma FH activity was found to be decreased, whereas plasma FH antigenic levels and FH gene analysis were normal, indicating that the presence of anti-FH antibodies led to an acquired functional FH deficiency. This report supports for the first time that HUS may occur in a context of an autoimmune disease with the development of anti-FH-specific antibody leading to an acquired FH deficiency. This new mechanism of functional FH deficiency may lead to the design of new approaches of diagnosis and treatment with a particular interest in plasma exchanges or immunosuppressive therapies.

Age Distribution↗

PubMed2004

Interaction of human factor H with PspC of Streptococcus pneumoniae.

BACKGROUND & OBJECTIVES: Streptococcus pneumoniae has acquired virulence factors such as the polysaccharide capsule and various surface proteins, which prevent opsonization mediated by the complement system. PspC is one of the multi-functional pneumococcal surface proteins capable of eliciting an antibody response in mice. Our study further explores the role of pneumococcal surface proteins in resistance to complement mediated opsonophagocytosis by providing evidence that PspC binds human Factor H (FH), a regulatory protein of the alternative complement pathway. The present study was carried out to map the binding regions on PspC and FH, and to assess the functional activity of FH upon binding to PspC. METHODS: FH binding to D39 and other pneumococcal strains was observed by flow cytometry. A series of FH truncated and deletion mutants and PspC mutants were used to localize binding regions within these molecules. The functional activity of FH upon binding to PspC was measured by a haemolysis assay. RESULTS: FH binding to D39 and not to TRE108 (PspC-) cells was demonstrated by flow cytometry. Pneumococcal isolates of 14 different strains varied in their ability to bind FH. The binding region of FH within PspC to the first 225 amino acids of the alpha-helical domain was localized. The corresponding binding site for PspC is located within the SCR 6-10 region of FH. Haemolysis of rabbit red blood cells was inhibited by FH even in the presence of PspC. INTERPRETATION & CONCLUSION: FH binding is specific to PspC on the pneumococcal cell surface. The binding region on PspC mapped to the non-conserved N-terminal region of the alpha-helical domain. The binding site on FH to PspC is different from the active site that functions in degradation of C3b. A haemolysis assay provided evidence that the functional activity of FH was maintained upon binding to PspC. Thus, binding of FH to PspC might be an important mechanism by which S. pneumoniae resist complement activation and opsonophagocytosis.

Bacterial Proteins↗

PubMed2006

Influence of family history to type 2 diabetes on the body composition and homeostasis model assessment: a comparison between young active and sedentary men.

AIM: Family history (FH) to type 2 diabetes mellitus (DM) is a risk factor to the development of illness, inducing early anthropometric and metabolic modifications in sedentary subjects. The aim of this paper was to study the FH to DM influence on body composition and glucose metabolism in young sedentary and active men. METHODS: In a cross-section analysis, we recorded anthropometric data, body composition (by BIA), plasmatic insulin and glucose in 60 young healthy Sicilian men (31 athletes and 29 sedentary subjects); FH was defined FH+ if subjects referred to have at least one family member of first degree with documented DM; men without FH to DM were defined FH-. RESULTS: In sedentary subjects, FH+ was associated with the highest values of body mass index (P<0.05) and an increase in the waist-hip ratio (P<0.0585). Sedentary FH+ had a worse body composition, because of an increase in fat mass (P<0.05 for absolute and percent values). Compared to FH- sedentary men, FH+, with lower basal plasmatic insulin, had lower levels of homeostasis model assessment (HOMA) (P<0.05). Between FH+ and FH- athletes no differences were found. CONCLUSIONS: In young men subjects, study confirms influence of FH to DM on physical data, body composition and glucose metabolism and the protective role of a regular physical activity. In subjects FH+ the promotion of health education can prevent the arising of obesity and diabetes; other studies on subjects of both sexes are necessary to assess relation between FH degree to type 2 DM and early physical and metabolic modifications.

Adult↗

PubMed1996

[Plasma renin activity, aldosterone and adrenergic activity in patients with hypertension and in normotensives with a family history of hypertension].

UNLABELLED: The aim of the study was to analyse plasma renin activity (PRA), aldosterone (Ald) and catecholamines at rest, after psychological stress and physical exercise in patients with essential hypertension (EH) and normotensive persons with (FH +) and without (FH-) family history of hypertension. MATERIALS AND METHODS: 100 men, aged 18-35 years, were investigated: 36 in EH, 32 in FH + and 32 in FH- groups. PRA, Ald and plasma level of adrenaline (A), noradrenaline (NA) and dopamine (D) were estimated at rest, after 30' of stress (Kraepelins test) and at the end and 30, after submaximal ergometric exercise. RESULTS: The groups did not differ in respect to PRA and Ald in all periods of study as well as to A and NA at rest and during stress. A in EH and FH + as well as NA in FH + were significantly higher than FH- at the end and 30 after exercise. D in EH was higher (p < 0.05) than in both normotensive groups and at rest and stress than FH- during exercise and recovery. There were also some correlations between PRA, Ald and catecholamines. In FH + and FH- but not in EH group PRA and Ald positively correlated at rest (r = 0.588 and 0.612) and during stress (r = 0.626 and 0.477). On the contrary in EH as well as FH + groups PRA positively correlated with A (r = 0.385 and 0.368) and NA (r = 0.370 and 0.386) at rest. In addition PRA correlated positively with A during stress (r = 0.368) as well as with NA during recovery (r = 0.313) in FH + groups. Ald correlated with D positively in FH + (r + 0.380) and negatively (r = 0.304) in FH- at rest, whereas Ald was positively correlated with A in EH (r = 0.511) as well as in FH + (r = 0.354) during exercise. CONCLUSIONS: Hypertension and family history of it changes adrenergic reactivity and influences the relationship between plasma renin activity, aldosterone, and catecholamines.

Adolescent↗

PubMed2026

Management and Consequences of Genotype-Positive Familial Hypercholesterolemia.

IMPORTANCE: Familial hypercholesterolemia (FH) is a common genetic condition that causes hypercholesterolemia and increased risk for premature atherosclerotic cardiovascular disease (ASCVD). The prevalence, management, and consequences of genetically confirmed FH across the US are poorly understood. OBJECTIVE: To identify genotype-positive FH in a national US cohort and describe its prevalence, consequences, and lipid-lowering management. DESIGN, SETTING, AND PARTICIPANTS: In the All of Us (AoU) cohort study, whole-genome sequencing and phenotypic data from US adult participants enrolled between May 2018 and July 2022 were analyzed to identify and study genotype-positive FH. Data were analyzed between May 2024 and May 2025. EXPOSURE: FH variants (pathogenic or likely pathogenic) in LDLR, APOB, and PCSK9 genes were manually classified with standard criteria. MAIN OUTCOMES AND MEASURES: The primary outcomes were demographic characteristics, lipid measurements, ASCVD, and prevalence of FH and noncarriers in AoU. Lipid management was then characterized among individuals with FH through lipid-lowering therapy (LLT) documentation and guideline-based low-density lipoprotein cholesterol (LDL-C) targets. RESULTS: A total of 245 388 participants were included, with mean (SD) age of 56.5 (16.9) years and 145 563 female participants (59.3%). Genotype-positive FH was identified in 865 participants (prevalence, 0.35%; 95% CI, 0.33%-0.38%; 1 in 287 participants). Among individuals with genotype-positive FH, 349 (40%) were prescribed statins, and 332 (38.4%) had LDL-C measured. Coronary artery disease, peripheral artery disease, and transient ischemic attack or stroke were significantly more common in genotype-positive FH carriers compared to noncarriers (coronary artery disease: odds ratio [OR], 2.91; 95% CI, 2.34-3.58; peripheral artery disease: OR, 1.51; 95% CI, 1.16-1.96; and transient ischemic attack or stroke: OR, 1.54; 95% CI, 1.11-2.09). Only 30.1% of participants positive for FH variants had LDL-C less than 100 mg/dL at their most recent result compared to 48.2% of noncarriers (P < .001). Of the total participants with ASCVD and LLT prescription, significantly fewer individuals with FH met the secondary prevention LDL-C target (<70 mg/dL; 19.33% vs 43.12%; P < .001) compared to noncarriers. CONCLUSIONS AND RELEVANCE: This cohort study finds a prevalence of genotype-positive FH in All of Us participants of 0.35% (95% CI, 0.33%-0.38%), with state-level variation. A minority of individuals with genotype-positive FH met guideline-recommended LDL-C targets and had increased rates of ASCVD.

Humans↗