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PubMed1999

Post mortem molecularly defined familial hypercholesterolemia and sudden cardiac death of young men.

Familial hypercholesterolemia (FH) is among the most common single-gene diseases and is due to mutations of the low-density lipoprotein (LDL) receptor gene. In heterozygous FH, serum LDL-cholesterol level is elevated two- to threefold compared to unaffected individuals, men in particular are prone to premature atherosclerosis and early cardiac deaths. However, very little data are available concerning the incidence of premature deaths in FH patients. In Finland two LDL receptor founder mutations cover two-thirds of FH cases, offering a unique possibility to study the potential role of FH in unexpected early cardiac deaths. We studied a total of 149 deceased who had suffered early (< or = 50 years) unexpected cardiac death due to coronary heart disease (CHD). Three individuals (2%) had molecularly defined heterozygous FH, and heterozygous FH was present in two (3%) of the 67 subjects who had demonstrable acute myocardial infarction (AMI). Considering that the two FH mutations cover two-thirds of FH cases in Finland, the overall prevalence of FH underlying early cardiac deaths caused by AMI may be estimated to be in the range 3 to 5%.

Adult↗
PubMed2002

The effect of long-term methylprednisolone treatment on the femoral head in growing pigs.

The effect of long term steroid treatment on coagulation, intraosseous pressure (IOP), femoral head (FH) blood flow, and histology in the normal organism was investigated in this study in growing pigs. From 24 growing female Danish Landrace pigs from 12 litters, 12 animals daily received 100 mg methylprednisolone orally for three months. Their 12 sister pigs served as controls without steroid treatment. Prothrombin time, activated partial thromboplastin time (aPTT), fibrinogen, and antithrombin III levels were recorded in jugular venous blood. Blood flow of the hip regions was measured by means of the radioactive microsphere technique. Metaphyseal and epiphyseal IOP of the left or right proximal femur were measured. Histomorphometry of the left or right FH epiphysis was performed. Major growth inhibition was found in the corticosteroid (CS) treated group. In CS pigs, aPTT was shortened to 50% compared to control pigs. Plasma fibrinogen was higher in the CS animals. Total FH blood flow was not different while regional blood flow in the cranial subregion of the FH epiphysis was higher in the CS group. Metaphyseal and epiphyseal IOP of the proximal femur were not different in the CS animals. Histomorphometrically, cancellous bone volume (23 +/- 1% vs. 34 +/- 2%; p < 0.001) and bone turnover (10 +/- 2% vs. 55 +/- 8%; p < 0.001) of the FH epiphysis was lowerin the CS than in the control group. The FH epiphysis of the CS animals invariably showed an irregular cartilage-bone interface with cartilaginous projections into the subchondral bone mainly in its cranial part. In normal growing pigs, long term high dose CS treatment has induced a hypercoagulable state of plasma via the intrinsic pathway of coagulation, cartilaginous projections into FH subchondral bone, FH osteopenia, and reduced bone turnover. Long-term steroid treatment did not produce FH necrosis or FH IOP alterations in the immature pig model.

Animals↗
PubMed1999

Analysis of heart rate in developing bird embryos: effects of developmental mode and mass.

Bird embryos may be regarded as developing in their thermo-neutral zone, at rest, and stay in the egg for a fixed period of time until hatching. It is therefore interesting to investigate if they follow the same 'rule' set for adult homeotherms, which states that, within a taxonomically or functionally defined category such as mammals or birds, the number of heart beats throughout the life span (sL) is more or less constant. This rule stems from the allometric relationships between heart rate (fH) and body mass (mB) and between sL and mB. As a step towards understanding the general allometric nature of avian embryonic physiology we analyzed the fH values of avian embryos in relation to their incubation span (sI). Data from 30 species were selected from the scientific literature for the analyses. Values obtained from invasive methods which were judged to grossly alter natural incubation conditions, or from undefined or unmatched temperature conditions were not used. These include most values obtained below the first 30% of the incubation. Also, data obtained after internal pipping were discarded since hatching activity influences them. Values for sI and egg mass (mE) as representatives of embryonic mass were also collected. Embryonic fH was normalized to 70.1-80% sI. At 20.1-30% sI it was only 85% of the value at 70.1-80% sI and increased to a plateau at about 50.1-60% sI. It was almost constant among species between 50.1 and 60% sI and pre-internal pipping (PIP) time and thus, the mean fH value between 50.1 and 60% sI and between 90.1 and 100% excluding pipped eggs (fH) was taken as a representative value for each given species. The fH (min-1) and the corresponding sI (days) values for the 30 species, scaled with mE (g) as follows: fH = 371.1.mE-0.112 and: sI = 12.29.mE+0.209. Both powers were significantly different from 0. The product of fH and sI (fH.sI), representing the total number of heartbeats throughout the incubation, scaled with mE for the entire data set as follows: fH.sI = 6.565 x 10(+6).mE+0.096, where the +0.096 power is significantly different from 0. Values for fH.sI from embryos of altricial birds tended to concentrate at the low mE end of the plot while those of the precocial ones tended towards the high end. Separate analyses showed that the mE power for the combined altricial and semi-altricial species (ASA), and the combined precocial and semi precocial species (PSP), of log fH.sI against log mE regressions, were both insignificantly different from 0. Thus, means of fH.sI for ASA and PSP were calculated. The mean ASA value of 7.27 x 10(+6) heartbeats for fH.sI, was significantly different from the mean PSP value of 10.93 x 10(+6). The difference of 3.66 x 10(-6) (33.5%) heartbeats can be attributed to either the more advanced stage of the PSP hatchlings at hatch, to the larger mE values of these hatchlings, to the difference in water fraction of the hatchlings or all. The result of a linear regression of fH.sI against the rate of sI completion (the inverse of incubation span, fI; day-1) was: fH.10(-6) = 0.205 + 3.940.sI-1. Thus, the faster is the average rate of development accomplished per day (shorter incubation) the higher is daily heart rate. Data tended to cluster such that large eggs, mostly of the PSP type with relatively low fH, complete 2-4% of their incubation per day, while small, ASA type eggs with relatively high fH, complete 6-8% of their incubation time per day. We conclude that, at this stage of knowledge, the data is insufficient to resolve whether the different modes of hatch stage alone can explain differences in the total number of heartbeats throughout embryonic life among all bird species, or egg mass and water content differences contribute variability. This should be investigated on a larger sample of species in more depth.

Animals↗
PubMed2003

Effect of family history of type 2 diabetes on white blood cell count in adult women.

OBJECTIVE: To evaluate the effect of a first-degree family history of type 2 diabetes on white blood cell (WBC) count, a risk factor for atherosclerotic vascular disease, in glucose-tolerant adult women. RESEARCH METHODS AND PROCEDURES: WBC count was measured in 174 normal weight, overweight, and obese female offspring of type 2 diabetic patients (FH(+)) and 174 age- and BMI-matched female controls with no family history of type 2 diabetes (FH(-)). Other measurements included fat mass (FM), measured by body impedance analysis; central fat accumulation, evaluated by waist circumference; insulin resistance, estimated by homeostatic model assessment for insulin resistance (HOMA(IR)); systolic and diastolic blood pressure; and fasting concentrations of glucose, insulin, and lipids. RESULTS: WBC count, waist circumference, systolic blood pressure, and fasting levels of glucose, insulin, and triglycerides were significantly higher in FH(+) than in FH(-) subjects. In FH(+) individuals, WBC count was positively associated with BMI, FM, waist circumference, HOMA(IR), and triglyceride and insulin concentrations, and negatively correlated with age and high-density lipoprotein-cholesterol. In FH(-) subjects, WBC count was directly associated with BMI, FM, waist circumference, and triglyceride and insulin concentrations, and inversely correlated with age and high-density lipoprotein-cholesterol. After multivariate analyses, WBC count maintained a significant association with age, systolic blood pressure, and HOMA(IR) in FH(+) subjects and with age, BMI, FM, and triglycerides in FH(-) individuals. DISCUSSION: This study indicates that WBC count is increased in adult women with genetic predisposition to type 2 diabetes, and its main correlates are insulin resistance in FH(+) and adiposity in FH(-) individuals.

Adipose Tissue↗
PubMed2003

Influence of LDL receptor gene mutations and the R3500Q mutation of the apoB gene on lipoprotein phenotype of familial hypercholesterolemic patients from a South European population.

Few data are available on genotype-phenotype interactions among familial hypercholesterolemia (FH) patients in South European populations and there are no data about the influence of R3500Q mutation on lipoprotein phenotype compared to low-density lipoprotein receptor (LDLR) mutations. The objective of the study is to analyze the influence of mutations in the LDLR and apolipoprotein B (apoB) genes on lipoprotein phenotype among subjects clinically diagnosed of FH living in East Spain. In all, 113 FH index patients and 100 affected relatives were studied. Genetic diagnosis was carried out following a protocol based on Southern blot and PCR-SSCP analysis. A total of 118 FH subjects could be classified into three groups according to the type of LDLR mutations (null mutations, missense mutations affecting the ligand binding 3-5 repeat, and missense mutations outside this domain). In addition, the lipoprotein phenotype of these FH groups was compared with 19 heterozygous subjects with familial ligand-defective apoB (FDB), due to R3500Q mutation. FH patients carrying missense mutations affecting the ligand binding repeat 3-5 showed total and LDL cholesterol levels significantly higher than FH patients with missense mutations in other LDLR domains or FDB patients. FH subjects carrying null mutations showed lower high-density lipoprotein cholesterol plasma values compared to FH carrying missense mutations. FDB subjects showed the lowest total and LDL cholesterol plasma values. In conclusion, the type of LDLR gene mutation and R3500Q mutation influences the lipoprotein phenotype of FH population from East Spain.

Adolescent↗
PubMed1997

Increased activity of platelet-activating factor acetylhydrolase in low-density lipoprotein subfractions induces enhanced lysophosphatidylcholine production during oxidation in patients with heterozygous familial hypercholesterolaemia.

Patients with heterozygous familial hypercholesterolaemia (FH) have elevated plasma concentrations of low-density lipoprotein (LDL) and develop premature atherosclerosis. There is increasing evidence that oxidative modification of LDL is important for the pathogenesis of atherosclerosis, and the LDL-associated platelet-activating factor acetylhydrolase (PAF-AH) seems to play a key role in LDL oxidation by hydrolysing the oxidized phospholipids of phosphatidylcholine (PC) and producing lysophosphatidylcholine (lyso-PC). We measured the total serum and high-density lipoprotein (HDL) levels of PAF-AH activity and studied the distribution of PAF-AH activity among three LDL subfractions isolated by gradient ultracentrifugation in 15 patients with heterozygous FH and 13 normolipidaemic control subjects. We also determined the lyso-PC production in each LDL subfraction during Cu2(+)-induced oxidation in vitro. The total serum PAF-AH activity in heterozygous FH patients was significantly higher than in control subjects, whereas the HDL-associated PAF-AH activity, expressed as a percentage of total serum PAF-AH activity, was significantly lower in the FH patients than in control subjects (13.9 +/- 6.6% vs. 30.6 +/- 4.4%, P < 0.001). Among the LDL subfractions, the PAF-AH activity in both normolipidaemic control subjects and FH patients, expressed as nmol mg-1 protein min-1, was significantly higher in the LDL3 subfraction (33.1 +/- 4.8 and 53.4 +/- 11.5 respectively) than in the LDL2 (18.6 +/- 5.3 and 26.8 +/- 10.4 respectively, P < 0.0001 for both comparisons) and LDL1 subfractions (5.1 +/- 1.5 and 7.8 +/- 2.6, respectively, P < 0.0001 for both comparisons). Additionally, the enzyme activity in each LDL subfraction of the heterozygous FH patients was significantly higher than in control subjects (P < 0.02 for LDL1, P < 0.03 for LDL2 and P < 0.0001 for LDL3). No difference was observed in the susceptibility to oxidation of each LDL subfraction among the heterozygous FH patients and the normolipidaemic control subjects. During oxidation, the PAF-AH activity decreased, whereas the lyso-PC levels significantly increased in all subfractions of both groups. The lyso-PC/sphingomyelin molar ratio in each LDL subfraction of the FH patients 3 h after the onset of the oxidation was significantly higher than in control subjects [0.38 +/- 0.05 and 0.27 +/- 0.04, respectively, for LDL1 (P < 0.006), 0.47 +/- 0.08 and 0.39 +/- 0.03, respectively, for LDL2 (P < 0.04), 0.55 +/- 0.11 and 0.42 +/- 0.06, respectively, for LDL3 (P < 0.02)]. Our results show that heterozygous FH patients exhibit higher PAF-AH activity than control subjects in all LDL subfractions, resulting in higher lyso-PC production during oxidation, which confers on these subfractions higher biological potency. This phenomenon, in combination with the diminished anti-atherogenic and antioxidant capability of HDL in these patients due to the relatively low HDL-cholesterol levels compared with LDL-cholesterol levels and, consequently, the relatively low HDL-associated PAF-AH activity, could contribute to the higher atherogenicity and incidence of coronary artery disease observed in FH patients.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1998

Carotid intima-media thickness and plaque in patients with familial hypercholesterolaemia mutations and control subjects.

BACKGROUND: In individuals with familial hypercholesterolaemia (FH), ultrasonographic measurement of carotid intima-media thickness (IMT) and plaque may provide a non-invasive assessment of cardiovascular risk. METHODS: We examined carotid artery IMT and its determinants in 79 non-smoking, normotensive, treated men and women with FH aged 26-46 years, and in 79 non-smoking, normotensive sex-, age- and body mass index-matched control subjects. FH was verified by molecular genetic analyses. The underlying mutation in the low-destiny lipoprotein receptor gene included a splice-site mutation, mutations predicted or shown to lead to class 2B mutations or other mutations that probably represent class I mutations (null alleles). RESULTS: The carotid bifurcation and common carotid artery IMT was increased in men with FH compared with control subjects (0.81 +/- 0.15 mm vs. 0.74 +/- 0.19 mm and 0.61 +/- 0.13 mm vs. 0.55 +/- 0.14 mm respectively; P < 0.05). The carotid bifurcation IMT was increased in women with FH compared with control subjects (0.74 +/- 0.17 vs. 0. 66 +/- 0.15; P = 0.005). More subjects with FH had carotid plaque (54% vs. 14%; P = 0.0001). In multivariate analysis, male gender, level of low-density lipoprotein-cholesterol, cholesterol-years score and xanthoma were associated with IMT and plaque in subjects with FH. FH subjects with class 2B mutations had lower cholesterol levels than subjects with mutations belonging to the other classes. They also had a tendency towards a decreased common carotid artery IMT. CONCLUSION: These findings confirm the importance of gender, xanthoma and lifetime cholesterol levels in relation to carotid atherosclerosis in FH. Whether the type of mutation causing FH modulates carotid artery IMT and plaque requires further study.

Adult↗
PubMed2003

Impact of genetic defects on coronary atherosclerosis in patients suspected of having familial hypercholesterolaemia.

BACKGROUND: In the present study we assessed whether the presence of genetic mutations typical of familial hypercholesterolaemia (FH) was associated with greater atherosclerosis in the coronary vessels in patients with severe hypercholesterolaemia and a family history of early cardiovascular disease. MATERIALS AND METHODS: Two hundred and thirty-five patients selected for having severe hypercholesterolaemia and a family history of cardiovascular disease were classified as FH (57 men and 38 women) or non-FH (84 men and 56 women) according to a genetic analysis of the LDL-R or ApoB genes. Coronary atherosclerosis was evaluated by performing a thoracic CT scan and exercise stress testing. RESULTS: Familial hypercholesterolaemia individuals had a significantly higher prevalence of coronary calcification than the non-FH patients from among both the men (OR = 3.90; 95% CI 1.86-8.19; P < 0.001) and the women (OR = 2.34; 95% CI 1.01-5.48; P = 0.05). In exercise stress testing, ECG abnormalities suggestive of cardiac ischaemia were found with a higher prevalence in the FH patients than the non-FH patients from among both the men (OR 6.15; 95% CI 2.16-17.5; P < 0.001) and the women (OR 4.76; 95% CI 0.91-24.6; P = 0.06). All differences were statistically significant after adjusting for age and cholesterol and for most classical risk factors that differed between the FH and non-FH groups. CONCLUSION: Among patients with severe hypercholesterolaemia and a family history of early cardiovascular disease, the presence of a genetically ascertained FH is associated with a higher prevalence of coronary artery calcifications and a positive exercise stress test. These results suggest that despite a similar phenotype, patients carrying mutations suggestive of FH may have a greater cardiovascular risk than patients without these mutations.

Adult↗
PubMed2001

Metabolic impact of a family history of Type 2 diabetes. Results from a European multicentre study (EGIR).

BACKGROUND: Insulin resistance was found in some but not in all previous studies of non-diabetic first degree relatives of Type 2 diabetic patients. Small study groups, ethnic differences and/or non-optimal techniques may explain the conflicting results. AIM: To study the impact of a family history of Type 2 diabetes on insulin action in a large group of non-diabetic Europeans using the 'gold standard' euglycaemic hyperinsulinaemic clamp technique. METHODS: Non-diabetic subjects (n = 235) with a positive family history of Type 2 diabetes (FH+) and 564 subjects with no family history of diabetes (FH-) were recruited from The European Group of Insulin Resistance (EGIR) database. This database includes measurements of insulin action using the insulin clamp technique (1 mU/kg per min) in normal glucose-tolerant individuals from 20 different European centres. In a subset of subjects the measurements were performed in combination with indirect calorimetry (n = 80 vs. 213 with and without family history of Type 2 diabetes). RESULTS: The body mass index (BMI) was slightly higher in FH+ compared with FH- (26.7 +/- 4.6 vs. 25.1 +/- 4.7 kg/m(2); P < 0.02). After correction for covariates according to differences between investigators and subject characteristics including BMI (multiple regression analysis), insulin-stimulated glucose disposal was lower in FH+ compared with FH- (P < 0.00001). Insulin-stimulated glucose oxidation was slightly increased in FH+ compared with FH-, and insulin-stimulated non-oxidative glucose metabolism was consequently markedly reduced in FH+ compared with FH- (P < 0.0005). CONCLUSION: Insulin resistance is present in European non-diabetic relatives of Type 2 diabetic patients. The insulin resistance is independent of degree of obesity and is restricted solely to the pathway of non-oxidative glucose metabolism. Diabet. Med. 18, 533-540 (2001)

Adult↗
PubMedDate not supplied

Long-term effect of simvastatin on the improvement of impaired myocardial flow reserve in patients with familial hypercholesterolemia without gender variance.

BACKGROUND: Impaired myocardial flow reserve (MFR) in patients with familial hypercholesterolemia (FH) without evidence of ischemia has been reported. However, it has not been clarified whether diminished MFR in such male or female patients with FH can be reversed by simvastatin. METHODS AND RESULTS: Sixteen patients with FH and 16 age-matched control subjects were studied. All patients were proved to have no evidence of exercise stress-induced myocardial ischemia. Baseline myocardial blood flow (MBF) and MBF during dipyridamole administration (MBF [DP]) were measured with positron emission tomography and nitrogen 13 ammonia; MFR was then calculated before and 9 to 15 months after therapy with simvastatin (5-10 mg/day). Total cholesterol level was significantly higher in patients with FH (277 +/- 49.0) than in control subjects (190 +/- 14.9) but was normalized after lipid-lowering therapy (205 +/- 40.3). Baseline MBF was comparable among FH patients before (77.6 +/- 11.6 mL/min/100 g) and after therapy (74.5 +/- 9.62 mL/min/100 g) and control subjects (78.5 +/- 29.9 mL/min/100 g). However, MBF (DP) in FH patients before therapy (178 +/- 50.9 mL/min/100 g) was significantly lower than that in control subjects (282 +/- 148 mL/min/100 g) and was significantly improved after therapy (228 +/- 91.6 mL/min/100 g, P <.05). In fact, there was no statistically significant difference in the MBF (DP) value in FH patients after therapy compared with that in control subjects (P =.09). MFR significantly improved after therapy in patients with FH (3.33 +/- 1.19 vs 2.27 +/- 0.625, P <.01) and was then statistically comparable to that in control subjects (3.54 +/- 1.11). Improvement of MFR was observed whether MBF (DP) before therapy was greater than or less than 200 mL/min/100 g. MFR was improved in both male and female patients with FH. There was a significant relationship between percent change in plasma total cholesterol concentration and percent change in MFR before and after lipid-lowering therapy (r = -0.57, P <.05). CONCLUSIONS: Diminished MFR in patients with FH without evidence of ischemia can be reversed by moderate- to long-term simvastatin therapy without gender variance.

Anticholesteremic Agents↗
PubMed2000

Each of the three binding sites on complement factor H interacts with a distinct site on C3b.

Factor H (fH) restricts activation of the alternative pathway of complement at the level of C3, both in the fluid phase and on self-structures, but allows the activation to proceed on foreign structures. To study the interactions between fH and C3b we used surface plasmon resonance analysis (Biacore(R)) and eight recombinantly expressed fH constructs containing fragments of the 20 short consensus repeat domains (SCRs) of fH. We analyzed the binding of these constructs to C3b and its cleavage products C3c and C3d. Three binding sites for C3b were found on fH. Site 1 was localized to the five amino-terminal SCRs (SCR1-5), and its reciprocal binding site on C3b was found to be lost upon the cleavage of C3b to C3c and C3d. Site 2 on fH was localized by exclusion probably within or near SCRs 12-14 (fragment SCR8-20 bound to C3b, C3c, and C3d; SCR8-11 did not bind to C3b at all; and SCR15-20 bound only to the C3d part of C3b). Site 3 on fH for C3b was localized to the carboxyl-terminal SCRs 19-20, and its reciprocal binding site was mapped to the C3d part of C3b. In conclusion, we confirmed and mapped three binding sites on fH for C3b and demonstrated that the three binding sites on fH interact with distinct sites on C3b. Multiple reciprocal interactions between C3b and fH can provide a basis for the different reactivity of the alternative pathway with different target structures.

Binding Sites↗
PubMed2002

Streptococcal beta protein has separate binding sites for human factor H and IgA-Fc.

The group B streptococcus (GBS) is the most important cause of life-threatening bacterial infections in newborn infants. Protective immunity to GBS infection is elicited by several surface proteins, one of which, the beta protein, is known to bind human IgA-Fc. Here, we show that the beta protein also binds human factor H (FH), a negative regulator of complement activation. Absorption experiments with whole human plasma demonstrated binding of FH to a GBS strain expressing beta protein but not to an isogenic beta-negative mutant. This binding was due to a direct interaction between beta and FH, as shown by experiments with purified proteins. Inhibition tests and studies with beta fragments demonstrated that FH and IgA-Fc bind to separate and nonoverlapping regions in beta. Heparin, a known ligand for FH, specifically inhibited the binding between beta and FH, suggesting that FH has overlapping binding sites for beta and heparin. Bacteria-bound FH retained its complement regulatory activity, implying that beta-expressing GBS may use bound FH to evade complement attack. The finding that beta protein binds FH adds to a growing list of interactions between human pathogens and complement regulatory proteins, supporting the notion that these interactions are of general importance in bacterial pathogenesis.

Antigens, CD↗
PubMed2003

The impact of a family history of breast cancer on screening practices and attitudes in low-income, rural, African American women.

BACKGROUND: Women with a family history of breast cancer are at increased risk for developing cancer and, therefore, might be expected to engage in early detection practices more actively than women without a family history. Alternatively, women with a family history may avoid thinking about cancer and have attitudes and practices that do not promote early detection. METHODS: This study examined breast cancer attitudes and practices among African American women aged >or=50 who had not had a mammogram in the last 2 years. RESULTS: Phone survey data from 320 female clients of low-income, rural primary care clinics (91% African American) indicated that 15% self-reported a family history of breast cancer (FH(+)). Half of the FH(+) women did not know their relative risk of developing breast cancer. Of those providing a risk estimate, 67% perceived themselves at low risk compared with other women their age. Perceived relative risk was comparable between FH(+) and FH(-) women. Further, FH(+) women did not indicate greater worry about breast cancer, nor did they have more accurate knowledge of mammography recommendations than FH(-) women. Two thirds of FH(+) women had never had a mammogram. Monthly breast self-examination did not differ between FH(+) and FH(-) women. CONCLUSIONS: Thus, neither knowledge of a positive family history nor perceived relative risk of breast cancer was associated with either increased or decreased early detection practices among these low-income, rural, African American women who have underused mammography. Furthermore, a substantial proportion of FH(+) women had not ever participated in screening mammography. Interventions to increase mammography rates in this population of underusers are indicated.

Black or African American↗
PubMed2004

Familial hypercholesterolemia, peripheral arterial disease, and stroke: a HuGE minireview.

Heterozygous familial hypercholesterolemia (FH) is an autosomal dominant disorder known to be associated with elevated cholesterol levels and increased risk of premature coronary heart disease. Since increased cholesterol levels lead to atherosclerosis, FH has also been proposed as a risk factor for peripheral vascular and ischemic cerebrovascular disease. Currently, the association between clinical FH and risk of stroke is unclear: Two studies conducted in the 1980s indicated an increased risk of stroke in FH subjects; however, two others found no higher risk, and all had methodological limitations. A recent prospective study of familial hypercholesterolemia by the United Kingdom-based Simon Broome Register Group did not find an excess risk of stroke mortality for subjects with clinical FH. By contrast, the prevalence of peripheral arterial disease is increased from five- to 10-fold in FH subjects compared with non-FH controls. In addition, the intima-media thickness of the carotid and/or femoral artery is increased in FH subjects. Better understanding of the association between FH and the incidence of ischemic stroke events could have a public health impact by improving the diagnosis, prognosis, and treatment of individuals with FH and their relatives and by elucidating the relation between cholesterol levels and ischemic cerebrovascular disease.

Adult↗
PubMed1996

Auxiliary partial orthotopic liver transplantation for fulminant hepatitis. The Paul Brousse experience.

OBJECTIVE: The authors objective is to report their experience with auxiliary partial orthotopic liver transplantation in fulminant hepatitis (FH) and to discuss the principles that may help in its safe application. SUMMARY BACKGROUND DATA: Auxiliary partial orthotopic liver transplantation is an attractive therapeutic method in FH because it provides hepatic function, whereas the remaining native liver is given the possibility to recover. Despite early encouraging reports, its place in the treatment of FH remains to be defined. METHODS: Evaluation of 5 cases of FH treated with auxiliary partial orthotopic liver transplantation from a collective of 22 transplantations for 35 cases of FH referred to the authors' center from January 1994 to November 1995. The grafts were one left lobe, two left livers, and two right livers. RESULTS: The native liver regenerated in three patients: one with Reye's syndrome who died of irreversible neurologic damage, one with FH caused by the hepatitis B virus who is alive 20 months after ABO incompatible graft removal, and one with FH caused by the hepatitis A virus who had her graft removed at 4 months. In two patients, regeneration did not occur: one with drug-induced FH who died of sepsis 3 months after surgery and one with FH of unknown origin who was retransplanted with a standard liver transplantation at 4 months for uncontrollable biliary rejection of an ABO incompatible graft (alive at 10 months). Two of the three patients who survived suffered severe neurologic complications. CONCLUSIONS: Auxiliary partial orthotopic liver transplantation is an attractive treatment for FH, especially in the presence of good prognostic factors for native liver regeneration: a young patient, rapid onset of the disease, and viral hepatitis. It should be considered cautiously in patients with advanced encephalopathy. By providing a smaller mass of liver tissue than with standard orthotopic liver transplantation, and as a more complex operative procedure, auxiliary partial orthotopic liver transplantation may not be as effective in arresting the progression of neurologic damage.

Adolescent↗
PubMed2003

Patterns of metastases in familial and non-familial melanoma.

Family history is a strong risk factor for the development of primary melanoma and is associated in a subset with inherited mutations in melanoma susceptibility genes. This study sought to determine whether differences in metastatic pattern exist between patients with a positive family history (FH+) and those with a negative family history (FH-). Such differences could have importance for clinical management and in the determination of the function of both known and putative melanoma susceptibility genes. A retrospective, nested case-controlled study was performed. Of the FH+ cohort (n = 38), 26 were from kindreds with two histologically verified affected first-degree relatives and 12 were from kindreds with three or more affected members, at least two of whom were first-degree relatives. Three FH- controls from the Sydney Melanoma Unit database were matched to each case for age, sex, stage at diagnosis, number of primary melanomas and year of diagnosis (n = 114). There were no statistically significant differences between the two groups with regard to overall survival from initial diagnosis (FH+, 57.4 months; FH-, 50.0 months; P = 0.99), median survival from time of first metastasis (FH+, 15.4 months; FH-, 15.9 months; P = 0.94), or median disease-free interval (FH+, 26.4 months; FH-, 29.7 months; P = 0.73). On multivariate conditional logistic regression analysis, there was no statistically significant difference between the two groups in the probability of developing initial metastases or of ever developing metastases at specific sites. Survival, disease-free interval and distribution of metastatic sites are similar in both familial and non-familial melanoma. Genetic susceptibility for melanoma may lower the threshold for entering an otherwise common molecular pathway for tumour development and evolution.

Adolescent↗
PubMed1990

Phagocyte function in familial hypercholesterolaemia: peripheral blood monocytes exposed to lipopolysaccharide show increased tumour necrosis factor production.

We studied functions of polymorphonuclear leucocytes (PMN) and monocytes from peripheral blood of subjects with familial hypercholesterolaemia (FH). FH monocytes exposed to Escherichia coli lipopolysaccharide (LPS) in 10% human AB serum generated tumour necrosis factor (TNF) significantly more than did control monocytes. After lowering of serum low-density lipoprotein (LDL) levels by drug treatment, FH monocytes exposed to LPS in the absence of exogenous lipoproteins generated significantly more TNF than did control monocytes. These findings suggest that increased TNF production is not affected by hypolipidaemic treatment and may not derive from differences between uptake of exogenous LDL by FH monocytes and control cells. Chemotaxis, chemokinesis, and random migration of both FH PMN and FH monocytes were normal, as determined by agarose assay and membrane filter assay. FH PMN showed increased luminol-enhanced chemiluminescence in response to 2.5 x 10(-8) M, but not to 2.5 x 10(-6) M, N-formyl-methionyl-leucyl-phenylalanine, and not to serum-treated zymosan or to phorbol myristate acetate. Luminol- and lucigenin-enhanced chemiluminescence responses of FH monocytes were normal. In summary, the major aberration found in the present study was that FH monocytes stimulated with LPS show enhanced production of TNF. The possibility that exaggerated TNF production contributes to an early development of atherosclerotic lesions in FH subjects warrants further studies.

Adult↗
PubMed2006

Family history of alcoholism and cognitive recovery in subacute withdrawal.

A family history of alcoholism has been demonstrated to be an important factor affecting cognitive function. However, no studies have yet been conducted to compare cognitive recovery of family history-positive (FH+) and family history-negative (FH-) alcoholics in the subacute withdrawal period. To tackle this problem, a neuropsychological test battery consisting of six computerized tests was administered to 19 FH+ and 20 FH- alcoholics at 2 and 7 weeks after abstinence. At 2 weeks after abstinence, overall performance of both FH+ and FH- groups was significantly poorer than that of healthy controls. At 7 weeks, these performances tended to recover, but in Trail Making A and Figure Position, performances of FH+ alcoholics remained worse than those of controls, while those of FH- alcoholics did not. Thus cognitive recovery during the subacute withdrawal period was worse among FH+ alcoholics than FH- alcoholics, and this finding should be considered when planning alcohol rehabilitation programs.

Adult↗