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PubMed1993

Effect of positive family history of hypertension on the blood pressure and catecholamine responses to a 6 hour adrenaline infusion.

1. The effects of 6 h infusion of adrenaline (INF-A) or dextrose (INF-D) and of post-infusion cold pressor test (CPT) were compared in normal subjects, with (FH+) and without (FH-) a family history of hypertension. 2. Increased urinary excretion rates suggested facilitated noradrenaline (NA) release during and after INF-A in both FH+ and FH-. 3. Urinary adrenaline (UADR) excretion increased during INF-A, as expected, and was also slightly higher after INF-A than INF-D. 4. The effect of INF-A on systolic blood pressure (SBP) was greater in FH- than in FH+ but diastolic blood pressure (DBP) did not fall as quickly with nocturnal recumbency after INF-A in FH+. 5. A significantly greater response in plasma NA to CPT was seen in FH+ than in FH- after INF-A. A similar trend was also seen after INF-D. 6. Increases in DBP due to CPT were higher in FH+ than in FH- after both infusions. 7. This study provides evidence of increased noradrenergic activity during and after INF-A, and also of a difference in response to sympathetic stimulation between FH+ and FH-.

Adult↗
PubMed1997

Familial hypercholesterolemia in the Finnish north Karelia. A molecular, clinical, and genealogical study.

A specific mutation termed FH-North Karelia [FH-NK] accounts for almost 90% of familial hypercholesterolemia [FH] cases in the Finnish North Karelia, with a population of about 180,000. Extensive search for its presence in the entire North Karelia province revealed 340 carriers of this mutation. Other mutations of the LDL receptor [LDLR] gene accounted for 67 cases of heterozygous FH. This gives a minimum FH prevalence of 1 in 441 inhabitants in North Karelia, with the highest density of patients in the Polvijärvi commune (1 in 143 inhabitants). Old parish records, confirmation records, and tax records were used to track a common ancestor for most of the present-day North Karelian FH-NK patients in the village of Puso, located within an area where the FH prevalence today is the highest. DNA analysis indicated that 2% of the subjects aged 1 to 25 years would have been diagnosed as false-negative and 7% as false-positive FH patients on the basis of LDL cholesterol [LDL-C] determinations alone. Common genetic variations of apolipoprotein E [apoE], XbaI, polymorphism of apolipoprotein B [apoB], and PvuII polymorphism of the intact LDLR allele contributed little to serum lipid variation in established carriers of the FH-NK allele, although apoE2/4 genotype and the presence of the PvuII restriction site tended to be associated with relatively low LDL-C levels. Coronary heart disease (CHD) was present in 65 (30%) out of the 179 FH gene carriers aged > or = 25 years, and 19 individuals had a previous history of acute myocardial infarction (AMI). The average age (mean +/- SD) at onset of CHD was 42 +/- 7 years for males and 48 +/- 11 years for females (P < .05). In stepwise logistic regression analysis carried out in carriers of the FH-NK allele, age, gender, smoking, and apoE allele E2 all emerged as independent determinants of risk of CHD or AMI. It may be concluded that the relatively high prevalence of FH patients in North Karelia province provides a unique founder population in which genetic and nongenetic factors modifying the course of FH can be effectively investigated.

Adolescent↗
PubMed2003

Family history and cardiovascular risk in familial hypercholesterolemia: data in more than 1000 children.

BACKGROUND: Elevated LDL cholesterol (LDL-C) levels in childhood predict cardiovascular disease (CVD) later in life. Familial hypercholesterolemia (FH) represents the paradigm of this relation. METHODS AND RESULTS: The objectives of this study were to (1) establish the LDL-C level that provides the most accurate diagnosis of FH in children from families with known FH and (2) assess whether lipoprotein variation in these children is associated with premature CVD in relatives. Foremost, however, it was our objective to identify children with FH who are at high risk and in need of early intervention. A total of 1034 consecutive children from FH kindreds were investigated. First, LDL-C levels >3.50 mmol/L had a 0.98 post-test probability (95% CI, 0.96 to 0.99) of predicting the presence of an LDL receptor mutation. Second, children with FH in the highest LDL-C tertile (>6.23 mmol/L) had a 1.7-times higher incidence (95% CI, 1.24 to 2.36) of having a parent with FH suffering from premature CVD (P=0.001). In addition, such a parent was found 1.8 times more often (95% CI, 1.20 to 2.59) among children with FH who had HDL-C <1.00 mmol/L (P=0.004). Last, children with FH whose lipoprotein(a) was >300 mg/L had a 1.45-times higher incidence (95% CI, 0.99 to 2.13) of having a parent with FH suffering from premature CVD (P=0.05). CONCLUSIONS: In FH families, LDL-C levels allow accurate diagnosis of FH in childhood. Moreover, increased LDL-C and lipoprotein(a) and decreased HDL-C levels in children identify FH kindreds with the highest CVD risk.

Adolescent↗
PubMed2003

Differential influence of family history of hypertension and premature myocardial infarction on systolic blood pressure and left ventricular mass trajectories in youth.

OBJECTIVE: To examine the influence of genetic susceptibility to essential hypertension (EH) and the genetic susceptibility to premature myocardial infarction (MI) on longitudinal development of systolic blood pressure (SBP) and left ventricular mass (LVM) in youth. METHODS: Individual SBP and LVM growth curves across age were created for a sample of 745 subjects (age range: 4.9-27.5 years) and a sample of 687 subjects (age range: 8.2-27.5 years), respectively. Each sample had an approximately equal proportion of African American and European American males and females, with annual assessments over a 10-year period. Family history (FH) of EH and FH of premature MI were used as measures of genetic susceptibility to EH and to premature MI, respectively. Positive FH (FH(+)) of EH and of premature MI were defined, respectively, as verified EH in 1 or both biological parents, and verified MI in any biological parent or grandparent before 55 years of age. RESULTS: Subjects with an FH(+) of EH had higher SBP levels and stronger increases in SBP over time than subjects with a negative FH (FH(-)) of EH. Subjects with an FH(+) of EH also showed higher LVM levels than subjects with an FH(-) of EH. In addition, the effect of an FH(+) of EH on LVM was stronger in females than males. The effects of FH of EH on SBP and LVM could not be explained by differences in socioeconomic status, but the effect on LVM was no longer significant after adjustment for BMI. FH of MI had no significant effects on SBP or LVM. CONCLUSIONS: Effects of genetic susceptibility to EH on SBP and LVM trajectories were observed in childhood, whereas no such effects were found for FH of MI. Genetic markers of EH may improve the understanding of individual differences in susceptibility to develop hypertension and LV hypertrophy.

Adolescent↗
PubMed2002

Macrophage lipoprotein lipase expression is increased in patients with heterozygous familial hypercholesterolemia.

FH is associated with accelerated atherosclerosis. Based on the crucial role of macrophage LPL in atherogenesis, we determined in the present study macrophage LPL expression in patients with FH. Monocytes isolated from 13 FH patients and 13 control subjects were differentiated into macrophages by culturing the cells for 9 days in 20% autologous or heterologous serum. Macrophages of patients with FH cultured in their own sera showed a significant increase in LPL mRNA levels, extracellular LPL mass, and activity compared with macrophages of control subjects. Although these alterations positively correlated with the levels of serum platelet-derived growth factor-BB (PDGF-BB) in FH subjects, increased LPL secretion by cultured FH macrophages was reduced neither by immunoneutralizing FH serum with an anti-PDGF-BB antibody, nor by culturing these cells in sera from control subjects. With the exception of LPL, levels of other cytokines and 8-isoprostane were not increased in the supernatants of macrophages of FH patients. Serum from FH patients also enhances the levels of LPL secreted by macrophages from control subjects. Immunoneutralization of FH serum with an anti-PDGF-BB antibody totally reversed this alteration. Overall, this study demonstrates that macrophages from FH subjects overproduce LPL and that PDGF present in the serum from FH patients stimulates LPL secretion by control macrophages. These findings suggest that macrophage LPL induction in patients with FH might be related to the increased atherogenesis observed in these subjects.

Anticoagulants↗
PubMed1984

Genetic polymorphism of human factor H (beta 1H).

Human Factor H (beta 1H) was found to be polymorphic after neuraminidase treatment and isoelectric focusing (IEF) under completely denaturing conditions. Three variants, FH 1, FH 2, and FH 3, were identified in a sample population of 81 unrelated caucasoid individuals. Family studies demonstrated correct mendelian segregation of FH 1, FH 2, and FH 3. Our data indicate that these genetic variants of human Factor H are encoded by three codominant alleles, FH*1, FH*2, and FH*3, at a single autosomal locus FH. In the sample analyzed, the gene frequencies of FH*1, FH*2, and FH*3 were, respectively, 0.691, 0.302, and 0.006.

Alleles↗
PubMed1993

Clinical and pathological analyses of patients with a family history of colorectal cancer. Registry Committee, Japanese Research Society for Cancer of the Colon and Rectum.

Patients who were registered by the Japanese Society for Cancer of the Colon and Rectum between 1978 and 1983 were examined clinically and pathologically, in terms of colorectal cancer with familial accumulation. The incidence of patients with a family history of colorectal cancer (FH+ group)--patients with adenomatosis coli were excluded--was 6.5% in 15,369 colorectal cancer patients. The incidence of patients with a family history of malignant tumors other than colorectal cancer was 27.7%. Comparison of the FH+ group with the FH- group (patients without a family history of colorectal cancer) revealed the incidence of colonic cancer to be significantly higher than that of rectal cancer in the FH+ group (P < 0.01). The patients with colonic cancer in the FH+ group were significantly younger than those in the FH- group (P < 0.01), but there was no age-dependent difference between patients with rectal cancer in the two groups. There was no difference in sex ratio and there was little difference in the subsite of the primary lesion in the colon between the FH+ and FH- groups. The incidence of multiple primary colorectal cancer was significantly higher in patients with colonic cancer in the FH+ group than in the FH- group (P < 0.01). The incidence of multiple primary cancer in sites other than the colon and rectum was significantly higher in the FH+ group (P < 0.01), but no significant difference was found in the site of lesions. The prognosis of patients in the FH+ group was significantly better than that of those in the FH- group; however, there were no differences in background factors such as findings of the primary lesion, status of metastasis, clinical stage and rate of curative resection between the groups.

Adenocarcinoma↗
PubMed1994

A new missense mutation (Cys297-->Phe) of the low density lipoprotein receptor in Italian patients with familial hypercholesterolemia (FHTrieste).

During a survey of the mutations of the low density lipoprotein receptor (LDL-R) gene in Italian patients with familial hypercholesterolemia (FH), we identified a novel point mutation, that creates a new EcoRI site at the 5' end of exon 7, in a heterozygous FH subject (FH-100). The sequence of a cDNA fragment encompassing exon 7 showed the presence of a G-->T transversion in codon 297; this created a new EcoRI site and produced a missense mutation, leading to a Cys297-->Phe substitution in repeat A of the epidermal growth factor (EGF) precursor homology domain of LDL-R. Since the substitution of Cys297 disrupts the intracellular transport of the LDL-R protein, as previously demonstrated by site-directed mutagenesis, we suggest that this mutation is the cause of FH in the FH-100 proband. We screened the DNA of 303 Italian FH patients by amplification of exon 7 from genomic DNA followed by digestion with EcoRI or by Southern blotting. Two individuals (FH-64 and FH-127) were found to be carriers of the Cys297-->Phe mutation. Restriction fragment length polymorphism analysis demonstrated that, in two kindreds (FH-64 and FH-100), the haplotype in linkage with the Cys297-->Phe mutation was the same, suggesting the presence of a common ancestor. The Cys297-->Phe mutation has been designated FHTrieste after the name of the city in Northern Italy from which probands FH-100 and FH-127 originate.

Base Sequence↗
PubMed1996

Estimation of the prevalence of familial hypercholesterolaemia in a rural Afrikaner community by direct screening for three Afrikaner founder low density lipoprotein receptor gene mutations.

We have determined the prevalence of familial hypercholesterolaemia (FH) in a rural Afrikaner community by means of direct DNA screening for three founder-related Afrikaner low density lipoprotein (LDL) receptor gene mutations. A random sample of 1612 persons, aged 15-64 years, was selected as a subsample of 4583 subjects from an Afrikaner community living in the south-western Cape, South Africa. Participants who had a total serum cholesterol (TC) in the high TC category as defined in the consensus recommendations by the Southern African Heart Foundation, were screened for three founder-related LDL receptor gene mutations, causing FH in 90% of Afrikaners. Of the subsample, 201 participants (12.5%) had TC levels above the 80th percentile. In this group the combined prevalence of the three common Afrikaner LDL receptor gene defects (D206E, FH Afrikaner-1; V408M, FH Afrikaner-2; D154N, FH Afrikaner-3) was calculated as 1: 83. When taking into account the reported background prevalence of other FH gene defects of 1:500 in this community, their overall prevalence of FH was estimated to be 1:72. The significant differences found between the FH patients and other high risk patients with raised cholesterol levels were higher TC and LDL cholesterol levels and lower high density lipoprotein cholesterol levels in FH patients. The treatment status of the molecularly identified FH patients and other hypercholesterolaemic persons suggests that this condition is inadequately diagnosed and poorly managed in this study population. An extrapolation to the entire South African population suggests that there are about 112000 FH patients in the country who are under-diagnosed as a group and therefore not receiving the care that would help to reduce the burden of FH-associated ischaemic heart disease in South Africa.

Adolescent↗
PubMed2004

Influence of TNF gene polymorphism in patients with acute and fulminant hepatitis.

BACKGROUND: Tumor necrosis factor (TNF) is involved in liver damage, especially in fulminant hepatitis (FH). Our previous data showed that the serum level of TNF-alpha was markedly increased in FH. To investigate the mechanism of the overproduction of TNF in FH patients, polymorphism of the TNF gene was studied. METHODS: We analyzed 120 healthy subjects (controls), 63 patients with acute hepatitis (AH), and 32 patients with FH. Of the 32 FH patients, 21 died or received liver transplantation (FH-D), and 11 survived with intensive therapy (FH-S). The TNF-alpha promoter region at -1031, -863, -857, -308, and -238, and TNF-beta Nco1 polymorphism sites were studied. RESULTS: (1) The four groups showed no differences in polymorphisms of positions -857, -308, and -238. The allelic frequencies of positions -1031C and -863A in the FH-D patients were significantly higher compared to findings in control subjects. (2) The allelic frequency of B2 in the TNF-beta gene was significantly higher in FH patients, and particularly in the FH-D patients, compared to control subjects. (3) When the patients were divided into four groups by etiology, hepatitis A virus (HAV), HBV, HCV, and non-A non-B non-C, the allelic frequencies of positions -863A and TNF-beta B2 in FH patients were increased in the non-A non-B non-C group compared to controls. CONCLUSIONS: FH patients with a poor prognosis had higher frequencies of positions -1031C and -863A in the TNF-alpha promoter region, and higher frequencies of the B2 allele of the TNF-beta gene. These data suggest that the genomic background may be associated with the prognosis of acute liver failure.

Acute Disease↗
PubMed1993

Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics.

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein cholesterol levels early in childhood and very early coronary disease in both men and women. Treatment with multiple medications and diet can normalize cholesterol levels in many persons with FH and prevent or delay the development of coronary atherosclerosis. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. Previously published blood cholesterol criteria greatly underdiagnosed new cases of FH among members of known families with FH in Utah and overdiagnosed FH among participants of general population screening, revealing the need for different cholesterol screening criteria in persons from these 2 different settings. The statistical concept of a priori probabilities was applied to derive 2 sets of practical screening criteria: one for persons participating in general population screening studies and another for close relatives of confirmed FH cases, showing dramatic differences. At a cholesterol level of 310 mg/dl, only 4% of persons in the general population would have FH but 95% of persons who were first-degree relatives of known cases would have FH. Detailed tables were derived to provide practical total and low-density lipoprotein blood cholesterol screening criteria for diagnosing FH in different screening settings and specific age groups. In population screening the new FH criteria require a total cholesterol > 360 mg/dl for age 40+ (or 270 mg/dl in youth). Among first-degree relatives of confirmed cases in families with FH, the new total cholesterol criteria are much lower (> 290 mg/dl for age 40+, > 220 mg/dl for youth).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects.

The in vivo turnover of autologous lipoprotein(a) (Lp(a)) was studied in four heterozygous familial hypercholesterolaemic (FH) subjects and four subjects who were hyperlipidaemic but not FH. Each of the FH subjects exhibited a much lower fractional catabolic rate (FCR) for LDL than each of the non-FH subjects. Lp(a) was purified by sequential density gradient centrifugations and was radio-iodinated. The labelled Lp(a) ran as a single band on electrophoresis in gradient polyacrylamide gels. Less than 5% of the label was in lipid, with about 40% of the remainder on apolipoprotein B (apo B) and 60% on apo(a). Labelled and unlabelled Lp(a) competed equally poorly with LDL for binding to LDL receptors on cultured fibroblasts. The FCR of Lp(a), calculated from the decay of the specific radioactivity of the Lp(a) isolated from the daily blood samples, was the same in FH subjects as in non-FH subjects. There was no consistent relationship between Lp(a) FCR and the plasma Lp(a) concentration or between FCR and the Lp(a) phenotype, at least within this sample of subjects. There was a strong association between Lp(a) concentration and production rate, with values for non-FH and FH subjects falling on the same line. The rate of decline of radioactivity in whole plasma was consistently slower than the fall in specific radioactivity of the isolated Lp(a). This difference was more marked in FH subjects than in non-FH subjects and resulted from the accumulation of radioactivity derived from the injected Lp(a) at a lower density than Lp(a), in the fractions containing LDL. The amount of radioactivity in this fraction increased for the first few days after injection and then fell, the fall being more rapid in non-FH than in FH subjects. These results provide no evidence for the involvement of LDL receptors in the catabolism of Lp(a) itself but suggest that they could be responsible for some of the clearance of the lipid and apo B components after removal of apo(a) in the circulation.

Adult↗
PubMed1996

Abnormal regulation of the LDL-R and HMG CoA reductase genes in subjects with familial hypercholesterolemia with the "French Canadian mutation".

Familial hypercholesterolemia (FH) is seen with high frequency in the province of Québec, Canada. A large deletion (> 10 kb) of the 5'-end of the low density lipoprotein receptor (LDL-R) gene is the major mutation of the LDL-R in FH subjects in Québec (approximately 60% of FH subjects). No mRNA is produced from the allele bearing the mutation, and cellular cholesterol obtained by receptor-mediated endocytosis is under the control of the non-deletion allele. We have previously reported that some patients with the 10-kb deletion (approximately 9%) fail to respond to the hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase) inhibitor class of medications. We studied mRNA levels of the LDL-R and HMG CoA reductase genes in response to the HMG CoA reductase inhibitor lovastatin in a time- and dose-dependent fashion in cultured human skin fibroblasts and we devised an in vitro model to study the response to drug therapy in subjects with FH. We determined mRNA levels by RNase protection assay in skin fibroblasts obtained from controls (n = 3) and FH subjects with the > 10-kb deletion (responders, n = 3; non responders, n = 3; to drug therapy). We measured 125I-LDL binding on skin fibroblasts grown in the presence of lipoprotein-deficient serum with or without 1 microM lovastatin, using 10 micrograms/mL of 125I-LDL protein. Control subjects exhibited coordinate regulation of the LDL-R and HMG CoA reductase genes in response to lovastatin, 0.1-25 microM, for 0-24 h. Correlation coefficients between mRNA levels of both genes were > 0.9 in controls and FH subjects. However, by linear regression analysis, the corresponding slopes for the correlation between both genes were 0.98 (controls), 3.36 and 3.63 (FH responders and non-responders), indicating a pattern of dissociated but still coordinate regulation in FH subjects. The magnitude of increase of mRNA levels of the LDL-R gene was approximately five-fold over LPDS in controls, two-fold in FH responders and two-fold in non-responders. Binding studies using 125I-LDL reveal that a control subject and all responders had a 2-2.5-fold increase in binding to cell surface receptors but two out of three FH non-responders showed no increase in binding in response to 1 microM lovastatin. The LDL-R and HMG CoA reductase genes are expressed in coordinate regulation in fibroblasts from subjects with FH due to the > 10-kb deletion, but with a proportionately greater up-regulation of the HMG CoA reductase gene. Some subjects, with FH caused by the > 10-kb deletion of the LDL-R gene, who fail to respond to HMG CoA reductase inhibitors have abnormal LDL receptor binding activity at the cell surface in response to lovastatin in vitro.

Anticholesteremic Agents↗
PubMed2006

Family history of diabetes is a major determinant of endothelial function.

OBJECTIVES: We evaluated whether endothelial dysfunction was present in nondiabetic persons with a family history (FH) of diabetes and assessed its relationship with insulin resistance and atherosclerosis risk factors. BACKGROUND: Atherosclerosis is frequently present when type 2 diabetes (T2D) is first diagnosed. Endothelial dysfunction contributes to atherogenesis. METHODS: Oral glucose tolerance and brachial artery flow-mediated, endothelium-dependent vasodilation (EDV) were assessed in 38 nondiabetic subjects; offspring of two parents with T2D (FH+) or with no first-degree relative with diabetes (FH-). RESULTS: Although fasting glucose was higher in FH+ than FH- (5.3 +/- 0.1 mmol/l vs. 4.9 +/- 0.1 mmol/l, p < 0.03), glycemic burden assessed as 2-h or area-under-the-curve glucose after glucose load or glycosylated hemoglobin (HbA1c), and measures of insulin sensitivity or inflammation did not differ. Brachial artery flow-mediated EDV was reduced in FH+ (7.1 +/- 0.9% vs. 11.7 +/- 1.6%, p < 0.02), with no difference in nitroglycerin-induced endothelium-independent vasodilatation. In the combined cohort, only FH+ (r2 = 0.12, p < 0.02) and HbA1c (r2 = 0.14, p < 0.02) correlated with EDV. Insulin resistance, assessed by tertile of homeostasis model assessment of insulin resistance (HOMA-IR), was associated with impaired endothelium-dependent vasodilatation in FH- (p < 0.03, analysis of variance), but not in FH+, as even the most insulin-sensitive FH+ offspring had diminished endothelial function. In multiple regression analysis, including established cardiac risk factors, blood pressure and lipids, HbA1c, and HOMA-IR, FH remained a significant determinant of EDV (p = 0.04). CONCLUSIONS: Bioavailability of nitric oxide is lower in persons with a strong FH of T2D. Glycemic burden, even in the nondiabetic range, can contribute to endothelial dysfunction. Abnormalities of endothelial function may contribute to atherosclerosis before development of overt diabetes.

Adult↗
PubMed2002

Interleukin 1alpha alters hippocampal serotonin and norepinephrine release during open-field behavior in Sprague-Dawley animals: differences from the Fawn-Hooded animal model of depression.

Detection of two biogenic amine neurotransmitters, serotonin (5-HT) and norepinephrine (NE) within the CA1 region of the hippocampus (HPC) of behaving male laboratory animals (Rattus norvegicus), was performed with miniature carbon sensors (BRODERICK PROBES) and in vivo semidifferential microvoltammetry after acute administration of the soluble immune factor, human recombinant, interleukin (IL) 1alpha (10 and 100 ng/kg i.p.). Two animal models were compared, i.e., (a) the Sprague-Dawley (SD) model, a strain neither biochemically nor immune-challenged and (b) the Fawn-Hooded (FH) model, a biochemically (5-HT-deficient) and immune-challenged animal. Open-field behaviors, locomotion (ambulations) and stereotypy (fine movements of sniffing and grooming) were monitored with infrared photobeams while 5-HT and NE were selectively and separately detected within seconds in real time. Subchronic studies were performed in the same animals 24 h later at which time no further drug was administered. Results from acute treatment studies showed that IL-1alpha altered HPC monoamines and behavior viz-a-viz habituation values (baseline) in the SD strain differently from those in the FH strain as follows: (1) although 5-HT release was significantly increased within CA1 region of HPC in both SD and FH strains (P<.0001), the extent of the HPC 5-HT increase in the 5-HT-deficient FH strain was significantly less than that of the SD strain at both doses (P<.0001). The subchronic studies showed that 5-HT release within the HPC in the SD strain significantly increased (135%) over drug treatment values (P<.001), whereas HPC 5-HT release in the FH strain remained the same as that seen in the acute drug treatment studies; the difference between strains for the subchronic study was also statistically significant (P<.01). (2) IL-1alpha significantly decreased HPC NE release in the SD strain (P<.0004) while IL-1alpha decreased HPC NE release in the FH strain only at the 10-ng/kg dose (P<.001); at the 100-ng/kg dose in the FH strain, NE rebounded towards baseline and increased 15% above baseline reaching statistical significance (P<.05). Subchronic studies in the SD strain showed a further decreased NE signal to 38% below baseline (P<.0001), whereas subchronic studies in the FH strain showed a significant increase in NE release (P<.02). The difference between strains in the subchronic NE studies was significant (P<.001). (3) Ambulations were increased after IL-1alpha administration in acute studies in both the SD and the FH strains, but the increase did not reach statistical significance, whereas in the subchronic studies, both strains exhibited significant increases as revealed by post hoc analyses (P<.05). There was a statistically significant difference between strains in acute studies (P<.001), whereas no significant differences between models were seen in ambulation behavior in subchronic studies. (4) Fine movements increased over baseline after IL-1alpha administration in both animal models in acute studies, however, results did not reach statistical significance, likely due to the episodic effect of IL-1alpha on movement behavior in both the SD and the FH strains. However, the SD strain showed a significant increase in fine movement behavior during the subchronic studies (P<.02). Significant differences in fine movements between animal models were not observed either acutely or in subchronic studies. In summary, the data show that immune modulation by IL-1alpha affects HPC neurochemistry and behavior in SD versus FH animal models differently and/or to different degrees. The data show that while the FH animal model is subsensitive to 5-HT agonists, 5-HT function can be stimulated. Comparison of genetically diverse animal models provides a reliable means to identify and discern cytokine-induced depressive versus stressor properties. Selective sensor technology provides a powerful tool as movement behavior is monitored and interpreted as a function of monoamine neurotransmission.

Animals↗
PubMed2002

Constitutive expression and regulation of rat complement factor H in primary cultures of hepatocytes, Kupffer cells, and two hepatoma cell lines.

The 155-kd soluble complement regulator factor H (FH), which consists of 20 short consensus repeats, increases the affinity of complement factor I (FI) for C3b by about 15 times. In addition to its cofactor activity, it prevents factor B from binding to C3b and promotes the dissociation of the C3bBb complex. The primary site of synthesis of FH, as well as of FI, is the liver, but the cell types responsible for the hepatic synthesis of both factors have not yet been clearly identified. In contrast to FI-mRNA, which was detectable only in hepatocytes (HC), FH-specific mRNA was identified in both HC and Kupffer cells (KC). As calculated for equal amounts of mRNA isolated from both cell types, FH-specific mRNA was found to be nearly 10-fold higher in KC than in HC, leading to the conclusion that KC are an abundant source of FH. Of the investigated proinflammatory cytokines IL-6, TNF-alpha, IL-1beta, and IFN-gamma, only IFN-gamma up-regulated FH-specific mRNA up to 6-fold in both primary HC and KC. This was also demonstrable on the protein level. However, FH-specific mRNA was not inducible in the rat hepatoma cell line H4IIE, which did not express FH-specific mRNA and could not be up-regulated in FAO cells that constitutively expressed FH-specific mRNA. This demonstrates that transformed cell lines do not reflect FH regulation in isolated primary HC. In addition to IFN-gamma, the endotoxin lipopolysaccharide (LPS) up-regulated FH-specific mRNA nearly 10-fold in KC after stimulation at concentrations of 10 or 1 ng/ml. In contrast, concentrations of up to 2 microg LPS/ml did not show any effect on HC. Our data suggest that LPS does not regulate the expression of FH in HC.

Animals↗
PubMed2004

Increased renovascular response to angiotensin II in persons genetically predisposed to arterial hypertension disappears after chronic angiotensin-converting enzyme inhibition.

OBJECTIVE AND METHODS: Functional changes in the kidneys of healthy men with (FH+) (n = 15) and without (FH-) (n = 15) family history of primary arterial hypertension were examined during administration of low-dose exogenous angiotensin II (A2) (1 ng/kg per min) before and after acute (1 mg intravenous enalaprilat) and chronic (7 days oral enalapril, 30 mg/day) angiotensin-converting enzyme (ACE) inhibition. RESULTS: Before chronic ACE inhibition, A2 increased mean arterial blood pressure (FH+, 8.7 +/- 0.8 mmHg; FH-, 8.9 +/- 0.9 mmHg), plasma immunoreactive A2 (FH+, 21 +/- 2 pg/ml; FH-, 18 +/- 3 pg/ml) and plasma aldosterone (FH+, 64 +/- 7 pg/ml; FH-, 56 +/- 6 pg/ml) to a similar degree in both groups. Chronic ACE inhibition had no impact on A2 blood pressure, plasma A2, or plasma aldosterone effects. A2 significantly increased renal vascular resistance in both groups (FH+, 3956 +/- 462 dyne s cm(-5); FH-, 2219 +/- 550 dyne s cm(-5)), but the effect was more pronounced in FH+ (P = 0.02). Glomerular hemodynamics, estimated by a modified Gomez model, revealed increased afferent and efferent responsiveness to A2 in FH+ subjects. These differences disappeared after chronic ACE inhibition when total, afferent and efferent sensitivities to A2 were similar in both groups. CONCLUSIONS: Systemic blood pressure and plasma aldosterone responses to A2 were similar in men with or without a genetic disposition to primary arterial hypertension. However, our data demonstrate that men with a family history of hypertension have increased renovascular sensitivity to A2, and that chronic ACE inhibition normalizes their sensitivity.

Adolescent↗
PubMed2005

Putative regulatory T cells are impaired in cord blood from neonates with hereditary allergy risk.

The hygiene hypothesis implies that the increasing prevalence of allergy in 'westernized' countries is explained by reduced bacterial exposure in early life, but the underlying mechanism remains elusive. We therefore wanted to study the effect of bacterial lipopolysaccharide (LPS) on the generation of regulatory T (T(R)) cells in neonates, and to analyze differences between neonates with allergy risk because of a family history of atopy (FH+) and controls without such hereditary risk (FH-). Cord blood mononuclear cells from the FH+ and FH- groups were stimulated with beta-lactoglobulin in the presence of LPS. T-cell phenotypes suggestive of T(R) cells [CD25+, CD25high and integrin (CD103+)], and the intracellular proliferation antigen Ki-67 were quantified by flow cytometry. Release of the immunosuppressive cytokine transforming growth factor beta1 (TGF-beta1) from its inactive complex was determined by enzyme-linked immunosorbent assay. The analyses revealed the generation of T-cell phenotypes suggestive of T(R) cells including a CD25high T-cell subset which was inversely related to T-cell proliferation (r=-0.54, p<0.05) and to activation-induced release of TGF-beta1 (r=-0.80, p<0.001). The CD25high T-cell subset tended to be impaired in the FH+ group (% of CD3+ T cells: FH+, 5.1% vs. FH-, 12.6%), and notably, the FH+ group showed a significantly reduced capacity for generation of both CD25+ (FH+, 16.2% vs. FH-, 34.9%; p<0.01) and T cells (FH+, 2.1% vs. FH-, 3.9%; p<0.05). Our findings suggested that early-life exposure to a dietary antigen in the presence of LPS might modulate the immune system by generating T(R) cells. This capacity was impaired in neonates with hereditary allergy risk, but clinical follow-up will be required to determine a possible effect on allergy emergence.

Enzyme-Linked Immunosorbent Assay↗