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PubMed2000

High social anxiety and low aggression in Fawn-Hooded rats.

The Fawn-Hooded (FH) rat strain, with well-documented changes in their serotonergic and noradrenergic systems, is a putative genetic model for some neuropsychiatric disorders like depression, alcohol abuse, and anxiety. Because social phobia frequently occurs in combination with these disorders and there are no social anxiety-related data in FH rats in the literature, we measured the behavior of FH rats in the social interaction test. In addition, the effects of the anxiogenic Serotonin-2C (5-HT2C) receptor agonist, m-chlorophenylpiperazine (m-CPP), were studied. Male FH, Wistar (W), and Sprague-Dawley (SD) rats were used in two different test conditions of the social interaction test: the high light, unfamiliar arena, associated with high anxiety, and the low light, familiar arena, associated with low anxiety-like behavior. All social behaviors were markedly diminished in FH rats that suggested higher anxiety in these animals. Total social interaction time was reduced by 60-70% in FH rats compared either to W or SD rats under high light, unfamiliar or low light, familiar conditions, respectively. Aggressive behavior was reduced at least by 85% in FH rats. Locomotor activity and exploratory behavior were only minimally, in most comparisons, not significantly affected in FH rats. Total social interaction time, aggression, and locomotor activity were decreased, and self-grooming increased by m-CPP (0.5 mg/kg, ip) in all three strains. m-CPP decreased total social interaction time thus, caused anxiety most efficiently in FH rats (reduced by 69%, 50%, and 55% in FH, W, and SD rats, respectively), but other effects of the drug were similar in the three strains. Our studies provide evidence that the FH rat strain may be a genetic model of social phobia or other anxiety disorders with impaired social behavior.

Aggression↗
PubMed1998

Distribution of GABAA receptors in the limbic system of alcohol-preferring and non-preferring rats: in situ hybridisation histochemistry and receptor autoradiography.

The present study has employed quantitative receptor autoradiography and in situ hybridisation histochemistry to compare the expression of the mRNA encoding the alpha 1 and alpha 2 subunits of the GABAA receptor and the binding density of mature GABAA receptors in the limbic system of alcohol-preferring Fawn-Hooded rats (FH) with Wistar-Kyoto rats (WKY). Quantifiable levels of mRNA encoding the alpha 1 subunit were found in cortical regions, ventral pallidum, substantia nigra, horizontal limb of the diagonal band and the hippocampus of both rat strains. Interestingly, expression of the alpha 1 subunit mRNA was decreased by approximately 30% in the hippocampus of FH compared to WKY rats. Following a 28-day period with free access to 10% ethanol, expression of the alpha 1 subunit transcript, was significantly increased in the piriform cortex and horizontal limb of the diagonal band, unaltered in the hippocampus but decreased in the substantia nigra of FH rats. Quantifiable levels of mRNA encoding the alpha 2 subunit were found in nucleus accumbens, amygdala, cortical regions, lateral septal nucleus, hippocampus, medial habenula and ventral pallidum of both strains. Expression of the alpha 2 subunit mRNA was decreased by approximately 35% in both the hippocampus and occipital cortex of FH compared to WKY rats. However, consumption of 10% ethanol in FH rats had no impact upon expression of the mRNA encoding the alpha 2 subunit in any region examined. Mature GABAA receptors were studied by autoradiography utilising the antagonist radioligand [3H]SR95531 and the agonist radioligand [3H]muscimol. Topographic binding throughout the limbic system of both strains was observed for both radioligands. Specifically, [3H]SR95531 binding was higher in the occipital cortex, hippocampus, lateral septal nucleus, superior colliculus and ventral pallidum of the FH rats compared to WKY rats; however, in the nucleus accumbens [3H]SR95531 binding was lower in FH compared to WKY. Ethanol consumption had no measurable effect on the binding of [3H]SR95531 in FH rats. In the case of [3H]muscimol, binding was higher in the cortex, lateral septum and ventral pallidum of FH compared to WKY. Furthermore, ethanol consumption resulted in a 25-30% increase in [3H]muscimol binding in the lateral septum and striatum of FH rats. These data provide evidence for differential expression of GABAA receptor subunits in FH and WKY rats, and additionally indicate anatomically defined variations in GABAA receptor binding between the two rat strains.

Alcohol Drinking↗
PubMed2001

Coexpression of hepatocyte growth factor-Met: an early step in ovarian carcinogenesis?

Since autocrine regulation of HGF-Met is implicated in many forms of human cancer, we investigated whether the predisposition to develop ovarian cancer in women with hereditary ovarian cancer syndromes involves changes in the expression of HGF-Met by the tissue of origin of epithelial ovarian cancers, the ovarian surface epithelium (OSE). We compared cultures of normal OSE from women with (FH-OSE) (n=20) and with no (NFH-OSE) (n=48) family histories of ovarian cancer, SV40 Tag immortalized OSE lines (IOSE, n=5) and ovarian cancer cell lines (n=3). Cultures derived from 21/22 women with NFH-OSE and 13/13 women with FH-OSE expressed Met mRNA initially. After two to three passages, Met was downregulated in 37% of NFH-OSE cultures but persisted in 100% of FH-OSE cultures and ovarian cancer lines, like other epithelial differentiation markers that are stabilized in FH-OSE and neoplasia. HGF and Met mRNA were concomitantly expressed by NFH-OSE from only three of 32 women but in FH-OSE from eight of 13 women, and also in five of five IOSE and two of three ovarian cancer lines. Conditioned media from FH-OSE, but not NFH-OSE, contained immunoreactive HGF and induced cohort migration which was inhibited by neutralizing HGF antibody. Several signaling molecules of the PI3K pathway, including Akt2 and p70 S6K, were constitutively activated in FH-OSE from six of six women but in NFH-OSE from only four of eight women. Exogenous HGF was mitogenic in OSE, and that effect was regulated through the MAP kinase (ERK1/ERK2) and FRAP/p70 S6K pathways. The proliferative response to HGF was greater in NFH-OSE than in FH-OSE cultures. The results show that FH-OSE cultures differ from NFH-OSE by increased stability of Met expression and by HGF secretion. Constitutive phosphorylation of kinases and a diminished growth response to HGF suggest the presence of autocrine regulation in FH-OSE. In analogy with other cell types where an autocrine HGF-Met loop has been implicated in tumorigenic transformation, this change in FH-OSE may play a role in the enhanced susceptibility to ovarian carcinogenesis in women with hereditary ovarian cancer syndromes.

Autocrine Communication↗
PubMed2003

A family aggregation study: the influence of family history and other risk factors on language development.

Substantial evidence continues to accrue for familial transmission of specific language impairment (SLI). The incidence in families with a history of SLI is estimated at approximately 20%-40%, whereas in the general population the estimated incidence is about 4%. Typical aggregation studies compare data on the speech and language status of parents and siblings of individuals with SLI (the probands) to similar data from family members of control individuals with no speech or language disorder history. In the present study, family aggregation of SLI was examined for a unique sample of children who were ascertained before 6 months of age and thus did not have SLI, but were born into a family with a positive history of SLI (FH+). No study to date has examined the pattern of affectance in families of children ascertained at such a young age. In addition, the ratio of boys to girls born into such families was investigated, as previous studies have suggested alterations in the expected gender ratios. Consistent with prior research, SLI was found to aggregate in families; the average affectance rate in FH+ families was 32%, with significantly more boys (41%) reported as having SLI than girls (16%). A comparison of FH+ and control families (FH-) on sociodemographic factors and medical history revealed differences in the overall rate of autoimmune diseases; FH+ families reported a significantly higher incidence (35%) compared to FH- families (9%). Finally, the 3-year language abilities of a subset of 32 children from FH+ families were compared with those of 60 children from FH- families. Children from FH+ families scored significantly lower on standardized measures of language and were more likely to fall below the 16th percentile (28%) than children from FH- families (7%). These results provide converging evidence that children from FH+ families are indeed at greater risk of developing language delay compared to children from control families.

Autoimmune Diseases↗
PubMed2000

Oxidizability of atherogenic low-density lipoprotein subspecies in severe familial hypercholesterolemia: impact of long-term low-density lipoprotein apheresis.

BACKGROUND: Oxidative modification of low-density lipoprotein (LDL) plays a key role in the pathophysiology of atherosclerosis. LDL-apheresis, which involves direct removal of plasma LDL from circulating blood, is an efficient treatment of homozygous familial hypercholesterolemia (FH). METHODS: We evaluated impact of long-term LDL apheresis treatment on the atherogenicity of the major LDL subclasses (light, LDL1, and LDL2, density [d] 1.018-1.030 g/mL; intermediate, LDL3, d 1.030-1.040 g/mL, and dense LDL, LDL4 and LDL5, d 1.040-1.065 g/mL) separated by density gradient ultracentrifugation in severe FH patients. Therefore, we compared the oxidative resistance as well as the chemical and physical properties of each LDL subpopulation in the FH group with those in the corresponding LDL subfractions from normocholesterolemic control subjects. RESULTS: Both intermediate and dense LDL subfractions were significantly more resistant to copper-mediated oxidation in FH patients treated regularly by LDL-apheresis than their counterpart controls. The lag phases for LDL3, LDL4, and LDL5: 63.9+/-11.6, 55.8+/-1.2, and 47.2+/-6.5 min. in FH patients were significantly longer than those of the corresponding subfractions in normocholesterolemic controls (P <.01 for LDL3 and LDL5, P<.005 for LDL4). This protective effect was reflected in the delayed formation of biologically active lipid oxidation products such as oxysterols, lipid hydroperoxides, dienes, and dienals in the intermediate and dense LDL subfractions of FH patients. These findings may result from lower "seed" contents of lipid hydroperoxide (LOOH) detected as dienes in plasma LDL from apheresis-treated FH patients; indeed, baseline LOOH/diene contents in all 5 LDL subclasses from FH patients were significantly lower than those of the corresponding subclasses in normolipidemic subjects (P<.0005). On the other hand, the enhanced oxidative resistance of both intermediate (LDL3) and dense (LDL4 and LDL5) LDL subpopulations in FH patients could not be accounted for by any consistent modification in chemical composition or in lipophilic antioxidant content, although minor differences were observed between patients and controls in unsaturated fatty acid profile. In contrast, sphingomyelin content was enriched in FH LDL subclasses, potentially resulting in reduced penetration of the hydrophilic surface layer of LDL by oxygen radicals. CONCLUSION: We conclude that low concentrations of preformed lipid hydroperoxides and dienes, together with surface sphingomyelin enrichment, can account for the enhanced oxidative resistance of intermediate (LDL3) and atherogenic dense LDL (LDL4, LDL5) induced by long-term LDL apheresis in severe FH patients.

Adolescent↗
PubMed2000

Do all girls with apparent idiopathic precocious puberty require gonadotropin-releasing hormone agonist treatment?

OBJECTIVE: To evaluate prospectively pubertal and predicted adult height progression until final height (FH) or near FH in girls with apparent idiopathic precocious puberty who were not treated. STUDY DESIGN: The decision not to treat at the time of initial evaluation was based on evidence of slowly progressive puberty as shown by bone age (BA) advancement <2 years above the chronologic age, whatever the hypothalamic pituitary ovarian axis activation, or no evidence of hypothalamic pituitary ovarian axis activation, whatever the BA advancement. During follow-up, patients who showed a significant decrease in predicted FH were treated with gonadotropin-releasing hormone agonist. RESULTS: Twenty-six girls with idiopathic precocious puberty were studied at a mean chronologic age of 7.4 +/- 0.9 years during a follow-up period of 6.6 +/- 2.2 years until FH or near FH. During the first 2 years of follow-up, most of the patients (group 1, n = 17; 65% of the cases) showed no substantial changes in predicted FH. They never required treatment, and menarche occurred at a mean chronologic age of 11.9 +/- 0.6 years. Their mean FH (or near FH) at 160.7 +/- 5.7 cm was close to their target height (161.3 +/- 4.7 cm). On the other hand, after a mean follow-up period of 1.4 +/- 0.8 years, 9 patients (group 2) had acceleration of bone maturation and deterioration of their predicted FH (from 162.1 +/- 6. 2 cm to 155.3 +/- 5.6 cm; P <.01), which was at that time significantly lower than their target height (P <.05) (mean target height = 159.8 +/- 4.6 cm). They received a gonadotropin-releasing hormone agonist for 2.1 +/- 0.7 years, resulting in a restoration of growth prognosis (mean FH or near FH = 160.2 +/- 6.7 cm). CONCLUSIONS: This study demonstrates that not all patients with apparent idiopathic precocious puberty require medical treatment, notably when there is no evidence of hypothalamo-pituitary ovarian activation or no significantly advanced BA to impair height potential. Most show a slowly progressing puberty. However, careful follow-up of these patients is necessary up to at least 9 years of age, because until then height prediction may deteriorate, necessitating gonadotropin-releasing hormone agonist treatment in one third of the cases.

Child↗
PubMed2004

Furcatin hydrolase from Viburnum furcatum Blume is a novel disaccharide-specific acuminosidase in glycosyl hydrolase family 1.

Furcatin hydrolase (FH) is a unique disaccharide-specific acuminosidase, which hydrolyzes furcatin (p-allylphenyl 6-O-beta-D-apiofuranosyl-beta-D-glucopyranoside (acuminoside)) into p-allylphenol and the disaccharide acuminose. We have isolated a cDNA coding for FH from Viburnum furcatum leaves. The open reading frame in the cDNA encoded a 538-amino acid polypeptide including a putative chloroplast transit peptide. The deduced protein showed 64% identity with tea leaf beta-primeverosidase, which is another disaccharide glycosidase specific to beta-primeverosides (6-O-beta-D-xylopyranosyl-beta-D-glucopyranosides). The deduced FH also shared greater than 50% identity with various plant beta-glucosidases in glycosyl hydrolase family 1. The recombinant FH expressed in Escherichia coli exhibited the highest level of activity toward furcatin with a Km value of 2.2 mm and specifically hydrolyzed the beta-glycosidic bond between p-allylphenol and acuminose, confirming FH as a disaccharide glycosidase. The FH also hydrolyzed beta-primeverosides and beta-vicianoside (6-O-alpha-L-arabinopyranosyl-beta-D-glucopyranoside) but poorly hydrolyzed beta-gentiobiosides (6-O-beta-D-glucopyranosyl-beta-d-glucopyranosides), indicating high substrate specificity for the disaccharide glycone moiety. The FH exhibited activity toward p-allylphenyl beta-D-glucopyranoside containing the same aglycone as furcatin but little activity toward the other beta-D-glucopyranosides. Stereochemical analysis using 1H NMR spectroscopy revealed that FH is a retaining glycosidase. The subcellular localization of FH was analyzed using green fluorescent protein fused with the putative N-terminal signal peptide, indicating that FH is localized to the chloroplast. Phylogenetic analysis of plant beta-glucosidases revealed that FH clusters with beta-primeverosidase, and this suggests that the disaccharide glycosidases will form a new subfamily in glycosyl hydrolase family 1.

Amino Acid Sequence↗
PubMed1998

A novel sialic acid binding site on factor H mediates serum resistance of sialylated Neisseria gonorrhoeae.

Factor H (fH), a key alternative complement pathway regulator, is a cofactor for factor I-mediated cleavage of C3b. fH consists of 20 short consensus repeat (SCR) domains. Sialic acid binding domains have previously been localized to fH SCRs 6-10 and 13. To examine fH binding on a sialylated microbial surface, we grew Neisseria gonorrhoeae in the presence of 5'-cytidinemonophospho-N-acetylneuraminic acid, which sialylates lipooligosaccharide and converts to serum resistance gonococci previously sensitive to nonimmune serum killing. fH domains necessary for binding sialylated gonococci were determined by incubating organisms with recombinant human fH (rH) and nine mutant rH molecules (deletions spanning the entire fH molecule). rH and all mutant rH molecules that contained SCRs 16-20 bound to the sialylated strain; no mutant molecule bound to serum-sensitive nonsialylated organisms. Sialic acid was demonstrated to be the fH target by flow cytometry that showed a fourfold increase in fH binding that was reversed by neuraminidase-mediated cleavage of sialic acid off gonococci. Functional specificity of fH was confirmed by decreased total C3 binding and almost complete conversion to iC3b on sialylated gonococci. Sialic acid can therefore bind fH uniquely through SCRs 16-20. This blocks complement pathway activation for N. gonorrhoeae at the level of C3.

Antigens, Bacterial↗
PubMedDate not supplied

Neuropsychological differences between male familial and nonfamilial alcoholics and nonalcoholics.

The hypothesis was tested that neuropsychological differences exist between males who have an alcoholic parent, sister, or brother (FH+) versus those who do not (FH-). Neuropsychological tests measuring verbal, learning/memory, abstracting/problem solving, and perceptual-motor performance were given to four groups of middle-aged subjects: alcoholic FH+ (n = 41); alcoholic FH- (n = 27); nonalcoholic FH+ (n = 19); and nonalcoholic FH- (n = 43). FH+ subjects performed significantly poorer than FH- subjects on the abstracting/problem solving and perceptual-motor tasks, and approached significance on the verbal and learning/memory measures. Alcoholics performed more poorly than nonalcoholics on abstracting/problem solving and learning/memory tasks. There were no groups by family history significant interactions. From these results we suggest: a performance deficit in abstracting/problem solving and possibly learning/memory may antedate the alcoholic stage in FH+ individuals; alcoholism and positive family history of alcoholism have independent, additive deleterious effects on cognitive-perceptual functioning; and future neuropsychological studies of alcoholism should consider the frequency of FH+ and FH- individuals in both alcoholic and control groups.

Adult↗
PubMed1995

Family history of alcoholism and the mediation of alcohol intake by catalase: further evidence for catalase as a marker of the propensity to ingest alcohol.

Earlier studies have suggested that catalase activity (CA) may represent a biological marker of alcohol intake in animals and in humans. An initial study was designed to rule out the possibility that CA is induced as a function of acute alcohol intake. Subjects (n = 80) were presented with either an alcohol (0.5 g/kg of body weight) or control solution, and asked to provide four 100-microliters blood samples at 0.0, 0.5, 2.0, and 24.0 hr. Results showed no differences in CA between individuals who had received alcohol, and controls, even when the effects of previous drinking history were covaried out. This lack of effect of acute alcohol intake on the possible induction of CA further supported the notion that CA may be a viable marker of alcohol intake, rather than the converse. In the second study, the relation between CA and alcohol intake was investigated in individuals with a family history (FH) of alcoholism (FH+), and in those without a family history of alcoholism (FH-). Subjects (n = 607) completed the Michigan Alcoholism Screening Questionnaire, the MacAndrew Scale, and the Concordia University Alcohol Screening Questionnaire; answered questions concerning their FH for alcoholism; and provided a 100-microliters blood sample. Results showed that FH+ individuals had higher mean CA compared with FH- individuals. When individuals with FH+ were compared with those with FH-, differences in the pattern of relation between CA and alcohol intake were observed. Although a significant relation between CA and alcohol intake was obtained for both FH- and FH+ individuals, this relation was significantly higher (p < 0.001) for individuals with FH+.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1997

Neonatal diagnosis of familial hypercholesterolemia in newborns born to a parent with a molecularly defined heterozygous familial hypercholesterolemia.

This study was designed to compare blood lipid levels in newborn individuals with molecularly defined heterozygous familial hypercholesterolemia [FH] to those in non-affected babies and to clarify the value of lipid determinations in assessment of diagnosis of FH at birth and 1 year of age. Twenty-five babies were born to 21 parents with DNA-documented heterozygous FH. Analysis of their cord blood samples revealed 11 newborns with the FH-North Karelia [FH-NK] mutation, 3 newborns with the FH-Helsinki [FH-HKI] mutation, and 11 nonaffected newborns. Cord serum total [TC] and LDL cholesterol [LDL-C] levels (mean +/- SD) in affected newborns (2.60 +/- 0.70 and 1.77 +/- 0.56, respectively) were significantly (P < .001) higher than those in nonaffected ones (1.54 +/- 0.23 and 0.78 +/- 0.15, respectively) and another cohort of 30 randomly selected control samples from apparently healthy newborns (1.84 +/- 0.46 and 1.03 +/- 0.30, respectively). However, there was overlapping of individual lipid levels in these three groups precluding the use of TC or LDL-C determinations in neonatal diagnosis of FH. In contrast, 1 year follow-up samples from 10 affected and 7 nonaffected individuals, as well as additional samples collected from another group of 8 affected and 9 nonaffected individuals, indicated that serum cholesterol levels showed much greater increment in children with FH. Thus, at the age of 1 year the mean serum TC and LDL-C levels in the affected infants (8.38 +/- 1.18 and 7.02 +/- 1.07, respectively) were much higher (P < .001) than the corresponding levels (4.40 +/- 0.66 and 2.89 +/- 0.68, respectively) in the nonaffected infants, and the individual ranges of TC and LDL-C levels were nonoverlapping in these two groups. Serum HDL cholesterol [HDL-C] levels in 1-year-old children with FH (0.95 +/- 0.14) were approximately 20% lower than those of their similar at birth. In conclusion, phenotypic expression of heterozygous FH, as defined by molecular analysis of genomic DNA, is evident in serum LDL-C (but not HDL-C) levels already at birth, but for diagnostic purposes blood lipid determinations carried out at the age of 1 year are highly superior to those performed at birth.

Adult↗
PubMed2004

Coronary artery calcification and family history of premature coronary heart disease: sibling history is more strongly associated than parental history.

BACKGROUND: The objective of the study was to assess the association of a family history (FH) of premature coronary heart disease (CHD) with coronary artery calcification (CAC) in asymptomatic individuals and to compare the effects of sibling or parental FH on the risk of subclinical atherosclerosis. METHODS AND RESULTS: CAC by electron beam tomography was performed in 8549 asymptomatic individuals (69% men; mean age, 52+/-9 years). The prevalence and odds of any CAC and extent of CAC stratified according to FH of premature CHD were determined. Those with (1) no FH of CHD, (2) FH of premature CHD in parents, or (3) FH in siblings had a prevalence of CAC of 55%, 64%, and 78% (P<0.0001) among men and 27%, 36%, and 56% (P<0.0001) among women, respectively. The multivariate regression analysis demonstrated that the odds ratio (95% confidence interval) for the presence of CAC was 1.3 (1.1 to 1.6) among those with positive FH of premature CHD in parents only, 2.3 (1.7 to 3.1) and 2.5 (1.8 to 3.3) among those in siblings and a combined FH compared with those without FH of CHD in men, respectively. Among women, the corresponding odds ratios were 1.3 (1.0 to 1.8), 2.3 (1.7 to 3.6), and 1.9 (1.3 to 3.1), respectively. A similar trend was observed in the association of FH of premature CHD with increasing CAC scores. CONCLUSIONS: Our study demonstrates a highly significant association between FH of premature CHD and the presence and extent of CAC. Furthermore, within the limits of self-reporting of family history, our findings suggest that a sibling history is more strongly associated with subclinical coronary atherosclerosis than a parental history of premature CHD.

Adult↗
PubMed1979

Metabolic studies in familial hypercholesterolemia. Evidence for a gene-dosage effect in vivo.

To investigate the gene-dosage effect in familial hypercholesterolemia (FH), metabolic studies were conducted in a group of well-characterized patients with either heterozygous (n = 7) or homozygous (n = 7) FH and the results were compared to those obtained in normal subjects (n = 6). The turnover of (125)I-labeled low-density lipoprotein (LDL) was measured in all of the normals, all but one of the FH heterozygotes, and in all of the homozygotes. Chemical cholesterol balance was performed simultaneously with the (125)I-LDL turnover in all seven of the homozygotes. With regard to (125)I-LDL turnover, FH homozygotes, who possess two doses of the mutant FH gene, exhibited a threefold increase in the rate of apoLDL synthesis while the fractional catabolic rate (FCR) for the apoprotein was only about one-third of normal. Heterozygotes, who have only one dose of the mutant FH gene, exhibited intermediate values for both parameters; that is, the FCR was two-thirds of normal and the apoLDL synthetic rate was 1.7-fold greater than normal. THE DATA INDICATE THAT THE SINGLE GENE DEFECT IN FH PRODUCES TWO DISTINCT ABNORMALITIES OF LDL METABOLISM: (a) an increase in the synthetic rate for apoLDL and (b) a decrease in the efficiency of apoLDL catabolism. Both defects are more severe in FH homozygotes than in heterozygotes. The FCR for apoLDL in the homozygotes appeared to be fixed at congruent with 17%/d whereas the plasma LDL level varied about twofold. These findings suggest that the twofold variation in plasma LDL levels observed in these seven patients is caused by variation in the plasma apoLDL synthetic rates. Consistent with this conclusion was the finding that the correlation between the plasma LDL level and the apoLDL synthetic rates in the seven FH homozygotes was 0.943. The rate of total body cholesterol synthesis determined by chemical cholesterol balance did not appear to clearly differ between normals and patients with either one or two mutant FH genes. Two of the youngest FH homozygotes exhibited cholesterol overproduction but the other five did not. No consistent abnormality of bile acid metabolism was observed in these patients. Because the daily plasma flux of cholesterol on LDL is about threefold greater than the amount of cholesterol produced per day, a significant amount of the cholesterol liberated from LDL degradation must be reused.

Adolescent↗
PubMed1993

EEG, autonomic and subjective correlates of the risk for alcoholism.

Electroencephalographic, autonomic and subjective reactions to alcohol were examined among 78 young nonalcoholic men, cross-classified with respect to the presence/absence of a family history of alcoholism (FH) and the presence/absence of a personal history of antisocial personality disorder (ASP). Both an alcohol placebo and alcohol (0.32 ml/kg) were administered in a single laboratory session. The four groups of subjects were compared at baseline, and at several discrete time points before and after consumption of placebo and alcoholic beverages. During the baseline period, ASP+ subjects exhibited significantly more body sway and faster frontal EEG activity than their ASP- counterparts. The combination of ASP with FH was associated, at baseline, with an excessive amount of high frequency (18.6-27.6 Hz) beta activity in the right frontal EEG. After beverage consumption, several significant FH effects emerged that were independent of the effects of ASP. After placebo consumption, FH+ subjects exhibited significantly more fast alpha (10.9-12.5 Hz) activity at the right frontal electrode than FH- subjects. This difference persisted until blood alcohol concentrations began to rise, at which time fast alpha activity in FH+ subjects declined to FH- levels. Differences between the two FH groups were also apparent in their subjective reactions to the placebo and alcoholic beverages. Relative to FH- subjects, FH+ subjects rated themselves as more intoxicated after consuming the placebo but less intoxicated after consuming alcohol. FH+ subjects expressed greater confidence in their ability to resist the offer of an alcoholic drink across most time points.

Adult↗
PubMed2004

Demonstration of the involvement of outer surface protein E coiled coil structural domains and higher order structural elements in the binding of infection-induced antibody and the complement-regulatory protein, factor H.

Factor H (fH) is an important regulator of the alternative complement cascade. Several human pathogens have been shown to bind fH to their surface, a process that facilitates immune evasion or cell to cell interaction. Among the pathogens that bind fH are some Borrelia species associated with Lyme disease and relapsing fever. The fH-binding proteins of the Lyme spirochetes form two classes (I and II). In Borrelia burgdorferi B31MI, class I includes the outer surface protein E (OspE) paralogs, L39, N38, and P38, whereas the class II group includes A68 and additional proteins that have not yet been identified. To identify the OspE determinants involved in fH and OspE-targeting infection-induced Ab (iAb) binding, deletion, random, and site-directed mutagenesis of L39 were performed. Mutations in several different regions of L39 abolished fH and or iAb binding, indicating that separable domains and residues of OspE are required for ligand binding. Some of the mutants that lost the ability to bind fH, iAb, or both had only a single amino acid change. Site-directed mutagenesis of three putative coiled coil motifs of OspE revealed that these higher order structures are required for fH binding but not for iAb binding. The data presented within demonstrate that the binding of fH and iAb to the OspE protein is mediated by higher order structures and protein conformation. These studies advance our understanding of fH binding as a virulence mechanism and facilitate ongoing efforts to use fH-binding proteins in the development of microbial vaccines.

Amino Acid Motifs↗
PubMed1999

[High prevalence of TT virus(TTV) in patients with non A to non G fulminant hepatitis: differences of clinical features and prognosis between TTV positive and negative patients].

We detected TTV-DNA in sera from 36 patients with fulminant hepatitis(FH) and evaluated differences in clinical features and prognosis between TTV-DNA positive and negative patients with nonA-nonG FH. TTV-DNA in sera was measured by nested PCR. Twenty of 36 patients with FH were diagnosed nonA-nonG FH. The TTV-DNA in sera was detected in 14 patients(38.9%) with FH, 9(64%) showed nonA-nonG FH and 3 were HBV FH and 2 were drug-induced FH. Although we compared clinical features(gender, age, distribution history of blood transfusion, initial symptoms of hepatitis, and liver function tests) and prognosis between TTV positive and negative patients with nonA-nonG FH, there were no significant differences between the two groups. These data suggest that although TTV may be a infectious agent related to nonA-nonG FH, further study is needed to clarify the role of TTV in the pathogenesis of FH.

Adult↗
PubMed2000

5-HT transporter sites and 5-HT1A and 5-HT3 receptors in Fawn-Hooded rats: a quantitative autoradiography study.

BACKGROUND: The neuroanatomical profiles of 5-HT1A receptors, 5-HT3 receptors, and 5-HT transporters (5-HTT) in the brain of the Fawn-Hooded (FH) rat, particularly mesocorticolimbic regions, are not fully elucidated. METHODS: By means of in vitro quantitative autoradiography, we used [3H]citalopram, [3H]8-OH-DPAT, and [3H]GR65630 to label 5-HTT, 5-HT1A receptors, and 5-HT3 receptors in the brain of alcohol-naïve FH rats, Wistar-Kyoto (WKY) rats, and FH rats given free access to 5% ethanol and/or after 24 to 48 hr withdrawal. RESULTS AND CONCLUSIONS: In alcohol-naïve rats, FH rats displayed significantly higher (p < 0.05) densities of [3H]citalopram binding in the nucleus accumbens (+30%), lateral septum (+37%), ventral pallidum (+21%), and ventral tegmental area (+24%), as well as an increased binding of [3H]8-OH-DPAT to 5-HT1A receptors in the frontal and parietal cortex (+33%), occipital and temporal cortex (+25%), and hippocampal CA3 region (+31%), compared with WKY rats, whereas both strains exhibited comparable [3H]GR65630 binding to 5-HT3 receptors. Compared with control FH (naive) rats, chronic ethanol consumption significantly decreased (p < 0.(15)[3H]8-OH-DPAT binding in the frontal and parietal cortex (-15%) but significantly increased binding (p < 0.05) in the entorhinal cortex (+25%), retrosplenial granular cortex (+20%), and hippocampal CA1 (+14%) and CA3 regions (+18%). Moreover, ethanol withdrawal induced the same extent of increased [3H]8-OH-DPAT binding in the entorhinal and retrosplenial cortex as seen in FH (chronic) rats. In contrast, [3H]8-OH-DPAT binding in the hippocampal CA1 and CA3 regions was decreased by -9% and -20% from the level of chronic ethanol-treated FH rat (p < 0.05) and returned to the control level seen in FH (naïve) rats. SIGNIFICANCE: The elevated 5-HT transporters and 5-HT1A receptors in the mesocorticolimbic areas in FH rats may reflect a potential innate altered transmission at serotonergic synapses, which possibly may affect the high intake of alcohol in FH rats. The region-specific alterations of 5-HT1A receptors in FH rat brain after ethanol challenges suggest that 5-HT1A receptors are sensitive to ethanol challenges, whereas 5-HTT are apparently insensitive.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1984

Urinary and renal kallikrein in hypertensive fawn-hooded (FH/Wjd) rats.

Urinary excretion of kallikrein (UKal), sodium, potassium, protein, and creatinine, as well as the kidney content of kallikrein and renin, was studied in spontaneously hypertensive FH/Wjd (FH) male and female rats and in age- and sex-matched normal Wistar rats. With the exception of 1-month-old rats UKal excretion was significantly lower in FH rats than in Wistar rats. FH females also excreted less UKal than Wistar females. No UKal inhibitor or increased degradation of this enzyme in the urine of FH rats was detected. There was no difference in creatinine clearance, blood urea nitrogen, or serum electrolytes, and calcium between 5-month-old FH and Wistar males. Wistar rat kidneys contained about twice as much kallikrein as FH rat kidneys. From the age of 2 months FH males excreted more sodium, as well as urine, than all other groups. No differences in potassium excretion were observed. Only FH males, 4 months and older, developed proteinuria. FH males and females became hypertensive at the ages of 2 and 4.5 months, respectively. Plasma renin activity, as well as renal renin activity, was significantly lower in FH than in Wistar males. In conclusion, the decrease in UKal activity which precedes the onset of hypertension suggests that the abnormality in the renal kallikrein system may be involved in the pathogenesis of hypertension in FH rats.

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