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FH
Terms modified by FH Selected AbstractsFlow cytometric evaluation of CD38 expression assists in distinguishing follicular hyperplasia from follicular lymphoma,CYTOMETRY, Issue 5 2009Kristin Mantei Abstract The distinction of follicular lymphoma (FL) from reactive follicular hyperplasia (FH) can be a diagnostic challenge in flow cytometry. In this study, the median fluorescent intensity (MFI) of CD38 as assessed by flow cytometry on B and T cell subpopulations in 102 lymph nodes specimens with histopathologically confirmed FL was compared with 55 cases of FH. The MFI of CD38 was highly significantly reduced in the neoplastic B cells in FL when compared with the reactive germinal center B cells in FH (P < 1.0E-16). The MFI of CD38 did not differ between the non-neoplastic B-cells in FL and nongerminal center B-cells in FH (P = 0.14) or between T-cells and non-neoplastic B-cells in FL (P = 0.63). A marginal increase in the MFI of CD38 was seen for T cells in FL compared with FH (P = 0.04). An increased difference in the MFI of CD38 was identified for T-cells compared with nongerminal center B-cells in FH (P = 0.005). No difference in CD38 expression was seen between Grades 1, 2, or 3 FL. The study also confirmed increased expression of CD10 (P < 1.0E-9), decreased CD19 (P < 1.0E-22), and CD20 (P < 1.0E-16) in FL in comparison with FH, as has been previously reported. This study identified decreased CD38 as a common finding in FL in comparison with FH and provides an additional tool to help differentiate FL from FH by flow cytometry. © 2009 Clinical Cytometry Society [source] Infant information processing and family history of specific language impairment: converging evidence for RAP deficits from two paradigmsDEVELOPMENTAL SCIENCE, Issue 2 2007Naseem Choudhury An infant's ability to process auditory signals presented in rapid succession (i.e. rapid auditory processing abilities [RAP]) has been shown to predict differences in language outcomes in toddlers and preschool children. Early deficits in RAP abilities may serve as a behavioral marker for language-based learning disabilities. The purpose of this study is to determine if performance on infant information processing measures designed to tap RAP and global processing skills differ as a function of family history of specific language impairment (SLI) and/or the particular demand characteristics of the paradigm used. Seventeen 6- to 9-month-old infants from families with a history of specific language impairment (FH+) and 29 control infants (FH,) participated in this study. Infants' performance on two different RAP paradigms (head-turn procedure [HT] and auditory-visual habituation/recognition memory [AVH/RM]) and on a global processing task (visual habituation/recognition memory [VH/RM]) was assessed at 6 and 9 months. Toddler language and cognitive skills were evaluated at 12 and 16 months. A number of significant group differences were seen: FH+ infants showed significantly poorer discrimination of fast rate stimuli on both RAP tasks, took longer to habituate on both habituation/recognition memory measures, and had lower novelty preference scores on the visual habituation/recognition memory task. Infants' performance on the two RAP measures provided independent but converging contributions to outcome. Thus, different mechanisms appear to underlie performance on operantly conditioned tasks as compared to habituation/recognition memory paradigms. Further, infant RAP processing abilities predicted to 12- and 16-month language scores above and beyond family history of SLI. The results of this study provide additional support for the validity of infant RAP abilities as a behavioral marker for later language outcome. Finally, this is the first study to use a battery of infant tasks to demonstrate multi-modal processing deficits in infants at risk for SLI. [source] The relationship of behavioural undercontrol to alcoholism in higher-functioning adultsDRUG AND ALCOHOL REVIEW, Issue 5 2006MARC A. SCHUCKIT Abstract Externalising behaviours, including the personality characteristics of behavioural undercontrol (BU), represent one of several genetically influenced domains that impact on the alcoholism risk. Because genes explain only about 60% of the vulnerability toward alcohol use disorders (AUDs), an optimal understanding of how such behaviours affect the risk requires evaluation of their impact in the context of additional influences. Few studies have addressed this question regarding BU among relatively well-functioning adults. This paper presents results from testing a BU-based mediational model of risk in men from the San Diego Prospective Study. Structured research instruments were used with 430 adult Caucasian males to evaluate the performance of BU in predicting AUDs at the 15-year follow-up using Pearson product-moment correlations among domains and an AMOS-based structural equation model (SEM). While both the family history of AUDs (FHalc) and BU predicted alcohol-related outcome, BU by itself did not mediate the relationship of the FH to alcohol disorders. The impact of BU on alcohol problems was mediated by alcohol expectancies, peer drinking and by coping. The SEM explained 42% of the variance for AUDs. The current results indicate that BU contributed to the risk for alcohol-related problems, even among more highly functional subjects and after excluding the impact of the antisocial personality disorder, but by itself did not mediate the relationship of FH to outcome in these subjects. [source] Echocardiographic Parameters in Athlete and Nonathlete Offspring of Hypertensive ParentsECHOCARDIOGRAPHY, Issue 1 2008Patrícia Horváth M.D. Background: According to several reports, some cardiovascular signs of hypertension (left ventricular [LV] hypertrophy, impaired diastolic filling) can be found in the normotensive offspring of hypertensive parents. It is also well known that regular physical exercise decreases the risk of hypertension. Aim: The aim of the present study is to determine whether or not regular physical training influences these early hypertensive traits in the offspring of hypertensive parents. Methods: Echocardiographic data of 215 (144 males, 71 females) 22- to 35-year-old nonathlete and athlete offspring of hypertensive (positive family history, FH+) and normotensive parents (negative family history, FH,) were compared in a cross-sectional design. Results: In the nonathlete FH+ males and females, LV dimensions were not larger than in the FH, subjects. The E/A quotient was lower in the FH+ subjects in both genders. Absolute and heart rate adjusted isovolumetric relaxation times were slightly longer in the FH+ men than in their FH, peers. No differences were seen between athlete FH, and FH+ subjects. Conclusion: Regular physical exercise decreases the incidence of the adverse cardiac signs, which can be associated with hypertension in the normotensive offspring of hypertensive parents. [source] Circulating mononuclear cells nuclear factor-kappa B activity, plasma xanthine oxidase, and low grade inflammatory markers in adult patients with familial hypercholesterolaemiaEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2010J. T. Real Eur J Clin Invest 2010; 40 (2): 89,94 Abstract Background, Few data are available on circulating mononuclear cells nuclear factor-kappa B (NF-kB) activity and plasma xanthine oxidase (XO) activity in heterozygous familial hypercholesterolaemia (FH). The goal of the study was to analyse circulating mononuclear cells NF-kB and plasma XO activities in FH patients. Materials and methods, Thirty FH index patients and 30 normoglycaemic normocholesterolaemic controls matched by age, gender, body mass index, abdominal circumference and homeostasis model assessment index were studied. Plasma XO and inflammatory markers were measured by standard methods. NF-kB was assayed in circulating mononuclear cells. Results, Familial hypercholesterolaemia patients showed a significantly higher NF-kB (75·0 ± 20·7 vs. 42·7 ± 16·8 relative luminiscence units) and XO (0·44 ± 0·13 vs. 0·32 ± 0·09 mU mL,1) activities than controls. In addition, interleukin-1, interleukin-6, high sensitivity C reactive protein (hsCRP) and oxidized LDL (LDL-ox) were also significantly higher in FH patients. In the total group (FH and controls), XO was significantly associated with LDL-cholesterol (LDL-C), apolipoprotein B (apoB), NF-kB and hsCPR, and NF-kB activity was significantly associated with XO, hsCPR, LDL-ox, LDL-C and apoB plasma values. Using multiple regression analysis, XO was independently associated with hsCPR and NF-kB, and NF-kB activity in circulating mononuclear cells was independently associated with apoB and LDL-ox plasma values. Conclusion, Familial hypercholesterolaemia patients show increased activities of NF-kB and XO, and higher values of low grade inflammatory markers related to atherosclerosis. NF-kB activity was independently associated with apoB plasma values. These data could explain in part the high cardiovascular disease risk present in these patients. [source] CD31+/Annexin V+ microparticles in healthy offsprings of patients with coronary artery diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2009D. Bulut ABSTRACT Background, First-degree relatives of patients with premature coronary artery disease (CAD) develop endothelial dysfunction even in the case they are apparently healthy. In this study we wanted to clarify whether reduced blood levels of circulating endothelial progenitor cells (EPCs), an endogenous repair mechanism to replace dysfunctional endothelium, or elevated endothelial-derived microparticles (EMPs), an indicator and a mediator of increased endothelial cell damage/apoptosis, are an initial step in the pathogenesis of endothelial dysfunction in genetically predisposed subjects. Materials and methods, Fifty-six healthy young men (aged 23 to 31 years) from a fire brigade were enrolled, of which 20 subjects had a positive family history (FH) for premature CAD. Subjects with or without a positive FH did not differ with respect to age, body mass index, risk factors and C-reactive protein. Endothelial function was assessed by hyperaemia-mediated relaxation of the brachial artery, blood levels of EPCs (VEGFR2+CD34+ cells) and number of EMPs (CD31+(bright)/Annexin V+ particles) were analysed by flow cytometry. Results, Hyperaemia-mediated relaxation of the brachial artery was similar in both groups, and the blood levels of EPCs were comparable. However, the number of EMPs were significantly increased in subjects with a positive FH compared to those with a negative FH (neg. FH: 55·31 ± 4·88 vs. pos. FH: 70·37 ± 6·32 particles µL,1 platelet poor plasma; P < 0·05). Number of EMPs correlate inversely with the FMD response. Conclusions, These results suggest that increased plasma levels of EMPs may be an initial step in the development of endothelial dysfunction in genetically predisposed subjects. [source] Increased inflammatory markers in children with familial hypercholesterolaemiaEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2006T. Ueland Abstract Background, While data are abundant on increased levels of inflammatory markers in adult patients with hypercholesterolaemia, such data in children are limited. Therefore, we sought to investigate the degree and character of inflammation in children with heterozygous familial hypercholesterolaemia (FH) by measuring levels of neopterin, high-sensitivity C-reactive protein (hsCRP), and soluble CD40 ligand (sCD40L). Materials and methods, In the present study, we compared the concentration of inflammatory markers in children suffering from heterozygous FH (n = 207) with those in unaffected siblings (n = 84). Furthermore, we investigated the effect of 2-year treatment with pravastatin (20,40 mg qd) or placebo on plasma levels of those markers. Results, Our main finding was that serum levels of neopterin and hsCRP were significantly higher in FH children compared with healthy siblings, whereas sCD40L was not. Body mass index and high-density lipoprotein cholesterol levels were significant independent predictors of hsCRP and neopterin. Furthermore, pravastatin therapy decreased neopterin, but not hsCRP and sCD40L, in the FH children, but these changes were not different from the placebo group. Conclusion, These findings indicate low-grade monocyte/macrophage hyperactivity in the early stages of atherogenesis, but our findings also suggest that inflammation as well as anti-inflammatory effects of statins are less prominent features of atherosclerosis in FH children than in FH adults. [source] Impact of genetic defects on coronary atherosclerosis in patients suspected of having familial hypercholesterolaemiaEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2003O. S. Descamps Abstract 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. [source] C5a anaphylatoxin as a product of complement activation up-regulates the complement inhibitory factor H in rat Kupffer cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2004Gerald Schlaf Abstract The 155-kDa complement regulator factor H (FH) is the predominant soluble regulatory protein of the complement system. It acts as a cofactor for the factor I-mediated conversion of the component C3b to iC3b, competes with factor B for a binding site on C3b and C3(H2O) and promotes the dissociation of the C3bBb complex. The primary site of synthesis is the liver, i.e. FH-specific mRNA and protein were identified in both hepatocytes (HC) and Kupffer cells (KC). Previous studies in rat primary HC and KC had shown that the proinflammatory cytokine IFN-, influences the balance between activation and inhibition of the complement system through up-regulation of the inhibitory FH. In this study we show that C5a, as a product of complement activation, stimulates the expression of FH-specific mRNA and protein in KC and thus induces a negative feedback. Quantitative-competitive RT-PCR showed an approximate threefold C5a-induced up-regulation of FH. ELISA analyses revealed a corresponding increase in FH protein in the supernatants of KC. The up-regulation of FH was completely inhibited by the C5a-blocking monoclonal antibody 6-9F. Furthermore, an involvement of LPS and IFN-, was excluded, which strongly indicates a direct effect of C5a on the expression of FH in KC. [source] HUMAN STUDY: Heavy drinking relates to positive valence ratings of alcohol cuesADDICTION BIOLOGY, Issue 1 2009Carmen Pulido ABSTRACT A positive family history of alcohol use disorders (FH) is a robust predictor of personal alcohol abuse and dependence. Exposure to problem-drinking models is one mechanism through which family history influences alcohol-related cognitions and drinking patterns. Similarly, exposure to alcohol advertisements is associated with alcohol involvement and the relationship between affective response to alcohol cues and drinking behavior has not been well established. In addition, the collective contribution that FH, exposure to different types of problem-drinking models (e.g. parents, peers) and personal alcohol use have on appraisal of alcohol-related stimuli has not been evaluated with a large sample. We investigated the independent effects of FH, exposure to problem-drinking models and personal alcohol use on valence ratings of alcohol pictures in a college sample. College students (n = 227) completed measures of personal drinking and substance use, exposure to problem-drinking models, FH and ratings on affective valence of 60 alcohol pictures. Greater exposure to non-familial problem-drinkers predicted greater drinking among college students (, = 0.17, P < 0.01). However, personal drinking was the only predictor of valence ratings of alcohol pictures (, = ,0.53, P < 0.001). Personal drinking level predicted valence ratings of alcohol cues over and above FH, exposure to problem-drinking models and demographic characteristics. This suggests that positive affective responses to alcohol pictures are more a function of personal experience (i.e. repeated heavy alcohol use) than vicarious learning. [source] Breast Cancer Knowledge and Preventive Behaviors An Urban Emergency Department-based SurveyACADEMIC EMERGENCY MEDICINE, Issue 12 2000Kevin M. Takakuwa MA Abstract. Objective: To assess general knowledge and preventive behaviors regarding breast cancer among women who present to an urban emergency department. Methods: During a six-month study period, a convenience sampling of women aged 21 years and older who were in treatment and waiting areas was surveyed. The anonymous written survey asked about demographic variables, knowledge, and preventive behaviors regarding breast cancer. Knowledge was assessed with questions about the recommended frequency of breast self-examination and the recommended age for first mammography. Performance was assessed by questions about breast self-exam and mammography. Subgroup analysis was done by age (above and below 40 years old), race, income (above and below the median), insurance type, history of breast lump, and family history (FH) of breast cancer. Results: Four hundred women completed surveys. Two hundred twelve (53%) correctly knew the answers to the two knowledge questions. Knowledge was greater in women with private insurance. Knowledge of the frequency of breast self-exam was significantly greater among whites and Native Americans than among African Americans, Asians, or Hispanics. Stated performance of preventive behaviors was 72% (288) for breast self-exam and for mammography. Preventive behaviors were significantly more likely to be performed by higher-income and privately-insured women. Breast self-exam was more likely to be done in older women, those with a history of a breast lump, and those with a FH of breast cancer. Conclusions: Women with lower income and without private insurance were less likely to be knowledgeable and practice preventive measures for detecting breast disease. [source] Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: Genetic linkage analysis and FISH studiesGENES, CHROMOSOMES AND CANCER, Issue 3 2004Karen L. Gross Recently, germline mutations of the fumarate hydratase (FH) gene, in 1q42.1, have been found to be involved in syndromes associated with uterine leiomyomas (ULs). Compelling evidence also supports a genetic liability to develop nonsyndromic UL, although susceptibility genes have not been reported to date. Loss of heterozygosity (LOH) studies have found no or rare evidence of LOH of FH in nonsyndromic UL. However, the karyotypes of these tumors were not reported, and cytogenetic aberrations of 1q42,44 have been observed infrequently in UL. To determine whether FH mutations also may predispose women to developing nonsyndromic UL, we performed a genetic linkage study with DNA from 123 families containing at least one affected sister pair. In addition, to assess the frequency of FH loss specifically in UL with 1q rearrangements, we performed a fluorescence in situ hybridization (FISH) analysis of UL with 1q rearrangements. Analysis of the genotyping data revealed evidence suggestive of linkage to the FH region among study participants who were less than 40 years of age at diagnosis (Zlr 1.7 at D1S547, P = 0.04). FISH results showed that one copy of FH was absent in 9 of 11 ULs. These data indicate that loss of FH might be a significant event in the pathogenesis of a subset of nonsyndromic ULs. © 2004 Wiley-Liss, Inc. [source] G-substrate gene promoter SNP (,1323T>C) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: Intra-familial association study in an eight-generation hyperlipidemic kindredGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2 2004Yukiko Nobe Background: Plasma lipid and lipoprotein generally reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity. Methods: In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH, to examine possible genetic modification of lipoprotein phenotype by ,modifier locus'. G-substrate (GSBS) is an endogenous substrate for cGMP-dependent protein kinase. We carried out an intrafamilial correlation analysis of modifier effect of ,1323T>C substitution in the GSBS gene among 85 LDLR-mutation carriers and 75 non-carriers. Results: In the LDLR - mutation carriers, the plasma cholesterol levels were highest among ,1323C homozygotes (mean ± SD = 454 ± 101 mg/dL), lowest among ,1323T homozygotes (mean ± SD, 307 ± 72 mg/dL) and intermediate among ,1323T/C heterozygotes (mean ± SD, 314 ± 62 mg/dL; P = 0.015). Similarly, in the LDLR-mutation carriers, the plasma triglyceride levels were highest among ,1323C homozygotes (mean ± SD, 371 ± 381 mg/dL), lowest among ,323T homozygotes (mean ± SD, 171 ± 94 mg/dL), and intermediate among ,1323T/C heterozygotes (mean ± SD, 218 ± 130 mg/dL; P = 0.003). No such gene-interactive effect was observed among non-carriers of the LDLR-mutation. Conclusion: These results indicate a significant modification of the phenotype of FH with defective LDLR allele, by GSBS-1323C allele in the kindred studied. [source] Update of the molecular basis of familial hypercholesterolemia in The Netherlands,HUMAN MUTATION, Issue 6 2005Sigrid W. Fouchier Abstract Autosomal-dominant hypercholesterolemia (ADH) has been identified as a major risk factor for coronary vascular disease (CVD) and is associated with mutations in the low-density lipoprotein receptor (LDLR) and the apolipoprotein B (APOB) gene. Since 1991 DNA samples from clinically diagnosed ADH patients have been routinely analyzed for the presence of LDLR and APOB gene mutations. As of 2001, 1,641 index patients (164 index patients per year) had been identified, while from 2001 onward a more sensitive, high-throughput system was used, resulting in the identification of 1,177 new index patients (average=294 index patients per year). Of these 1,177 index cases, 131 different causative genetic variants in the LDLR gene and six different causative mutations in the APOB gene were new for the Dutch population. Of these 131 mutations, 83 LDLR and four APOB gene mutations had not been reported before. The inclusion of all 2,818 index cases into the national screening program for familial hypercholesterolemia (FH) resulted in the identification of 7,079 relatives who carried a mutation that causes ADH. Screening of the LDLR and APOB genes in clinically diagnosed FH patients resulted in approximately 77% of the patients being identified as carriers of a causative mutation. The population of patients with ADH was divided into three genetically distinct groups: carriers of an LDLR mutation (FH), carriers of an APOB mutation (FDB), and non- LDLR/non- APOB patients (FH3). No differences were found with regard to untreated cholesterol levels, response to therapy, and onset of CVD. However, all groups were at an increased risk for CVD. Therefore, to ultimately identify all individuals with ADH, the identification of new genes and mutations in the genes that cause ADH is of crucial importance for the ongoing national program to identify patients with ADH by genetic cascade screening. Hum Mutat 26(6), 550,556, 2005. © 2005 Wiley-Liss, Inc. [source] LDL-receptor mutations in Europe,HUMAN MUTATION, Issue 6 2004George V.Z. Dedoussis Abstract Familial hypercholesterolemia (FH) is a clinical definition for a remarkable increase of cholesterol serum concentration, presence of xanthomas, and an autosomal dominant trait of either increased serum cholesterol or premature coronary artery disease (CAD). The identification of the low-density lipoprotein (LDL)-receptor (LDLR) as the underlying cause and its genetic characterization in FH patients revealed more insights in the trafficking of LDL, which primarily transports cholesterol to hepatic and peripheral cells. Mutations within LDLR result in hypercholesterolemia and, subsequently, cholesterol deposition in humans to a variable degree. This confirms the pathogenetic role of LDLR and also highlights the existence of additional factors in determining the phenotype. Autosomal dominant FH is caused by LDLR deficiency and defective apolipoprotein B-100 (APOB), respectively. Heterozygosity of the LDLR is relatively common (1:500). Clinical diagnosis is highly important and genetic diagnosis may be helpful, since treatment is usually effective for this otherwise fatal disease. Very recently, mutations in PCSK9 have been also shown to cause autosomal dominant hypercholesterolemia. For autosomal recessive hypercholesterolemia, mutations within the so-called ARH gene encoding a cellular adaptor protein required for LDL transport have been identified. These insights emphasize the crucial importance of LDL metabolism intra- and extracellularly in determining LDL-cholesterol serum concentration. Herein, we focus on the published European LDLR mutation data that reflect its heterogeneity and phenotypic penetrance. Hum Mutat 24:443,459, 2004. © 2004 Wiley-Liss, Inc. [source] Molecular characterization of familial hypercholesterolemia in German and Greek patients,,HUMAN MUTATION, Issue 3 2004George V. Z. Dedoussis Abstract We used the denaturing gradient gel electrophoresis (DGGE) method to define mutations in the promoter region, the 18 exons, and their flanking intronic sequences of the low-density lipoprotein (LDL) receptor gene LDLR, causing familial hypercholesterolemia (FH) phenotype in 100 German and in 100 Greek hypercholesterolemic individuals. In addition, we tested all patients for the presence of mutations in codons 3456-3553 of the gene encoding apolipoprotein B-100 (APOB). Twenty-six aberrant DGGE patterns were identified and subsequently directly sequenced. In LDLR, two novel missense mutations (c.1957G>T/p.V653F, c.647 G>A/p.C216Y) and one novel homozygous base substitution c.1-156 C>T in the repeat 2 of the promoter region were identified among German FH patients; one novel splice site c.1060+10C>G was identified among Greek FH patients. One of the German FH patients was a carrier for the mutations c.1171G>A/p.A391T and p.V653F, and two of the Greek FH patients were compound heterozygotes for the mutations c.1150C>T/p.Q384X and c.1158C>G/p.D386E. Two German FH patients carried the mutation p.R3500Q within APOB. Comparing the mutations within the LDLR gene of the two European FH populations, the German population seems to be more heterogeneous than the Greek cohort. Further studies in progress are trying to elucidate the responsiveness to drug therapy in association with LDLR genotype and the nutritional habits of the two FH populations. © 2004 Wiley-Liss, Inc. [source] The UMD-LDLR database: additions to the software and 490 new entries to the database,HUMAN MUTATION, Issue 2 2002Ludovic Villéger Abstract Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia (FH), one of the most frequent hereditary dominant disorders. The protein defect was identified in 1973, the gene was localized by in situ hybridization in 1985, and since, a growing number of mutations have been reported. The UMD-LDLR database is customized software that has been developed to list all mutations, and also to provide means to analyze them at the nucleotide and protein levels. The database has been recently modified to fulfill the recommendations of the Nomenclature Working Group for human gene mutations. However, in the current version, both the nomenclature and usual LDLR gene mutation names are reported since the latter are more commonly used. The software has also been modified to accommodate the splicing mutations and alleles that carry two nucleotide variations. The current version of UMD-LDLR contains 840 entries, of which 490 are new entries. Point mutations account for 90% of all mutations in the LDLR gene; the remaining are mostly major rearrangements, due to the presence of Alu sequences. Three new routines have been implemented in the software, thus giving users access to 13 sorting tools. In addition to the database, a Web site containing information about polymorphisms, major rearrangements, and promoter mutations is available. Both are accessible to the scientific community (www.umd.necker.fr) and should help groups working on LDLR to check their mutations and identify new ones, and greatly facilitate the understanding of functional classes/genotype relationships and of genotype/phenotype correlations. © 2002 Wiley-Liss, Inc. [source] Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patientsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Sanna K. Ylisaukko-oja Abstract Germline mutations in fumarate hydratase (FH) gene at 1q43 predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. In HLRCC, the most common clinical features are leiomyomas of the skin and uterus, and in a subset of the families, renal cell cancer (RCC) and uterine leiomyosarcoma (ULMS) occur frequently at young age. This study was conducted to evaluate the possible contribution of FH mutations in a population-based series of early onset (,45 years) ULMSs. Eighty-one cases were identified through the national cancer registry, and samples from 67 cases (83%) were available for FH mutation screening and analysis of allelic imbalance (AI) at the FH locus. Seventeen percent of tumors showed AI. In the mutation analysis, a novel missense mutation K424R was found. The mutation was also found from the patient's normal tissue. To study whether this variant has functional consequences, FH enzyme activity assay was performed in a cell model. The activity of the mutated protein was significantly reduced as compared to wild type (p = 0.009). This study shows that FH germline mutations can occur in seemingly nonsyndromic cases of ULMS (1/67, 1.5%). It appears that on the population level hereditary FH defects do play a role in pathogenesis of sporadic early onset ULMSs, albeit rarely. © 2006 Wiley-Liss, Inc. [source] Heterozygote men with familial hypercholesterolaemia may have an abnormal triglyceride response post-prandially.INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 3 2005Evidence for another predictor of vascular risk in familial hypercholesterolaemia Summary Familial hypercholesterolaemia (FH) is associated with premature coronary heart disease (CHD). Post-prandial hypertriglyceridaemia has also been associated with cardiovascular disease. Thus, an abnormal post-prandial triglyceride (TG) clearance may contribute to the heterogeneity in the risk of CHD in heterozygous (h) FH. Therefore, we investigated the response of TG levels to a fatty meal in men with hFH. We studied 26 Greek men divided into two groups: the hFH group of 14 men, mean age 39 (SD = 11) years and the control group of 12 healthy men, mean age 43 (50:5) years. An increased TG response to the fatty meal was defined as a post-prandial TG concentration (at 4, 6 or 8 h) greater than the highest TG concentration in any hour in any control individual. All hFH patients had normal baseline fasting TG levels. However, seven hFH men showed an abnormal TG response after the fatty meal; these patients had higher baseline fasting TG levels than others [1.5 (0.2) vs. 1.0 (0.4) mmol/l, p = 0.005]. The hFH men constituted a heterogeneous group regarding their TG response to the fatty meal compared with healthy men because 50% with higher, but nevertheless ,normal' basal TG levels, had an abnormal post-prandial TG response. The reduced activity of low-density lipoprotein receptors in hFH together with other defects in TG handling may explain the abnormal rise of TG levels post-prandially. [source] Molecular one-electron properties using the multireference Hartree,Fock CI methodINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 13 2008A. M. C. Sobrinho Abstract The recently introduced multireference Hartree,Fock configuration interaction (MRHFCI) method has been applied to the calculation of the dipole moment of the LiH, BH, FH, CO, and H2O molecules. The results obtained indicate that MRHFCI wave functions, much more compact but of the same quality of the orthogonal full CI ones, can provide better dipole moments than the corresponding full CI wave functions. The value of the dipole moments obtained with the MRHFCI wave functions is quite insensitive to the choice of the HF references but the same is not true for the electronic energy. Therefore, further studies are necessary to develop a criterion for selecting a set of HF references which could provide the best values of energy and dipole moment. Also, it would be important to verify if other one-electron properties can be computed with the same degree of accuracy obtained for the dipole moments. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008 [source] GSA algorithm applied to electronic structure: Hartree,Fock,GSA methodINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 5 2005M. D. de Andrade Abstract A stochastical algorithm to investigate the real closed-shell Hartree,Fock problem is proposed. The approach is based on a global optimization method, the generalized simulated annealing. We tested this methodology by determining the Hartree,Fock ground state of the H2, LiH, BH, Li2, OH,, FH, CO, N2, BeH2, CH2, H2O, NH3, HCHO, CH4 molecular systems using minimal, double-zeta, and triple-zeta bases. The main characteristic of this method is that it enables mapping the electronic hypersurface to find minima with the guarantee of finding the absolute minimum of the functional in focus. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005 [source] Homozygous familial hypercholesterolemia: Long term clinical course and plasma exchange therapy for two individual patients and review of the literatureJOURNAL OF CLINICAL APHERESIS, Issue 6 2009Roy Beigel Abstract Familial hypercholesterolemia (FH) is an autosomal dominant disease. Homozygous FH (HFH) manifests with severe hypercholesterolemia since birth (cholesterol levels >5,6 the upper normal limit), which, if untreated, leads to early onset accelerated atherosclerosis and premature coronary death, usually before the 2nd or 3rd decades of life. Various invasive procedures (iliocecal bypass, porto-caval shunt, liver transplant, and gene therapy) have been introduced for lowering low density lipoprotein (LDL) aiming at reducing atherosclerosis and improving survival of HFH patients. Of all the various methods, LDL apheresis has become the most attractive. Although its impressive effect on LDL-C reduction is well established, its long-term (of more than 10 year) effect on the atherosclerotic process and specifically cardiac end-points in HFH is hardly documented. We herewith report on the longest term lipophoresis so far reported in two HFH patients, each treated with plasma-exchange and LDL-apheresis for more than 20 years. The observations provide an opportunity to focus on various aspects regarding not only the procedure itself but also its effect on various clinical endpoints. By this description together with reviewing the literature, we discuss several issues, some of them are generalized while others are individualized, dealing with the approach of long term LDL apheresis in HFH. J. Clin. Apheresis 2009. © 2009 Wiley-Liss, Inc. [source] Commentary on Wang RH, Cheng CP and Chou FH (2008) A causal model of contraceptive intention and its gender comparison among Taiwanese sexually inexperienced adolescents.JOURNAL OF CLINICAL NURSING, Issue 23 2008Journal of Clinical Nursing 1 [source] Mesenchymal stem cells and platelet-rich plasma enhance bone formation in sinus grafting: a histomorphometric study in minipigsJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 6 2008Francesco Pieri Abstract Objectives: Autologous, allogenic, and alloplastic materials for sinus augmentation have specific drawbacks, which has stimulated an ongoing search for new materials and tissue-engineering constructs. We investigated whether mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) seeded on a fluorohydroxyapatite (FH) scaffold can improve bone formation and bone-to-implant contact (BIC) in maxillary sinus grafting. Material and Methods: Bilateral sinus augmentation procedures were performed in eight minipigs. MSCs, PRP, and FH scaffold (test site) or FH alone (control site) were grafted in each maxillary sinus. Distal to the osteotomy, one dental implant per sinus was placed in the grafting material through the facial sinus wall. The animals were killed 3 months after grafting, and block sections of the implant sites were harvested and prepared for histomorphometric analysis. Results: After 12 weeks, a significant increase in bone formation occurred in the test sites compared with the control sites (42.51%versus 18.98%; p=0.001). In addition, BIC was significantly greater in the test sites compared with the control sites in the regenerated area (23.71%versus 6.63%; p=0.028). Conclusions: These findings show that sinus augmentation with MSCs,PRP, combined with FH may enhance bone formation and osseointegration of dental implants compared with FH alone in minipigs. [source] Plasma and urine levels of urinary trypsin inhibitor in patients with acute and fulminant hepatitisJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2 2002SHI DE LIN Abstract Background and Aim Urinary trypsin inhibitor (UTI) is synthesized by hepatocytes and excreted into urine. Plasma and urine UTI levels have been measured to evaluate whether these levels may be useful markers in various pathological conditions. However, there has been no study on plasma and urine UTI levels in patients with acute liver diseases. The aim of the present study was to evaluate plasma and urine UTI levels and their relationship with the severity of hepatic damage in patients with acute liver diseases. Methods Plasma and urine UTI levels were measured by newly developed enzyme-linked immunosorbent assay in 15 patients with acute hepatitis (AH), 12 patients with acute severe hepatitis (ASH) and 10 patients with fulminant hepatitis (FH), as assessed on admission. The serial changes in plasma and urine UTI were also observed in some patients with AH and ASH. Results Plasma UTI levels (U/mL, median [25,75th percentile]) were: 11.0, (9.5,16.1) in patients with AH; 7.8 (5.6,11.5) in those with ASH; 6.5 (4.0,9.5) in patients with FH; and 9.7 (7.3,11.0) in normal controls. Plasma UTI levels in patients with FH were significantly lower than in those with AH. Plasma UTI levels showed significant positive correlations with the levels of prothrombin time (PT), hepaplastin test, antithrombin III, ,2-plasmin inhibitor, plasminogen (Plg) and fibrinogen. After the recovery of liver dysfunction, increased plasma UTI levels in patients with AH were decreased, whereas previously decreased plasma UTI levels in patients with ASH were increased. Urine UTI levels were significantly increased in patients with AH compared with those of normal controls. In patients with ASH and FH, urine UTI levels were increased but not significantly. Urine UTI levels significantly positively correlated with PT and Plg. After the recovery of liver dysfunction, previously increased urine UTI levels in patients with AH were decreased. The correlation between plasma UTI and urine UTI levels was not significant. Conclusions The findings of the present study suggested that the levels of plasma and urine UTI changed in patients with AH and were closely related to the abnormalities of coagulo-fibrinolysis, including PT. Further studies are needed to clarify whether these levels may be useful markers to predict the prognosis of acute hepatitis. [source] Prevalence and significance of cardiovascular risk factors in a large cohort of patients with familial hypercholesterolaemiaJOURNAL OF INTERNAL MEDICINE, Issue 2 2003P. R. W. De Sauvage Nolting Abstract., de Sauvage Nolting PRW, Defesche JC, Buirma RJA, Hutten BA, Lansberg PJ, Kastelein JJP (Academic Medical Center, Amsterdam; Clinical Research, Haarlem; Slotervaart Hospital, Amsterdam; the Netherlands). Prevalence and significance of cardiovascular risk factors in a large cohort of patients with familial hypercholesterolaemia. J Intern Med 2003; 253: 161,168. Objective., Patients with familial hypercholesterolaemia (FH) vary widely in terms of onset of cardiovascular disease (CVD). Design., The association between cardiovascular risk factors and prevalent CVD was examined in a cross-sectional study in order to elucidate their contribution to atherogenesis. Setting and subjects., Patients were recruited from 37 Dutch Lipid Clinics. The diagnosis of FH was based on a uniform diagnostic protocol, confirmed by DNA analysis in 62% of the cases. All patients were investigated free from any lipid-lowering drug for at least 6 weeks. Main outcome measures., Differences in lipids, lipoproteins and other risk factors for CVD were analysed in FH patients with and without CVD. Results., A total of 526 patients were assessed and more than 37% had a history of CVD with a mean age of onset of 46.8 years. Mean LDL cholesterol (LDL-C) levels were severely elevated (8.38 ± 2.13 mmol L,1). In univariate analysis, age, presence of hypertension or diabetes, body mass index, triglycerides (TG) and low HDL cholesterol (HDL-C) were all significantly associated with CVD. Also in multivariate analysis, all these risk factors, except TG and diabetes, were significantly linked to CVD. Conclusion., A high CVD risk in this large well-documented characterized sample of FH patients is not only conferred by elevated LDL-C but also by low HDL-C. [source] Association of coronary heart disease with age-adjusted aortocoronary calcification in patients with familial hypercholesterolaemiaJOURNAL OF INTERNAL MEDICINE, Issue 4 2000J. M. Jensen Abstract. Jensen JM, Gerdes LU, Jensen HK, Christiansen TM, Brorholt-Petersen JU, Faergeman O (Aarhus Amtssygehus University Hospital, Aarhus, Denmark). Association of coronary heart disease with age-adjusted aortocoronary calcification in patients with familial hypercholesterolaemia. J Intern Med 2000; 247: 479,484. Objectives. Existing algorithms of risk of coronary heart disease (CHD) do not pertain to patients with familial hypercholesterolaemia (FH), whose arteries have been exposed to hypercholesterolaemia since birth. We studied a cohort of FH patients to compare four diagnostic models of CHD: traditional risk factors of CHD (age, sex, cholesterol, hypertension, smoking and body mass index), cholesterol year score, and aortic as well as coronary calcium measured by spiral computed tomography (CT). Subjects. We invited 88 individuals with molecularly defined FH of whom 80 (91%) decided to participate. Results. Analysis of receiver operating characteristic curves showed that the age-adjusted coronary calcium score was more strongly associated with clinical manifestations of CHD than were traditional risk factors (P < 0.002), cholesterol year score (P << 0.0001), and the age-adjusted aortic calcium score (P < 0.0004). Conclusions. Age-adjusted coronary calcium score shows promise as an indicator of CHD in FH patients. [source] Legal Implications of Fetal Heart AssessmentJOURNAL OF OBSTETRIC, GYNECOLOGIC & NEONATAL NURSING, Issue 5 2000Laura Mahlmeister RN The standard of care requires perinatal nurses to perform fetal heart (FH) assessment competently and safely. Failure to adhere to established guidelines and standards for FH assessment may result in negative outcomes for the fetus or newborn and contributes to claims of nursing negligence. The perinatal nurse must be fully cognizant of professional guidelines and standards for FH assessment and comply with agency policies and procedures when conducting assessment of the fetal heart. Guidelines for FH assessment during the antepartum and intrapartum period are discussed within the context of restructured health care settings and today's medicolegal climate. [source] Delay Discounting Behavior and White Matter Microstructure Abnormalities in Youth With a Family History of AlcoholismALCOHOLISM, Issue 9 2010Megan M. Herting Background:, Youth with family history of alcohol abuse have a greater risk of developing an alcohol use disorder (AUD). Brain and behavior differences may underlie this increased vulnerability. The current study examined delay discounting behavior and white matter microstructure in youth at high risk for alcohol abuse, as determined by a family history of alcoholism (FH+), and youth without such family history (FH,). Methods:, Thirty-three healthy youth (FH+ = 15, FH, = 18), ages 11 to 15 years, completed a delay discounting task and underwent diffusion tensor imaging. Tract-based spatial statistics (Smith et al., 2006), as well as follow-up region-of-interest analyses, were performed to compare fractional anisotropy (FA) between FH+ and FH, youth. Results:, FH+ youth showed a trend toward increased discounting behavior and had significantly slower reaction times (RTs) on the delay discounting paradigm compared to FH, youth. Group differences in FA were seen in several white matter tracts. Furthermore, lower FA in the left inferior longitudinal fasciculus and the right optic radiation statistically mediated the relationship between FH status and slower RTs on the delay discounting task. Conclusions:, Youth with a family history of substance abuse have disrupted white matter microstructure, which likely contributes to less efficient cortical processing and may act as an intrinsic risk factor contributing to an increased susceptibility of developing AUD. In addition, FHP youth showed a trend toward greater impulsive decision making, possibly representing an inherent personal characteristic that may facilitate substance use onset and abuse in high-risk youth. [source] Suppression of Heavy Drinking and Alcohol Seeking by a Selective ALDH-2 InhibitorALCOHOLISM, Issue 11 2009Maria P. Arolfo Background:, Inherited human aldehyde dehydrogenase 2 (ALDH-2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH-2 and suppresses heavy drinking in rodents. Decreased drinking due to ALDH-2 inhibition is attributed to aversive properties of acetaldehyde accumulated during alcohol consumption. However, daidzin can reduce drinking in some rodents without necessarily increasing acetaldehyde. Therefore, a selective ALDH-2 inhibitor might affect other metabolic factors involved in regulating drinking. Methods:, Aldehyde dehydrogenase 2 inhibitors were synthesized based on the co-crystal structure of ALDH-2 and daidzin. We tested the efficacy of a highly selective reversible ALDH-2 inhibitor, CVT-10216, in models of moderate and high alcohol drinking rats. We studied 2-bottle choice and deprivation-induced drinking paradigms in Fawn Hooded (FH) rats, operant self-administration in Long Evans (LE), FH, and inbred P (iP) rats and in cue-induced reinstatement in iP rats. We also assayed blood acetaldehyde levels as well as dopamine (DA) release in the nucleus accumbens (NAc) and tested possible rewarding/aversive effects of the inhibitor in a conditioned place preference (CPP) paradigm. Results:, CVT-10216 increases acetaldehyde after alcohol gavage and inhibits 2-bottle choice alcohol intake in heavy drinking rodents, including deprivation-induced drinking. Moreover, CVT-10216 also prevents operant self-administration and eliminates cue-induced reinstatement of alcohol seeking even when alcohol is not available (i.e., no acetaldehyde). Alcohol stimulates DA release in the NAc, which is thought to contribute to increased drinking and relapse in alcoholism. CVT-10216 prevents alcohol-induced increases in NAc DA without changing basal levels. CVT-10216 does not show rewarding or aversive properties in the CPP paradigm at therapeutic doses. Conclusion:, Our findings suggest that selective reversible ALDH-2 inhibitors may have therapeutic potential to reduce excessive drinking and to suppress relapse in abstinent alcoholics. [source] | |||||||||||||||||||||||||||||||||||||||||||