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PubMed1992

Hyperhomocysteinaemia: a risk factor for extracranial carotid artery atherosclerosis.

Hyperhomocysteinemia arising from impaired methionine metabolism, and usually due to a deficiency of cystathionine beta-synthase is a significant and independent risk factor for symptomatic vascular disease. It is not known if hyperhomocysteinemia in apparently healthy asymptomatic subjects is associated with atherosclerosis and whether such a relationship is independent of conventional risk factors. The prevalence of asymptomatic extracranial carotid artery atherosclerosis was determined by duplex ultrasound examination in 25 obligate heterozygotes with respect for cystathionine beta-synthase deficiency (whose children were known to be homozygous for this genetic defect) and in 21 controls. Hyperhomocysteinemia was determined by a standard methionine-loading test and conventional risk factors were also recorded. Twelve of 25 obligate heterozygotes and 8 of 21 normal controls had evidence of extracranial carotid artery atherosclerosis. Hyperhomocysteinemia as a genetic trait was not a significant risk marker, but the actual homocysteine level was associated with an increased risk of carotid disease. After adjustment for the effects of other significant risk factors, the odds ratio of hyperhomocysteinemia for carotid disease was 1.038 per unit increase in homocysteine level (P = 0.03). Hyperhomocysteinemia is a weak risk factor for asymptomatic extracranial carotid atherosclerosis and the relative risk associated with this genetic trait is less than that observed in a study of patients presenting with clinical manifestations of vascular disease.

Adult↗
PubMed2001

Augmented hepatic interferon gamma expression and T-cell influx characterize acute hepatitis progressing to recovery and residual lifelong virus persistence in experimental adult woodchuck hepatitis virus infection.

Woodchucks infected with woodchuck hepatitis virus (WHV) have profiles of liver disease and age-dependent rates of progression to chronic hepatitis (CH) comparable with those seen in human hepatitis B. The mechanism of recovery from acute hepadnaviral infection or its evolution to chronicity remains unknown, although the liver immune responses are expected to play an important role. To determine the dynamics of intrahepatic cytokine expression and T-cell involvement, and to assess their value in predicting the outcome of acute hepatitis (AH) in the adult onset of WHV infection, we evaluated liver transcription of interferon gamma (IFN-gamma); tumor necrosis factor alpha (TNF-alpha); interleukins (IL)-2, -4, and -6; and the T-cell influx in relation to disease histologic severity and virus load in serial liver biopsies collected during the life span of experimentally infected woodchucks. Our results show that recovery from viral AH in adulthood is preceded by a significantly greater hepatic expression of IFN-gamma and CD3, an increased TNF-alpha transcription, lower hepatic WHV load, and a greater degree of liver inflammation than those in acute infection with CH outcome. Furthermore, we have learned that the elevated IFN-gamma, TNF-alpha, and CD3 expression in the liver endures for years not only in CH, but also, although to a lesser extent, in apparently completely resolved infection. This is consistent with our previous findings that residual WHV replication and remnant liver inflammation continue for life after recovery from AH. This study indicates that antiviral cytokines, in particular IFN-gamma, may play a central role in the long-term control of occult hepadnavirus persistence in the liver.

Acute Disease↗
PubMed2000

Posttranscriptional inhibition of class I major histocompatibility complex presentation on hepatocytes and lymphoid cells in chronic woodchuck hepatitis virus infection.

Woodchuck hepatitis virus (WHV), similar to human hepatitis B virus, causes acute liver inflammation that can progress to chronic hepatitis and hepatocellular carcinoma. WHV also invades cells of the host lymphatic system, where it persists for life. We report here that acute and chronic hepadnavirus hepatitis is characterized by a profound difference in the expression of class I major histocompatibility complex (MHC) molecules on the surface of infected hepatocytes and, notably, lymphoid cells. While acute WHV infection is accompanied by the enhanced hepatocyte surface presentation of class I MHC antigen and upregulated transcription of the relevant hepatic genes, inhibition of class I antigen display on liver cells is a uniform hallmark of chronic WHV infection. This inhibition in chronic hepatitis occurs despite augmented (as in acute infection) expression of hepatic genes for class I MHC heavy chain, beta(2)-microglobulin, and transporters associated with antigen processing (TAP1 and TAP2). Further, the class I antigen inhibition is not related to the histological severity of hepatocellular injury, the extent of lymphocytic infiltrations, the level of intrahepatic gamma interferon induction, or the hepatic WHV load. Importantly, the antigen expression is also inhibited on organ lymphoid cells of chronically infected hosts. The results obtained in this study demonstrate that the defective presentation of class I MHC molecules on cells supporting persistent WHV replication is due to viral posttranscriptional interference. This event may diminish the susceptibility of infected hepatocytes to virus-specific T-cell-mediated elimination, hinder virus clearance, and deregulate the class I MHC-dependent functions of the host immune system. This multifarious effect could be critical for perpetuation of liver damage and evasion of the antiviral immunological surveillance in chronic infection and therefore could be supportive of hepadnavirus persistence.

Acute Disease↗
PubMed2001

A family genetic study of autism associated with profound mental retardation.

We sought to determine if the family loading for either the broader autism phenotype or for cognitive impairment differed according to whether or not autism was accompanied by severe mental retardation. The sample comprised 47 probands with autism meeting ICD-10 criteria, as assessed by the Autism Diagnostic Interview and the Autism Diagnostic Observation Schedule. Family history interview and findings were compared with those for the higher IQ autism and Down syndrome samples in the Bolton et al. (1994) study. The familial loading for autism and for the broader phenotype was closely comparable to that in the study of higher IQ autism, and different from that for Down syndrome. The family loading for scholastic achievement difficulties was slightly, but significantly, higher when autism was accompanied by severe retardation.

Adolescent↗
PubMed2000

Genetic evidence for the in planta role of phloem-specific plasma membrane sucrose transporters.

A major question in plant physiology is how the large amount of sucrose made in leaves is transported to the rest of the plant. Although physiological, biochemical, and anatomical investigations have been performed in this field, to date there have been very few genetic studies. Using a reverse genetic screen, we have identified mutant Arabidopsis plants containing transferred DNA insertions in the gene encoding a phloem-specific sucrose transporter, SUC2. SUC2 is thought to function in loading sugar from the apoplast into the conducting sieve tubes. In the homozygous state, these mutations resulted in stunted growth, retarded development, and sterility. The source leaves of mutant plants contained a great excess of starch, and radiolabeled sugar failed to be transported efficiently to roots and inflorescences. These data provide genetic proof that apoplastic phloem loading is critical for growth, development, and reproduction in Arabidopsis and that SUC2 is at least partially responsible for this step.

Arabidopsis↗
PubMed2006

Normal iron metabolism and the pathophysiology of iron overload disorders.

Iron overload disorders represent a heterogenous group of conditions resulting from inherited and acquired causes. If undiagnosed they can be progressive and fatal. Early detection and phlebotomy prior to the onset of cirrhosis can reduce morbidity and normalise life expectancy. We now have greater insight into the complex mechanisms of normal and disordered iron homeostasis following the discovery of new proteins and genetic defects. Here we review the normal mechanisms and regulation of gastrointestinal iron absorption and liver iron transport and their dysregulation in iron overload states. Advances in the understanding of the natural history of iron overload disorders and new methods for clinical detection and management of hereditary haemochromatosis are also reviewed. The current screening strategies target high-risk groups such as first-degree relatives of affected individuals and those with clinical features suggestive of iron loading. Potential ethical, legal and psychosocial issues arising through application of genetic screening programs need to be resolved prior to implementation of general population screening programs.

Journal Article↗
PubMed2005

Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease.

Alzheimer disease (AD) is a complex neurodegenerative disorder predisposed by multiple genetic factors. Mutations in amyloid beta precursor protein (APP) are known to be associated with autosomal dominant, early onset familial AD and possibly also late onset AD (LOAD). A number of genes encoding proteins capable of binding to APP have been identified, but their contribution to AD pathobiology remains unclear. Conceivably, mutations in these genes may play a role in affecting AD susceptibility, which appears to be substantiated by some genetic studies. Here we report results of the first genetic association study with APBB2, an APP binding protein (also known as FE65L), and LOAD, in three independently collected case-control series totaling approximately 2,000 samples. Two SNPs were significantly associated with LOAD in two sample series and in meta-analyses of all three sample sets (for rs13133980: odds ratio [OR](hom)=1.36 [95% CI: 1.05-1.75], OR(het)=1.32 [95% CI: 1.04-1.67], minor allele frequency=43%, P=0.041; and for hCV1558625: OR(hom)=1.37 [95% CI: 1.06-1.77], OR(het)=1.02 [95% CI: 0.82-1.26], minor allele frequency=48%, P=0.026). One of these SNPs, located in a region conserved between the human and mouse genome, showed a significant interaction with age of disease onset. For this marker, the association with LOAD was most pronounced in subjects with disease onset before 75 years of age (OR(hom)=2.43 [95% CI: 1.61-3.67]; OR(het)=2.15 [95% CI: 1.46-3.17]; P=0.00006) in the combined sample set. Our data raise the possibility that genetic variations in APBB2 may affect LOAD susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Resistance profiles observed in virological failures after 24 weeks of amprenavir/ritonavir containing regimen in protease inhibitor experienced patients.

Amprenavir (APV) is an HIV protease inhibitor (PI) used for the treatment of either naive or PI-experienced HIV-infected patients. Several genotypic resistance pathways in protease gene have been described to be associated to unboosted APV failure (I50V, V32I + I47V, I54L/M, or less commonly I84V, which may be accompanied by one ore more accessory mutations such as L10F, L33F, M46I/L). The aims of this study were to investigate the efficacy up to week 24 of an APV plus ritonavir containing regimen in PI experienced patients and to determine the genotypic resistance profiles emerging in patients failing to this therapy. Forty-nine, PI experienced but APV naïve patients were treated with APV (600 mg bid) plus ritonavir (100 mg bid). By intent-to-treat analysis, the median decrease in viral load (VL) was -1.32 log10 (min +0.6; max -2.8) and -1.46 log10 (min +0.5; max -2.8) 12 and 24 weeks after initiating APV plus ritonavir regimen, respectively. Twelve patients harboured a VL >200 copies/ml at week 24. Among these patients, the selection of mutations previously described with the use of APV as first PI (V32I, L33F, M46I/L, I50V, 54M/L, and I84V) was observed. However, in some cases, mutations classically described after the use of other PIs (V82F and L90M) were selected but always with APV-specific mutations. There was no relation between the resistance pathways selected with either APV or ritonavir plasma minimal concentration, but higher APV plasma minimal concentration were associated with a lower rate of resistance mutations selection.

Adult↗
PubMed2001

Quantity of cytomegalovirus DNA in different leukocyte populations during active infection in vivo and the presence of gB and UL18 transcripts.

The quantity of human cytomegalovirus (HCMV) DNA in the blood of immunocompromised individuals correlates with the development of HCMV disease. We wished to determine which leukocytes harboured DNA and whether this represented active viral replication. Magnetic bead separation techniques were used to obtain pure polymorphonuclear leukocyte (PMNL), monocyte, B and T cell fractions, and RT-PCR and quantitative-competitive PCR (QC-PCR) to detect HCMV glycoprotein B (gB; UL55) transcripts and quantify HCMV DNA levels, respectively, in each cell fraction. QC-PCR revealed that PMNLs contribute the greatest to the overall viral load in blood (median viral load: PMNLs, 10(5.37) genomes/ml of blood; monocytes, 10(4.40) genomes/ml; B cells, 10(3.70) genomes/ml; and T cells, 10(4.08) genomes/ml). However, monocytes have a viral burden of 0.65 genomes/monocyte which is greater than that within the other leukocyte populations (0.11 genomes/PMNL, 0.23 genomes/B cell, and 0.20 genomes/T cell). Glycoprotein B transcripts were detected in all four cell populations: 3/10 PMNL fractions, 6/13 monocyte fractions, 5/13 B cell fractions, and 4/13 T cell fractions. The data show that productive infection of these leukocyte subpopulations, including PMNLs, can occur in vivo. Furthermore, transcripts of gpUL18, the putative natural killer (NK) cell decoy, were detected in 2/6 monocyte fractions with active replication, and 1/4 T cell fractions but not in the other leukocyte fractions. The transient nature of UL18 gene expression, and the low abundance of the transcript relative to gB were confirmed.

B-Lymphocytes↗
PubMed2004

Genotypic resistance and HIV-1 subtype in Brazilian children on dual and triple combination therapy.

BACKGROUND: Antiretroviral therapy is provided by the Brazilian Ministry of Health to eligible HIV-infected individuals. Based on clinical and immunological classification, the Brazilian guidelines recommend dual or triple therapy for children. However, the development of drug-resistant strains or poor adherence to therapy could impact the efficacy of this approach. OBJECTIVES: We examined relationships between RNA levels, CD4+ T-cell counts, treatment history, and the prevalence of drug-resistant variants in a cohort of HIV-1-infected children in Rio de Janeiro, Brazil. STUDY DESIGN: Direct sequencing of reverse transcriptase and protease genes from plasma was performed. Virologic and CD4+ T-cell counts responses to therapy were assessed by changes in HIV-1 RNA levels and CD4+ T-cell counts from baseline. RESULTS: Thirty-seven patients were receiving dual therapy and 38 were on triple therapy at enrollment, segregated by antiretroviral history. Both groups had a higher increase in CD4+ T cell counts and a lower viral load in pre-treatment antiretroviral-naïve subjects. Notably, there was a direct correlation between the higher frequencies of drug-resistance mutations and cross-resistance with previous usage of antiretroviral (ARV) therapy in both groups. Non-B subtypes isolates were found in 21.3% of samples. A smaller increase in CD4+ T cell counts was found between non-B subtypes when compared to B-subtypes. CONCLUSIONS: These results suggest that less immunological recovery and a higher number of mutations related to drug resistance were associated with previous usage of ARV and consequent higher time under drug selective pressure in these HIV-infected Brazilian children. These facts suggest the preferential use of triple drug combination as first line regimen in children.

Adolescent↗
PubMed1999

Multiplex analysis of mutations in four genes using fluorescence scanning technology.

Multiplex analysis of genetic mutations using fluorescence scanning methodology is an accurate, efficient, and cost-effective approach to genotypic characterization. Fluorescence labeling during the synthesis of polymerase chain reaction primers allows the application of this technology to well-established protocols. We have simultaneously analyzed the four polymorphisms of factor V Leiden (G1691A), prothrombin G20210A, 5,10-methylenetetrahydrofolate reductase C677T, and cystathionine beta-synthase 844ins68. Three of these mutations have been associated with an increased risk of thrombosis. Following polymerase chain reaction with fluorescence-labeled primers, the polymerase chain reaction products were digested with an appropriate restriction enzyme (if necessary for detection of the mutation), diluted into one tube per sample for co-loading (multiplex loading), and analyzed with GeneScan software for fragment analysis following capillary electrophoresis on an ABI PRISM 310 Genetic Analyzer (Foster City, CA, USA). Multiplex loading increased throughput without compromising precision.

Cystathionine beta-Synthase↗
PubMed2003

Cystathionine beta-synthase polymorphisms and hyperhomocysteinaemia: an association study.

Hyperhomocysteinaemia is generally accepted as an independent and graded risk factor for both arterial occlusive disease and venous thrombosis. The only way of homocysteine degradation is conversion to cysteine in the transsulfuration pathway in which the regulating step is catalysed by cystathionine beta-synthase (CBS). Mild impairment of CBS function could therefore affect homocysteine concentration, in particular after methionine loading, and consequently cardiovascular disease (CVD) risk. We analysed two silent polymorphisms and one short tandem repeat in the CBS gene (ie 699C-->T, 1080C-->T and -5697 (GT) STR) as genetic markers potentially in linkage disequilibrium with a functional polymorphism. We assessed their association with fasting and post-methionine load homocysteine in 190 patients with arterial occlusive disease, and in 381 controls. No differences in CBS genotype frequencies between cases and controls were found, nor was a particular CBS genotype associated with an elevated risk of arterial occlusive disease. Although we did find a high rate of linkage disequilibrium between the two single nucleotide polymorphisms and the GT STR, none of the genotypes defined by the three CBS variants studied showed an association with elevated fasting, post-load or increase upon methionine loading homocysteine concentrations. In conclusion, we did not find any indication that genetic variation in the CBS gene is associated with increased homocysteine concentrations.

Adult↗
PubMed2001

Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses.

The immune response to HIV-1 in patients who carry human histocompatibility leukocyte antigen (HLA)-B27 is characterized by an immunodominant response to an epitope in p24 gag (amino acids 263-272, KRWIILGLNK). Substitution of lysine (K) or glycine (G) for arginine (R) at HIV-1 gag residue 264 (R264K and R264G) results in epitopes that bind to HLA-B27 poorly. We have detected a R264K mutation in four patients carrying HLA-B27. In three of these patients the mutation occurred late, coinciding with disease progression. In another it occurred within 1 yr of infection and was associated with a virus of syncytium-inducing phenotype. In each case, R264K was tightly associated with a leucine to methionine change at residue 268. After the loss of the cytotoxic T lymphocyte (CTL) response to this epitope and in the presence of high viral load, reversion to wild-type sequence was observed. In a fifth patient, a R264G mutation was detected when HIV-1 disease progressed. Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260. Phylogenetic analyses indicated that these substitutions emerged under natural selection rather than by genetic drift or linkage. Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.

Arginine↗
PubMed2002

Neurocognitive functioning and schizophrenia spectrum disorders can be independent expressions of familial liability for schizophrenia in community control children: the UCLA family study.

This study provided a further test of the hypothesis that certain neuromotor, language and verbal memory dysfunctions reflect genetic predisposition to schizophrenia, by examining the effects of family loading for schizophrenia (FLS) in normal controls without personal histories of schizophrenia or attention deficit hyperactivity disorder. In a case control design, 11 community controls (CC) with FLS were compared to 47 CC without FLS on tests of expressive and receptive language, visual motor coordination, full scale intelligence and verbal memory. In this study, FLS primarily reflects the incidence of schizophrenia spectrum diagnoses in the second-degree relatives of CC probands. CC probands with FLS had significantly poorer general intelligence, expressive and receptive vocabulary abilities, visual motor coordination and slower motor speed than CC probands without FLS. The variance in neurocognitive functioning associated with FLS is not due to the presence of any psychiatric disorders in CC probands, nor the presence of schizophrenia spectrum disorders in their parents. The relation between FLS and neurocognitive and neuromotor functioning in CC probands was moderated by the parent's cognitive functioning. The results of the present study indicate that familial liability to schizophrenia can be transmitted across two generations, independent of the presence of schizophrenia spectrum disorders in either the parent or proband, and account for significant variance in proband neurocognitive and neuromotor functioning. These findings suggest the neurocognitive and neuromotor functioning and schizophrenia spectrum disorders can be relatively independent expressions of familial liability to schizophrenia.

Adult↗
PubMedDate not supplied

One mechanostat or many? Modifications of the site-specific response of bone to mechanical loading by nature and nurture.

The concept of the mechanostat was not new in 1983, when Harold Frost coined the term to describe a mechanism by which bone responded to habitual exercise and changes in loading with structurally appropriate alterations in bone architecture. However, the word "mechanostat" has a meaning that is immediately apparent, and its adoption has led to a much wider appreciation of the process of functional adaptation by other scientists than those whose primary research focus is in the biology of adaptation. One problem exists though: it is widely thought that in a single individual, there is a setting for the mechanostat, just as a single thermostat might set the temperature for a whole house, and this is reflected in the idea that bones throughout the skeleton require a specific strain magnitude for maintenance. Increases in loading above that threshold are expected to induce bone formation and a stiffer structure that then experiences again the habitual strain magnitude. Reductions in strain magnitude supposedly induce resorption to reduce tissue mass and architectural properties so that the lower loading restores habitual strain magnitude. That widely held belief of a single unifying number of strain is fundamentally flawed. The purpose of this article is to explain the real basis of the mechanostat; that the skeleton responds to a complex strain stimulus, made up of numerous different parameters, of which peak magnitude is only one, and that the strain stimulus is different in different parts of the skeleton, so there is no universal number to describe a tissue strain magnitude that underlies the mechanostat's setting. Furthermore, males and females have different responses to loading, and those responses change in response to many factors including genetic constitution, age, concomitant disease, nutrient availability, and exposure to drugs or biochemicals. In summary then, there is not a single mechanostat controlling the skeleton of each of us. At a fundamental tissue level, small functional units of bone each have their own multifactorial threshold target strain stimuli for a given set of dynamic modifying influences. Understanding the biology behind the way that each of these mechanostats functions independently is likely to have pervasive consequences on our ability to control bone mass by manipulation of loading, either directly through different exercise regimens, or in a targeted manner using tailored site and individual specific pharmaceuticals.

Animals↗
PubMed2000

Discordance between bovine leukemia virus tax immortalization in vitro and oncogenicity in vivo.

Bovine leukemia virus (BLV) Tax protein, a transcriptional activator of viral expression, is essential for viral replication in vivo. Tax is believed to be involved in leukemogenesis because of its second function, immortalization of primary cells in vitro. These activities of Tax can be dissociated on the basis of point mutations within specific regions of the protein. For example, mutation of the phosphorylation sites at serines 106 and 293 abrogates immortalization potential in vitro but maintains transcriptional activity. This type of mutant is thus particularly useful for unraveling the role of Tax immortalization activity during leukemogenesis independently of viral replication. In this report, we describe the biological properties of BLV recombinant proviruses mutated in the Tax phosphorylation sites (BLVTax106+293). Titration of the proviral loads by semiquantitative PCR revealed that the BLV mutants propagated at wild-type levels in vivo. Furthermore, two animals (sheep 480 and 296) infected with BLVTax106+293 developed leukemia or lymphosarcoma after 16 and 36 months, respectively. These periods of time are within the normal range of latencies preceding the onset of pathogenesis induced by wild-type viruses. The phenotype of the mutant-infected cells was characteristic of a B lymphocyte (immunoglobulin M positive) expressing CD11b and CD5 (except at the final stage for the latter marker), a pattern that is typical of wild-type virus-infected target cells. Interestingly, the transformed B lymphocytes from sheep 480 also coexpressed the CD8 marker, a phenotype rarely observed in tumor biopsies from chronic lymphocytic leukemia patients. Finally, direct sequencing of the tax gene demonstrated that the leukemic cells did not harbor revertant proviruses. We conclude that viruses expressing a Tax mutant unable to transform primary cells in culture are still pathogenic in the sheep animal model. Our data thus provide a clear example of the discordant conclusions that can be drawn from in vitro immortalization assays and in vivo experiments. These observations could be of interest for other systems, such as the related human T-cell leukemia virus type 1, which currently lack animal models allowing the study of the leukemogenic process.

Animals↗
PubMed2005

Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease.

Experimental data have shown an upregulated expression of toll-like receptors, particularly toll-like receptor 4 (TLR4), in neurodegeneration. The Asp299Gly polymorphism of the TLR4 gene has been associated with an attenuated receptor signalling and a blunted inflammatory response. In the present study, we sought to determine whether this common genetic variant could influence susceptibility to late-onset Alzheimer's disease (LOAD) in an Italian population sample. A cohort of 277 LOAD patients and 300 cognitively healthy controls were genotyped for the TLR4 Asp299Gly polymorphism using restriction isotyping. The frequency of the minor 299Gly allele was significantly higher in the controls than in the LOAD cases (7.2% versus 3.1%, respectively, P=0.003). Additionally, the frequency of the variant genotypes (Asp/Gly and Gly/Gly) was 13.0% in the controls and 5.4% in LOAD patients (P=0.002). After adjustment for age, gender, and the APOE varepsilon4 carrier status, the odds ratio for the development of LOAD associated with the Asp/Gly and Gly/Gly versus Asp/Asp genotype was 0.37 (95% CI: 0.20-0.69, P=0.002). Our data further support a role for innate immunity in neurodegeneration and give the first evidence that the TLR4 Asp299Gly variant may be protective toward the development of LOAD.

ATP Binding Cassette Transporter 1↗