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Postprandial lipemic response is modified by the polymorphism at codon 54 of the fatty acid-binding protein 2 gene.

Polymorphism of the fatty acid-binding protein 2 (FABP2) gene has been shown to affect the affinity of intestinal FABP for fatty acids. This could cause changes in postprandial triglyceride metabolism. In the present study, postprandial lipemia was studied in normotriglyceridemic subjects with genetic variation in the FABP2 gene. Oral fat-loading tests were performed in 8 subjects homozygous for the Thr-encoding allele at codon 54 of the FABP2 gene and in 7 subjects homozygous for the Ala-encoding allele (wild type). There were no significant differences between these 2 groups in age, body mass index, fasting plasma triglyceride and cholesterol levels, or fasting glucose and insulin levels. The increase of plasma triglyceride concentration after the fat test meal was significantly greater in subjects who were homozygous for the Thr-54 allele (area under the response curve, 4.27+/-1.31 versus 2.49+/-1.18 mmol/L x h-1, P=0.04). The difference was seen in both chylomicron (2.51+/-0. 98 versus 1.41+/-0.74 mmol/L x h-1, P=0.03) and very low-density lipoprotein triglycerides (1.57+/-0.77 versus 0.99+/-0.40 mmol/L x h-1, P=0.04). Postprandial triglyceride response correlated with fasting triglycerides in the Ala-54 homozygotes (r=0.79, P=0.05) but not in the Thr-54 homozygotes (r=0.09), who showed a strong correlation between triglyceride and insulin responses (r=0.83, P=0. 02). With reservations related to a small number of subjects studied, these results indicate that the Thr-encoding allele of the FABP2 gene is associated with increased postprandial lipemia. The lipemic response was associated with postprandial insulin response, suggesting that in the Thr-54 homozygotes, altered postprandial lipemia may also modify insulin action or vice versa.

Carrier Proteins↗

Genetic diversity of noroviruses in raw and treated sewage water.

Human noroviruses cause gastroenteritis in humans, leading to high virus loads in sewage. Norovirus concentrations in raw and treated sewage samples from two sewage treatment plants (STP) were studied, along with virus removal and genetic diversity. Over one year, the average norovirus concentrations in raw sewage were approximately 10(5) pcr detectable units (pdu) per liter compared with 10(3) pdu/l of treated sewage. Similar sewage treatment processes at STP-A and STP-B led to 2.7 and 2.0 log(10)-units of virus removal, respectively. In total, 11 different norovirus variants were detected in 49 out of 53 sewage samples, with up to four different norovirus strains in a single sewage sample. Along with GGI.6 Sindlesham and GGII.2 Melksham, the GGIIb variant was one of the most prevalent noroviruses in both raw and treated sewage. This strain emerged among populations in Europe in 2000 and 2001. Treated sewage containing 10(2)-10(3) norovirus pdu is discharged into the surface water. The use of such fecally contaminated surface waters for shellfish culture, drinking water production and recreational purposes poses a potential health risk. We showed the presence of multiple norovirus strains in raw and treated sewage, confirming the need to clone before sequencing the RT-PCR products. Exposure to multiple norovirus strains in sewage contaminated food or water may lead to the occurrence of norovirus recombinants, which may be more virulent and pathogenic than the norovirus strains already circulating in the population.

Environmental Monitoring↗

Neuregulin-1 polymorphism in late onset Alzheimer's disease families with psychoses.

Probands with late onset Alzheimer's disease (LOAD) exhibit positive symptoms of psychosis, 30-60% of the time. Positive symptoms of psychosis have been shown to appear prior to the onset of dementia to be accompanied by greater cognitive deficits, and to predict a more rapid decline. A study of the distribution of AD with psychosis (ADP) in families from the NIMH Alzheimer's Disease Genetic Initiative sample indicates that the trait is heritable, and linkage studies of multiplex ADP families have found suggestive peaks on 2p, 6q, 8p, and 21q. A genome scan of idiopathic psychosis, schizophrenia, in the Icelandic population identified a risk haplotype within the 5' region of neuregulin-1 (NRG1) on 8p12. Associations with NRG1 SNPs have also been found in other schizophrenia populations from Scotland, Ireland, and China. Here, we report results demonstrating a significant linkage peak for ADP on 8p12 in the NIMH AD dataset, encompassing the NRG1 region. We also demonstrate that there is a significant association with a NRG1 SNP (single nucleotide polymorphism), rs392499, with ADP, chi2 = 7.0, P = 0.008. This same SNP is part of a 3-SNP haplotype preferentially transmitted to individuals with this phenotype. Our results suggest that NRG1 plays a role in increasing the genetic risk to positive symptoms of psychosis in a proportion of LOAD families.

Aged↗

The 79,370-bp conjugative plasmid pB4 consists of an IncP-1beta backbone loaded with a chromate resistance transposon, the strA-strB streptomycin resistance gene pair, the oxacillinase gene bla(NPS-1), and a tripartite antibiotic efflux system of the resistance-nodulation-division family.

Plasmid pB4 is a conjugative antibiotic resistance plasmid, originally isolated from a microbial community growing in activated sludge, by means of an exogenous isolation method with Pseudomonas sp. B13 as recipient. We have determined the complete nucleotide sequence of pB4. The plasmid is 79,370 bp long and contains at least 81 complete coding regions. A suite of coding regions predicted to be involved in plasmid replication, plasmid maintenance, and conjugative transfer revealed significant similarity to the IncP-1beta backbone of R751. Four resistance gene regions comprising mobile genetic elements are inserted in the IncP-1beta backbone of pB4. The modular 'gene load' of pB4 includes (1) the novel transposon Tn 5719 containing genes characteristic of chromate resistance determinants, (2) the transposon Tn 5393c carrying the widespread streptomycin resistance gene pair strA-strB, (3) the beta-lactam antibiotic resistance gene bla(NPS-1) flanked by highly conserved sequences characteristic of integrons, and (4) a tripartite antibiotic resistance determinant comprising an efflux protein of the resistance-nodulation-division (RND) family, a periplasmic membrane fusion protein (MFP), and an outer membrane factor (OMF). The components of the RND-MFP-OMF efflux system showed the highest similarity to the products of the mexCD-oprJ determinant from the Pseudomonas aeruginosa chromosome. Functional analysis of the cloned resistance region from pB4 in Pseudomonas sp. B13 indicated that the RND-MFP-OMF efflux system conferred high-level resistance to erythromycin and roxithromycin resistance on the host strain. This is the first example of an RND-MFP-OMF-type antibiotic resistance determinant to be found in a plasmid genome. The global genetic organization of pB4 implies that its gene load might be disseminated between bacteria in different habitats by the combined action of the conjugation apparatus and the mobility of its component elements.

Bacterial Proteins↗

Apolipoprotein E genotype and its pathological correlation in Chinese Alzheimer's disease with late onset.

In this study, we attempted to find a relationship between apoliprotein E (ApoE) genotypes and Alzheimer's disease (AD) pathology in different areas of the brain in Chinese. We also studied the borderline group of possible AD (Poss). There were 34 definite or probable AD (Ad), 18 Poss, and 123 brains from age-matched normal subjects (N). ApoE genotype was determined by nested polymerase chain reaction on genomic DNA extracted from archival paraffin-embedded materials. Hippocampus (including entorhinal cortex), amygdala, superior temporal lobe, middle frontal gyrus, and inferior parietal lobule of the brains of Ad and Poss were examined with beta amyloid (A beta) immunostaining, and the same regions plus medial occipital lobe were examined with tau immunostaining. The percentage of plaque area stained for A beta in each brain region was obtained by an image analyzer, and the average number of neurofibrillary tangles stained for tau was counted with an eyepiece graticule. ApoE epsilon4 frequency was increased in both Ad (22.1%, chi2, df = 1, P = .00005), and Poss (33.3%, P = .000005) compared with N (5.3%). A beta load was significantly increased in the neocortex in Ad examined with at least 1 copy of epsilon4 compared with subjects without epsilon4 (Mann-Whitney, P = .014). The same trend, though not statistically significant, occurred in Poss (P = .15). Tau expression was associated with ApoE epsilon4 in neither Ad nor Poss. Poss is genetically and histologically similar to Ad, although the overall A beta load is significantly increased in the latter. These findings support the recent Consensus Report's findings that all Alzheimer-type pathology may be significant.

Age of Onset↗

Abnormal erythrocyte Na+ K+ cotransport system, a proposed genetic marker of essential hypertension.

In erythrocytes, the extrusion of a cell sodium load is accomplished by the ouabain-sensitive sodium-potassium pump and by the furosemide-sensitive sodium-potassium cotransport, which operate against the passive sodium permeability. The precise characterization of these transport pathways requires the determination of the turnover rates of cation translocation and the affinities for substrates and effectors. The preliminary results of such kinetic study in essential hypertension is reported here. An abnormally low rate of net sodium extrusion by the sodium-potassium co-transport system was observed in essential hypertensive patients and in a high proportion of their young normotensive offspring. A normal cotransport system found in secondary hypertensive subjects devoid of familial history of hypertension confirmed that the abnormal cotransport system is not the consequence of high blood pressure per se. At the molecular level, the cotransport abnormality seems to be consecutive to a diminished apparent affinity for intracellular Na+. A 20-40% increase in the rate of net sodium extrusion by the sodium-potassium pump seems to compensate for the abnormal cotransport in erythrocytes from some young normotensive subjects born of essential hypertensive parents and from some benign essential hypertensive subjects. No difference could be detected between the passive sodium permeability of erythrocytes from hypertensive subjects and normotensive controls. In conclusion, essential hypertension seems to be associate with an inherited defect in the apparent affinity for intracellular Na+ of the sodium-potassium cotransport system. We propose therefore the laboratory study of this system for (i) the distinction between essential and secondary hypertension and (ii) the preventive investigation of young normotensive subjects in hypertensive families.

Biological Transport, Active↗

Genetic association of BACE1 gene polymorphism C786G with late-onset Alzheimer's disease in Chinese.

Beta-amyloid (Abeta) peptides are derived from the endoproteolytic processing of amyloid precursor protein (APP) and play a key role in the pathogenesis of Alzheimer's disease (AD). Beta-site APP-cleaving enzyme 1 ([BACE1] also known as beta-secretase) is responsible for cleaving APP to generate neurotoxic Abeta peptides in patients with AD. The BACE1 gene is located on chromosome 11q23.3, near the recently identified region with increased lod scores for AD. The biological functional and genetic association studies indicated that the BACE1 gene might be a genetic risk factor for late-onset Alzheimer's disease (LOAD). To investigate an association between the BACE1 C786G polymorphism and sporadic LOAD in Chinese, we examined 105 LOAD patients and 130 healthy controls. Our results showed higher frequency of the 786G-allele in LOAD patients (38.6%) than that in controls (28.5%), and a statistical significance was observed for an association of the G-allele with LOAD (odds ratio [OR] = 1.58, 95% confidence interval [CI] 1.07-2.23, p = 0.02). We also found a synergetic interaction between the G-allele and apolipoprotein E allele 4 (APOE e4) status on the risk of LOAD (OR = 1.91, 95% CI 1.23-2.95, p = 0.003). These results suggest that BACE1 gene polymorphism C786G might act as an APOE epsilon4 allele-dependent risk factor for developing LOAD in Chinese.

Adult↗

Prediction of residual time to AIDS and death based on markers and cofactors.

A model was constructed that estimates the probability of an HIV-infected individual developing AIDS or dying within a certain time span if left untreated, based on the most recent CD4 lymphocyte count, HIV-1 RNA load, and HIV-1 phenotype, together with age, time since seroconversion, and two genetic cofactors. The model helps clinicians in deciding when to start highly active antiretroviral treatment (HAART). Data from the Amsterdam Cohort Study among homosexual men restricted to individuals with an estimated date of seroconversion (N = 280) were used. Individual predictions based on several combinations of marker and cofactor values were obtained, and their accuracy was measured using two indices of predictive value. CD4 lymphocyte count and HIV RNA load have the highest predictive value and act independently. The predictive value of the HIV phenotype is only slightly lower and greatly enhances predictions at high CD4 counts. The CCR5-Delta32 and CCR2-64I alleles have no additional predictive value. Some predictive value is lost by not knowing time since seroconversion, and some effect of calendar period is present. In summary, for prognosis, the markers CD4 count, HIV-1 RNA load, and HIV-1 phenotype (at a high CD4 count) are equally important, and the genetic cofactors considered are of no use.

Adult↗

Effects of chemical contaminants on genetic diversity in natural populations: implications for biomonitoring and ecotoxicology.

The conservation of genetic diversity has emerged as one of the central issues in conservation biology. Although researchers in the areas of evolutionary biology, population management, and conservation biology routinely investigate genetic variability in natural populations, only a handful of studies have addressed the effects of chemical contamination on population genetics. Chemical contamination can cause population reduction by the effects of somatic and heritable mutations, as well as non-genetic modes of toxicity. Stochastic processes in small populations, increased mutation load, and the phenomenon of mutational meltdown are compounding factors that cause reduced fitness and accelerate the process of population extirpation. Although the original damage caused by chemical contaminants is at the molecular level, there are emergent effects at the level of populations, such as the loss of genetic diversity, that are not predictable based solely on knowledge of the mechanism of toxicity of the chemical contaminants. Therefore, the study of evolutionary toxicology, which encompasses the population-genetic effects of environmental contaminants, should be an important focus of ecotoxicology. This paper reviews the issues surrounding the genetic effects of pollution, summarizes the technical approaches that can be used to address these issues, and provides examples of studies that have addressed some of them.

Alleles↗

Integration of R91-5::Tn501 into the Pseudomonas putida PPN chromosome and genetic circularity of the chromosomal map.

Derivatives of the Pseudomonas aeruginosa plasmid R91-5, loaded with the transposon Tn501, were transferred to P. putida PPN. Over 90% of exconjugants, which arose at a frequency of ca. 10(-6) per donor cell, exhibited high-frequency (greater than 10(-2) per donor cell) polarized transfer of chromosomal markers. In one instance it was demonstrated by transduction that the plasmid had been inserted into a gene required for serine biosynthesis. The integrated nature of the plasmid in this and other P. putida (R91-5::Tn501) derivatives was supported by the failure to detect covalently closed circular DNA in these strains. The transfer origins of six different Hfr donors have been characterized genetically, and time-of-entry kinetics obtained from interrupted matings have enabled the construction of a circular genetic map 103 min in length and containing 35 markers. The genetic map of P. putida PPN shows significant differences in marker order to that of P. aeruginosa PAO.

Chromosome Mapping↗

New method for parallel computation of Hessian matrix of conformational energy function in internal coordinates.

A new algorithm for parallel calculation of the second derivatives (Hessian) of the conformational energy function of biomolecules in internal coordinates is proposed. The basic scheme of this algorithm is the division of the entire calculation of the Hessian matrix (called "task") into subtasks and the optimization of the assignment of processors to each subtask by considering both the load balancing and reduction of the communication cost. A genetic algorithm is used for this optimization considering the dependencies between subtasks. We applied this method to a glutaminyl transfer RNA (Gln-tRNA) molecule for which the scalability of our previously developed parallel algorithm was significantly decreased when the large number of processors was used. The speedup for the calculation was 32.6 times with 60 processors, which is considerably better than the speedup for our previously reported parallel algorithm. The elapsed time for the calculation of subtasks, data sending, and data receiving was analyzed, and the effect of the optimization using the genetic algorithm is discussed.

Algorithms↗

Exceptionally high levels of multiple mating in an army ant.

Most species of social insects have singly mated queens, although there are notable exceptions. Competing hypotheses have been proposed to explain the evolution of high levels of multiple mating, but this issue is far from resolved. Here we use microsatellites to investigate mating frequency in the army ant Eciton burchellii and show that queens mate with an exceptionally large number of males, eclipsing all but one other social insect species for which data are available. In addition we present evidence that suggests that mating is serial, continuing throughout the lifetime of the queen. This is the first demonstration of serial mating among social hymenoptera. We propose that high paternity within colonies is most likely to have evolved to increase genetic diversity and to counter high pathogen and parasite loads.

Animals↗

Natural history of hepatitis C.

Ten years after the discovery of the hepatitis C virus (HCV) and its association with NANB hepatitis as a major cause of chronic liver disease worldwide, our knowledge of the natural history of hepatitis C is still limited. The asymptomatic course of the disease in most patients, its slow and silent progression and heterogeneous outcome and the widespread use of interferon therapy during the past decade explain why many questions are still unsolved. The changing epidemiological pattern of HCV and the significant contribution of several cofactors to the severity of liver disease also complicate the development of a general model describing the natural history of hepatitis C. Available data indicate that HCV infection may resolve without any clinical signs of liver disease in individuals exposed to low dose inoculum and that these cases may develop T cell immunity even in the absence of anti-HCV seroconversion. Rates of complete biochemical and virological resolution of acute hepatitis C range between 10 and 50%, and are probably affected by the route of infection, size and type of inoculum and acute phase clinical features. Chronic HCV infection may develop with or without ALT abnormalities and with or without chronic inflammation and increasing fibrosis in the liver. Studies conducted in patients who acquired hepatitis C by blood transfusion 15-25 years ago indicate that 20-30% of them have now progressed to cirrhosis, including 5-10% with end stage liver disease and 4-8% who died of liver-related causes. Similar studies conducted in patients infected by other routes have shown a more benign course of hepatitis C, with little evidence of cirrhosis and no liver-related mortality during the first two decades. Outcomes after longer follow-up need to be assessed. In patients presenting with chronic hepatitis C, fibrosis progression is extremely variable over time and can be partially predicted by the age at infection, disease duration, liver histologic activity and stage of fibrosis and by the ALT profile. However, it is often difficult to predict clinical outcomes in individual cases. In patients who have developed cirrhosis, the 5-year risk of decompensation is between 15 and 20% and that of hepatocellular carcinoma around 10%. Several variables have been shown to influence the natural course of shown C, the most significant being age at infection, alcohol consumption and coinfection with HBV and HIV Studies are being performed to assess the role of host genetics. Viral factors, such as the HCV type and load, seem to have inconsistent or marginal effects.

Acute Disease↗

Blood glucose and serum insulin levels in lean and genetically obese mice.

Fed and 24 hour fasted lean and genetically obese mice (ob/ob) were given a fixed glucose load per gm body weight by intraperitoneal and intragastric administration. Intraperitoneal glucose injection into the obese mice produced a prolonged elevated blood glucose level with a concomitant significant decrease of circulating insulin. Possible interpretations of this observation are discussed. In those obese animals in which glucose was administered intragastrically the fed obese mice had a blood glucose concentration of 450-500 mg% for a period of one hour but there was no increase in circulating insulin, however, in the fasted obese mice in which the glucose concentration was about 350 mg% for one hour, there was a significant increase in the circulating insulin levels. The fed and fasted lean mice showed normal glucose tolerance curves and the expected increase in circulating insulin following either intraperitoneal orintragastric glucose loads. It is concluded that hyperglycaemia in the ob/ob mice is unlikely to be the principal cause of hyperinsulinaemia.

Animals↗

Thoracic and lumbar spinal curvatures in Nigerian adults.

The thoracic and lumbar curvatures of 105 Nigerian adults have been measured with a flexible rule (flexicurve). The lumbar curvature is relatively greater in women. Compared with a previous survey of Europeans, the curvatures in both men and women appear to be about 20 per cent greater in Nigerians. This is likely to be a genetic difference but the Nigerian practice of carrying heavy loads on the head may be a contributory factor.

Adult↗

Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection.

BACKGROUND: A vaccine is needed to prevent human immunodeficiency virus type 1 (HIV-1) infection. METHODS: A double-blind, randomized trial of a recombinant HIV-1 envelope glycoprotein subunit (rgp120) vaccine was conducted among men who have sex with men and among women at high risk for heterosexual transmission of HIV-1. Volunteers received 7 injections of either vaccine or placebo (ratio, 2 : 1) over 30 months. The primary end point was HIV-1 seroconversion over 36 months. RESULTS: A total of 5403 volunteers (5095 men and 308 women) were evaluated. The vaccine did not prevent HIV-1 acquisition: infection rates were 6.7% in 3598 vaccinees and 7.0% in 1805 placebo recipients; vaccine efficacy (VE) was estimated as 6% (95% confidence interval, -17% to 24%). There were no significant differences in viral loads, rates of antiretroviral-therapy initiation, or the genetic characteristics of the infecting HIV-1 strains between treatment arms. Exploratory subgroup analyses showed nonsignificant trends toward efficacy in preventing infection in the highest risk (VE, 43%; n=247) and nonwhite (VE, 47%; n=914) volunteers (P=.10, adjusted for multiple subgroup comparisons). CONCLUSIONS: There was no overall protective effect. The efficacy trends in subgroups may provide clues for the development of effective immunization approaches.

AIDS Vaccines↗

Towards reliable prenatal diagnosis of mtDNA point mutations: studies of nt8993 mutations in oocytes, fetal tissues, children and adults.

Prenatal diagnosis of mitochondrial DNA (mtDNA) mutations is technically possible, but has only rarely been attempted. This is largely because of uncertainty about the effects of mtDNA heteroplasmy, the mtDNA bottleneck, random segregation or selection of mtDNA species, and difficulty in correlating a particular mtDNA mutant load with clinical outcome. We have investigated the feasibility of prenatal diagnosis for two common mtDNA mutations at nucleotide (nt)8993 by determining mtDNA mutant loads in human oocytes and by reviewing data on 56 pedigrees with these mutations, and by reviewing six studies on mtDNA mutations in human fetuses. Data from heteroplasmic human and mouse oocytes demonstrate that the bottleneck occurs in early oogenesis. Analysis of mutant loads of the nt8993 mutations in fetal and adult tissues confirms that there is no substantial tissue variation, implying that the mutant load in a prenatal sample will represent the mutant load in other fetal tissues. The two nucleotide 8993 mutations each show a strong correlation between mutant load and symptom severity and between maternal blood mutant load and risk of a severe outcome. We generated empirical data for calculating recurrence risk and predicting the clinical outcome of a given mutant load. These predictive data can be used (cautiously) for genetic counselling and prenatal diagnosis of nucleotide 8993 mutations.

Adult↗

High calcium diet, different antihypertensive agents, and cytosolic free Ca2+ in spontaneously hypertensive rats.

Several studies have shown that increased dietary calcium decreases blood pressure (BP) in spontaneously hypertensive rats (SHR), but the underlying mechanisms are not fully understood. We compared the effects of a high calcium diet and different antihypertensive agents on BP and intracellular free Ca2+ concentration ([Ca2+]i) in lymphocytes of adult SHR. The calcium content of the normal chow was 1.1% and that of the high calcium chow was 2.5%. Antihypertensive drug treatments were performed by giving the animals trichlormethiazide (2 mg/kg/day), atenolol (25 mg/kg/day), and quinapril (10 mg/kg/day) in drinking water. Untreated SHR and normotensive Wistar-Kyoto (WKY) rats served as controls. After 14 weeks of study systolic BP (SBP) and [Ca2+]i in blood lymphocytes, measured with a fluorescent indicator quin-2, were higher in untreated SHR than in WKY rats. Trichlormethiazide, atenolol, quinapril, and the high calcium diet all decreased BP in SHR, but only quinapril and calcium-rich diet concurrently reduced [Ca2+]i. We conclude that the reduction in [Ca2+]i during high calcium intake does not result from decreased BP itself. If the changes in lymphocyte [Ca2+]i reflect Ca2+ metabolism in other tissues as well, especially in vascular smooth muscle, the normalization of [Ca2+]i may be involved in the BP-lowering mechanisms of oral calcium loading and angiotensin-converting enzyme (ACE) inhibition in genetic hypertension.

Animals↗