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PubMed1999

The transmission of prions to humans.

The identification of new-variant Creutzfeldt-Jakob disease (nvCJD) in 1996 led to the proposal that this new disease was caused by the transmission of bovine spongiform encephalopathy (BSE) to the human population. The ramifications of such a proposal have been extensive and profound, both politically and on the general public in the UK and other countries. Patients with nvCJD exhibit a consistent set of clinicopathological features, and cases of nvCJD continue to be reported almost exclusively in the UK, the country with by far the highest incidence of BSE. Laboratory studies, including transmission experiments in mice, provide strong support for the hypothesis that nvCJD is caused by BSE.

Animals↗
PubMed1987

Characteristics of L-glutamine transport in perfused rat skeletal muscle.

1. We have investigated glutamine transport in the perfused rat hindlimb using the paired-tracer isotope dilution technique. 2. Uptake of L-glutamine was stereospecific, saturable, sodium dependent, insulin sensitive and pH insensitive in the physiological range. The maximum capacity of transport (Vmax) under normal perfusate conditions at 37 degrees C, 145 mM-Na+ and in the absence of insulin was 1156 +/- 193 nmol min-1 g-1 with transport being half-maximal at a perfusate glutamine concentration of 9.25 +/- 1.15 mM. 3. The kinetics of Na+ dependence strongly suggested co-transport of Na+ and glutamine with a stoichiometry of 1:1; furthermore, Na+ activated the carrier without any change in the concentration of glutamine at which transport was half-maximal, i.e. a 'Vmax effect' rather than a 'Km effect'. 4. The characteristics of glutamine transport, especially its substrate specificity and the pattern of competitive and non-competitive inhibition of glutamine transport by other amino acids, suggest that it is mediated by a carrier or carriers for which asparagine and histidine are also suitable substrates. 5. The characteristics of muscle glutamine transport are related but distinct from those of system N identified in hepatocytes; we suggest that they are sufficiently distinct to justify the identification of a new variant of mammalian amino acid transport systems which may be identified by the symbol Nm. 6. The kinetic characteristics of system Nm are such that glutamine is likely to be the most rapidly exchanging amino acid across the muscle membrane at physiological intra- and extracellular glutamine concentrations. Its hormone and ion sensitivities are likely to be important in the physiological modulation of whole-body glutamine metabolism and also during derangements observed in disease and after injury.

Amino Acids↗
PubMed1995

Mapping the perceptual magnet effect for speech using signal detection theory and multidimensional scaling.

Recent experiments have demonstrated that the category goodness of speech sounds strongly influences perception in both adult and infants [Kuhl, Percept. Psychophys. 50, 93-107 (1991); Kuhl et al., Science 255, 606-608 (1992)]. Stimuli judged as exceptionally good instances of phonetic categories (prototypes) make neighboring tokens in the vowel space seem more similar, exhibiting a perceptual magnet effect. Three experiments further examined the perceptual magnet effect in adults. Experiment 1 collected goodness and identification judgments for 13 variants of the vowel /i/. Experiment 2 used signal detection theory to assess the discrimination of these tokens using a bias-free measure (d'). Experiment 3 employed multidimensional scaling (MDS) to geometrically model the distortion of the perceptual space due to the magnet effect. The results demonstrated a strong relationship between category goodness and discrimination. Vowel tokens receiving high goodness ratings in experiment 1 were more difficult to discriminate in experiment 2 and were more tightly clustered in the MDS solutions of experiment 3. These findings support the existence of a perceptual magnet effect, and may help explain some aspects of first language learning in infants and second language learning in adults.

Humans↗
PubMed2003

Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3).

For the elimination of environmental toxins and metabolic waste products, the body is equipped with a range of broad-specificity transporters that are generally present in the liver, kidney, and intestine. The polyspecific organic cation transporters OCT1, 2, and 3 (SLC22A1-3) mediate the facilitated transport of a variety of structurally diverse organic cations, including many drugs, toxins, and endogenous compounds. OCT1 and OCT2 are found in the basolateral membrane of hepatocytes, enterocytes, and renal proximal tubular cells. OCT3 has a more widespread tissue distribution and is considered to be the major component of the extraneuronal monoamine transport system (or uptake-2), which is responsible for the peripheral elimination of monoamine neurotransmitters. Studies with knockout mouse models have directly demonstrated that these transporters can have a major impact on the pharmacological behavior of various substrate organic cations. The recent identification of polymorphic genetic variants of human OCT1 and OCT2 that severely affect transport activity thus suggests that some of the interpatient differences in response and sensitivity to cationic drugs may be caused by variable activity of these transporters.

Alternative Splicing↗
PubMed2002

Identification, characterization, and distribution of a Shiga toxin 1 gene variant (stx(1c)) in Escherichia coli strains isolated from humans.

By using sequence analysis of Shiga toxin 1 (Stx 1) genes from human and ovine Stx-producing Escherichia coli (STEC) strains, we identified an Stx1 variant in STEC of human origin that was identical to the Stx1 variant from ovine STEC, but demonstrated only 97.1 and 96.6% amino acid sequence identity in its A and B subunits, respectively, to the Stx1 encoded by bacteriophage 933J. We designated this variant "Stx1c" and developed stxB(1) restriction fragment length polymorphism and stx(1c)-specific PCR strategies to determine the frequency and distribution of stx(1c) among 212 STEC strains isolated from humans. stx(1c) was identified in 36 (17.0%) of 212 STEC strains, 19 of which originated from asymptomatic subjects and 16 of which were from patients with uncomplicated diarrhea. stx(1c) was most frequently (in 23 STEC strains [63.9%]) associated with stx(2d), but 12 (33.3%) of the 36 STEC strains possessed stx(1c) only. A single STEC strain possessed stx(1c) together with stx(2) and was isolated from a patient with hemolytic-uremic syndrome. All 36 stx(1c)-positive STEC strains were eae negative and belonged to 10 different serogroups, none of which was O157, O26, O103, O111, or O145. Stx1c was produced by all stx(1c)-containing STEC strains, but reacted weakly with a commercial immunoassay. We conclude that STEC strains harboring the stx(1c) variant account for a significant proportion of human STEC isolates. The procedures developed in this study now allow the determination of the frequency of STEC strains harboring stx(1c) among clinical STEC isolates and their association with human disease in prospective studies.

Animals↗
PubMed2003

Bartonella strains from ground squirrels are identical to Bartonella washoensis isolated from a human patient.

The most likely animal source of a human case of cardiac disease in Washoe County, Nev., was identified by comparison of DNA sequences of three genes (citrate synthase gltA, 60-kDa heat shock protein gene groEL, and 16S rRNA gene) of Bartonella washoensis cultured from the human patient in question and of Bartonella isolates obtained from the following Nevada rodents: Peromyscus maniculatus (17 isolates), Tamias minimus (11 isolates), Spermophilus lateralis (3 isolates), and Spermophilus beecheyi (7 isolates). Sequence analyses of gltA amplicons obtained from Bartonella from the rodents demonstrated considerable heterogeneity and resulted in the identification of 16 genetic variants that were clustered within three groups in phylogenetic analysis. Each of the three groups was associated with a rodent genus, Peromyscus, Tamias, or Spermophilus: The gltA, 16S rRNA gene, and groEL sequences of a Bartonella isolate obtained from a California ground squirrel (S. beecheyi) were completely identical to homologous sequences of B. washoensis, strongly suggesting that these animals were the source of infection in the human case.

Animal Diseases↗
PubMed2003

Compartmentalization and transmission of multiple epstein-barr virus strains in asymptomatic carriers.

Infection with the Epstein-Barr virus (EBV) is often subclinical in the presence of a healthy immune response; thus, asymptomatic infection is largely uncharacterized. This study analyzed the nature of EBV infection in 20 asymptomatic immunocompetent hosts over time through the identification of EBV strain variants in the peripheral blood and oral cavity. A heteroduplex tracking assay specific for the EBV gene LMP1 precisely identified the presence of multiple EBV strains in each subject. The strains present in the peripheral blood and oral cavity were often completely discordant, indicating the existence of distinct infections, and the strains present and their relative abundance changed considerably between time points. The possible transmission of strains between the oral cavity and peripheral blood compartments could be tracked within subjects, suggesting that reactivation in the oral cavity and subsequent reinfection of B lymphocytes that reenter the periphery contribute to the maintenance of persistence. In addition, distinct virus strains persisted in the oral cavity over many time points, suggesting an important role for epithelial cells in the maintenance of persistence. Asymptomatic individuals without tonsillar tissue, which is believed to be an important source of virus for the oral cavity, also exhibited multiple strains and a cyclic pattern of transmission between compartments. This study revealed that the majority of patients with infectious mononucleosis were infected with multiple strains of EBV that were also compartmentalized, suggesting that primary infection involves the transmission of multiple strains. Both the primary and carrier states of infection with EBV are more complex than previously thought.

Adolescent↗
PubMed2005

Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn's disease.

BACKGROUND AND AIMS: Recent data suggest identification of causal genetic variants for inflammatory bowel disease in the DLG5 gene and in the organic cation transporter (OCTN) cluster, both situated in previously described linkage regions. PATIENTS AND METHODS: The polymorphisms in DLG5 (113 G-->A, 4136 C-->A, and DLG5_e26), SLC22A4 (1672 C-->T), and SLC22A5 (-207 G-->C) were assessed in 625 patients with Crohn's disease (CD), 363 patients with ulcerative colitis (UC), and 1012 healthy controls. Association with disease susceptibility, clinical phenotypes, and possible genetic interactions of these polymorphisms with disease associated CARD15/NOD2 mutations was analysed. RESULTS: No significant association of DLG5 polymorphisms with CD or UC was observed. Homozygosity for the OCTN-TC haplotype was associated with an increased CD risk (OR = 1.65), which was even greater in the presence of CARD15 mutations. Genotype-phenotype analysis revealed that this association was particularly strong in patients with colonic disease. The TC haplotype was associated with non-fistulising non-fibrostenotic disease, an earlier age of disease onset, and reduced need for surgery. CONCLUSION: Our observations argue against a role of DLG5 polymorphisms in the susceptibility for inflammatory bowel disease, whereas the OCTN polymorphisms are associated with CD. However, due to the comparable weak association observed herein, extended linkage disequilibrium analyses of these variants with the IBD5 haplotype tagged single nucleotide polymorphims might be advisable before definitive conclusions about their causative role in CD can be drawn.

Adolescent↗
PubMed1998

Haemoglobin Le Lamentin (alpha 20 (B1) His-->Gln) in a British family: identification by electrospray mass spectrometry.

The first identification of haemoglobin Le Lamentin (alpha 20 (B1) His-->Gln) in a British patient is described. The patient was a 69 year old asymptomatic white male being screened for diabetes, whose blood was undergoing its first ever analysis for glycated haemoglobin using a Glycomat II analyser. Identification of the haemoglobin variant was by electrospray mass spectrometry.

Aged↗
PubMed1980

Nasopharyngeal angiofibromas: hazards of embolization.

A systematic approach to the diagnosis and treatment of angiofibromas is presented. The distinction between true and false internal carotid supply to these tumors as well as identification of vascular anatomical variants that may represent potential hazards of embolization are emphasized. Areterial supply to the cranial nerves, prevention of neurologic complications, and the use of inappropriate embolization materials are also discussed.

Cerebral Angiography↗
PubMed1995

Transgenic animals in the study of blood pressure regulation and hypertension.

It is generally accepted that the etiology of essential hypertension is due to a complex interplay of genetic and environmental factors. A great deal of research effort over the past ten years has been focused on the identification of genes the variants of which predispose individuals to high blood pressure. Consequently, transgenic and knockout animals have become important research tools, providing experimental systems in which defined genetic manipulations can be introduced on uniform genetic backgrounds while minimizing environmental variation. These animal models have provided the means by which candidate genes thought to be involved in blood pressure regulation have been studied. Furthermore, these models can be used to test the significance of genes and gene variants identified via genome-wide searches as potential causes of hypertension. The purpose of this review is to provide a brief discussion of transgenic and knockout methodology and its application to study the genetic basis of hypertension.

Angiotensinogen↗
PubMed2004

A survey of genetic and epigenetic variation affecting human gene expression.

The identification of human sequence polymorphisms that regulate gene expression is key to understanding human genetic diseases. We report a survey of human genes that demonstrate allelic differences in gene expression, reflecting the presence of putative allele-specific cis-acting factors of either genetic or epigenetic nature. The expression of allelic transcripts in heterozygous samples is assessed directly by relative quantitation of intragenic marker alleles in messenger or heteronuclear RNA derived from cells or tissues. This survey used 193 single-nucleotide polymorphisms (SNPs) from 129 genes expressed in lymphoblastoid cell lines, to identify 23 genes (18%) with common allele-specific transcripts whose expression deviated from the expected equimolar ratio. A subset of these deviations, or "allelic imbalances," can be observed in multiple samples derived from reference CEPH ("Centre d'Etude du Polymorphisme Humain") pedigrees and demonstrate a spectrum of patterns of transmission, including cosegregation of allelic skewing across generations compatible with Mendelian inheritance as well as random monoallelic expression for three genes (IL1A, HTR2A, and FGB). Additional studies for BTN3A2 provide evidence of SNPs and haplotypes in complete linkage disequilibrium with high- and low-expressing transcripts. The pipeline described herein offers tools for efficient identification and characterization of allelic expression allowing identification of regulatory sequence variants as well as epigenetic variation affecting human gene expression.

Allelic Imbalance↗
PubMed1998

Human chromosome 9 pericentric homologies: implications for chromosome 9 heteromorphisms.

Pericentromeric polymorphisms of chromosome 9 include variations in the size of heterochromatin, pericentric inversions, and, more rarely, additional C-band-negative, G-band-positive material in either the proximal short arm or long arm or within the heterochromatin. It has been postulated that rearrangements involving the different classes of satellite DNA present in this relatively unstable region of the human genome constitute a mechanism for the origin of these variants. We report the identification, by molecular cytogenetic investigations, of homologous stretches of euchromatin shared by the proximal short and long arms of chromosome 9 that suggest that exchanges involving these regions may be an additional mechanism for the origin of chromosome 9 polymorphisms.

Centromere↗
PubMed2005

No genetic association between ATP binding cassette proteins and Japanese sporadic Alzheimer's disease.

The identification of the epsilon4 variant of apolipoprotein E as a genetic risk factor for late-onset Alzheimer's disease (AD) suggests that cholesterol may play a direct role in the pathogenesis of the disease. Recent studies have suggested that the ATP-binding cassette (ABC) protein G5 (ABCG5) may be involved in the regulation of intestinal cholesterol absorption. Furthermore, genetic variation of this locus may affect blood cholesterol concentrations. We therefore studied whether the ABCG5 C1950G (Gln640Glu) polymorphism affects the risk of AD. In addition, there was no difference in mean baseline cholesterol concentrations between individuals with the C/C genotype and carriers of the G allele. Recent studies have shown that genetic regions including the ABCA12 gene might also be associated with the risk of AD. The ABCA12 gene, located <1 Mb from the peak marker on chromosome 2q34, is also a member of the ABC transporter superfamily. In the current study, two common polymorphisms of the ABCA12 gene, rs952718 (T/G) and rs956133 (A/G), were analyzed in our subjects. These polymorphisms showed no association with the risk of AD. Furthermore, we observed weak linkage disequilibrium between these two single nucleotide polymorphisms. These results indicate that the common polymorphisms of the ABCG5 and ABCA12 genes investigated here are not associated with AD.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed1988

Recognition of two new phenotypes segregating the E1k allele for plasma cholinesterase.

The first identification of the cholinesterase variants E1kE1k and E1kE1s is reported from a family study. The evidence is based on the biochemical parameters of enzymic activity, and dibucaine, fluoride and RO2 numbers. Two individuals appear to be homozygotes E1kE1k and two are heterozygotes E1kE1s with family evidence supportive of these genotypes. The heterozygotes E1kE1s will be sensitive to suxamethonium.

Adult↗
PubMed1987

Relationships between different cytobiological aspects of myeloid leukaemias.

The present survey deals with the various cytobiological techniques, including the classical morphological and cytochemical approach, as well as the more recently introduced methods of study which may be employed for the characterization of malignant myeloid cells and the identification of particular leukaemic variants. The authors discuss in turn the advantages and limitations of the various approaches and draw attention to the possible relationships which may be detected using combined techniques between different cytobiological aspects, such as the expression of surface markers on the one hand and different degrees of proliferative activity on the other, and the presence of specific cytogenetic alterations as well as the existence of peculiar morphological and cytochemical patterns.

Cell Division↗