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At least 811 records · Page 45Linked to original sources
PubMed1998

Receptor organ damage causes loss of cortical surround inhibition without topographic map plasticity.

Following restricted peripheral damage, reorganization of adult sensory or motor cortex is believed to depend on loss of surround inhibition, which unmasks latent inputs to the deprived cortex. Here I demonstrate that limited damage to auditory receptors causes loss of functional surround inhibition in the cortex, unmasking of latent inputs and significantly altered neural coding. However, these changes do not lead to plasticity of the cortical map, defined by the most sensitive input from the receptor surface to each cortical location. Thus, in sensory cortex, loss of surround inhibition as a consequence of receptor organ damage does not necessarily result in cortical map plasticity.

Animals↗
PubMed2001

Neural correlates of change detection and change blindness.

Functional magnetic resonance imaging (fMRI) of subjects attempting to detect a visual change occurring during a screen flicker was used to distinguish the neural correlates of change detection from those of change blindness. Change detection resulted in enhanced activity in the parietal and right dorsolateral prefrontal cortex as well as category-selective regions of the extrastriate visual cortex (for example, fusiform gyrus for changing faces). Although change blindness resulted in some extrastriate activity, the dorsal activations were clearly absent. These results demonstrate the importance of parietal and dorsolateral frontal activations for conscious detection of changes in properties coded in the ventral visual pathway, and thus suggest a key involvement of dorsal-ventral interactions in visual awareness.

Adult↗
PubMed1994

Trends in primary cerebral lymphoma.

Primary non-Hodgkin lymphoma of the brain is rare, representing only 1% of all non-Hodgkin lymphomas (NHLs), but its incidence has been increasing rapidly in south-east England since 1985. Among 17,322 cases of NHL registered during the 18 year period 1973-90, there were 210 cases of primary cerebral NHL, of which 179 (86%) were diagnosed in the last third of this period, 1985-90. This increase in cerebral lymphoma is not adequately explained by improvements in the precision of diagnosis or by changes in disease coding or cancer registration practice. While there has also been a rapid increase in Kaposi sarcoma, neither immunosuppression acquired through HIV infection nor the overall trend in non-Hodgkin lymphoma can satisfactorily explain the recent increase in cerebral lymphoma, which affects all ages and both sexes similarly. Other possible causes for a true increase in cerebral lymphoma should be sought.

Adolescent↗
PubMed2004

Epigenetics in human disease and prospects for epigenetic therapy.

Epigenetic mechanisms, which involve DNA and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. The study of human disease has focused on genetic mechanisms, but disruption of the balance of epigenetic networks can cause several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. Great potential lies in the development of 'epigenetic therapies'--several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.

DNA Methylation↗
PubMed2000

Muscarinic1 and 2 receptor mRNA in the human caudate-putamen: no change in m1 mRNA in schizophrenia.

Studies using tissue obtained at autopsy suggest that changes in cholinergic neurons could be important in the pathology of schizophrenia.1-4 We have previously reported a decrease in [3H]pirenzepine binding5 and [3H]AF-DX 384 binding6 to caudate-putamen (CP) from subjects who had schizophrenia. Under the conditions chosen, [3H]pirenzepine would predominately bind to muscarinic1 (M1) and muscarinic4 (M4) receptors,7whereas [3H]AF-DX 384 would mainly bind to muscarinic2 (M2) and M4 receptors.8 Given the relative concentrations of M1, M2 and M4 receptors in the human CP and the magnitude of the decreases in radioligand binding in schizophrenia, our results most likely reflected a change in the density of M1 and M2 receptors in the CP from the schizophrenic subjects. In situ hybridisation has now been used to determine levels of m1 and m2 mRNA in CP from 14 schizophrenic and 16 control subjects previously used for radioligand binding. m2 mRNA in the CP from the schizophrenic and control subjects was below the sensitivity of in situhybridisation. There was no difference in the levels of m1 mRNA in CP from schizophrenic and control subjects (mean +/- SEM: 103 +/- 16 vs106 +/- 17 fmol [35S]oligonucleotide probe g-1estimated tissue equivalents, P = 0.91). In conclusion, data from our radioligand binding studies show decreases in [3H]pirenzepine binding that are likely to reflect a decrease in the density of M1 receptors in CP from schizophrenic subjects. Our data in this study show the absence of a concomitant change in mRNA coding for that receptor.

Adult↗
PubMed1999

Risk factors for infant mortality in Down's syndrome: a nationwide study.

The aim of this study was to assess risk factors for the excessive infant mortality rates (IMR) of infants with Down's syndrome (DS). The study population included all 847 Jewish DS births in Israel during 1979-83 and 1987-91. Cases were identified through the National DS Registry. Data were abstracted from hospitalisation records. Ninety-one per cent of the DS diagnoses were confirmed by a cytogenetic analysis. The DS IMR were 24.3 times higher than in the general population. Major risk factors affecting DS IMRs were health status, time period of birth and residential arrangement of the infant. Other known risk factors for infant mortality, such as young maternal age, high birth order and low birthweight, had a weaker impact on IMR in the DS population. Our results imply that the current better survival of infants with DS is a function of the changing attitude towards this population. The study identifies a potential for further reduction in the mortality rates of DS infants, provided there is willingness to adopt a more active and supportive treatment and further changes in ethical codes of the public.

Attitude↗
PubMed1999

Enzymatic characterization of four new mutations in the glucose-6 phosphatase (G6PC) gene which cause glycogen storage disease type 1a.

Glycogen storage disease type 1a (GSD1a) is caused by mutations in the gene of glucose-6 phosphatase (G6PC), encoding the last enzyme of gluconeogenesis and glycogenolysis. To study the effect of mutations previously identified, but not yet enzymatically characterized, in French GSD1a patients, we used an in vitro expression system of the human glucose-6 phosphatase (hGlc6Pase) cDNA. Wild type hGlc6Pase expressed in COS-7 cells exhibited kinetic features comparable to microsomal Glc6Pase from normal human liver and kidney. Four new mutations inducing aminoacid changes in the coding sequence, e.g. W77R, A124T, G184E and L211P, were inserted into the Glc6Pase cDNA by site-directed mutagenesis, and studied after transient expression in COS-7 cells. All four mutations totally abolished Glc6Pase activity.

Amino Acid Sequence↗
PubMed1999

Seven novel mutations of the PKD2 gene in families with autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous, with at least three chromosomal loci accounting for the disease. Mutations in the PKD2 gene on the long arm of chromosome 4 are expected to be responsible for approximately 15% of cases of ADPKD. METHODS: We report a systematic screening for mutations covering the 15 exons of the PKD2 gene in eight unrelated families with ADPKD type 2, using the heteroduplex technique. RESULTS: Seven novel mutations were identified and characterized that, together with the previously described changes, amount to a detection rate of 85% in the population studied. The newly described mutations are two nonsense mutations, a 1 bp deletion, a 1 bp insertion, a mutation that involves both a substitution and a deletion (2511AG-->C), a complex mutation in exon 6 consisting of a simultaneous 7 bp inversion and a 4 bp deletion, and the last one is a G-->C transversion that may be a missense mutation. Most of these mutations are expected to lead to the formation of shorter truncated proteins lacking the carboxyl terminus of PKD2. We have also characterized a frequent polymorphism, Arg-Pro, at codon 28 in this gene. The clinical features of these PKD2 patients are similar to the previously described, with the mean age of end-stage renal disease being 75.5 years (SE +/- 3.8 years). CONCLUSIONS: Our results confirm that many different mutations are likely to be responsible for the disease and that most pathogenic defects probably are point or small changes in the coding region of the gene.

Amino Acid Sequence↗
PubMed1989

Allelic sequence variations in the hypervariable region of a T-cell receptor beta chain: correlation with restriction fragment length polymorphism in human families and populations.

Direct sequence analysis of the human T-cell antigen receptor (TCR) V beta 1 variable gene identified a single base-pair allelic variation (C/G) located within the coding region. This change results in substitution of a histidine (CAC) for a glutamine (CAG) at position 48 of the TCR beta chain, a position predicted to be in the TCR antigen binding site. The V beta 1 polymorphism was found by DNA sequence analysis of V beta 1 genes from seven unrelated individuals; V beta 1 genes were amplified by the polymerase chain reaction, the amplified fragments were cloned into M13 phage vectors, and sequences were determined. To determine the inheritance patterns of the V beta 1 substitution and to test correlation with V beta 1 restriction fragment length polymorphism detected with Pvu II and Taq I, allele-specific oligonucleotides were constructed and used to characterize amplified DNA samples. Seventy unrelated individuals and six families were tested for both restriction fragment length polymorphism and for the V beta 1 substitution. The correlation was also tested using amplified, size-selected, Pvu II- and Taq I-digested DNA samples from heterozygotes. Pvu II allele 1 (61/70) and Taq I allele 1 (66/70) were found to be correlated with the substitution giving rise to a histidine at position 48. Because there are exceptions to the correlation, the use of specific probes to characterize allelic forms of TCR variable genes will provide important tools for studies of basic TCR genetics and disease associations.

Alleles↗
PubMed2004

The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis.

Intracellular cobalamin is converted to adenosylcobalamin, coenzyme for methylmalonyl-CoA mutase and to methylcobalamin, coenzyme for methionine synthase, in an incompletely understood sequence of reactions. Genetic defects of these steps are defined as cbl complementation groups of which cblC, cblD (described in only two siblings), and cblF are associated with combined homocystinuria and methylmalonic aciduria. Here we describe three unrelated patients belonging to the cblD complementation group but with distinct biochemical phenotypes different from that described in the original cblD siblings. Two patients presented with isolated homocystinuria and reduced formation of methionine and methylcobalamin in cultured fibroblasts, defined as cblD-variant 1, and one patient with isolated methylmalonic aciduria and deficient adenosylcobalamin synthesis in fibroblasts, defined as cblD-variant 2. Cell lines from the cblD-variant 1 patients clearly complemented reference lines with the same biochemical phenotype, i.e. cblE and cblG, and the cblD-variant 2 cell line complemented cells from the mutant classes with isolated deficiency of adenosylcobalamin synthesis, i.e. cblA and cblB. Also, no pathogenic sequence changes in the coding regions of genes associated with the respective biochemical phenotypes were found. These findings indicate heterogeneity within the previously defined cblD mutant class and point to further complexity of intracellular cobalamin metabolism.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2000

Recency and suffix effects with immediate recall of olfactory stimuli.

In contrast to our understanding of the immediate recall of auditory and visual material, little is known about the corresponding characteristics of short-term olfactory memory. The current study investigated the pattern of immediate serial recall and the associated suffix effect using olfactory stimuli. Subjects were trained initially to identify and name correctly nine different odours. Experiment 1 established an immediate correct recall span of approximately six items. In Experiment 2 participants recalled serially span equivalent lists which were followed by a visual, auditory, or olfactory suffix. Primacy was evident in the recall curves for all three suffix conditions. Recency, in contrast, was evident in the auditory and visual suffix conditions only; there was a strong suffix effect in the olfactory suffix condition. Experiment 3 replicated this pattern of effects using seven-item lists, and demonstrated that the magnitude of the recency and suffix effects obtained in the olfactory modality can equate to that obtained in the auditory modality. It is concluded that the pattern of recency and suffix effects in the olfactory modality is reliable, and poses difficulties for those theories that rely on the presence of a primary linguistic code, sound, or changing state as determinants of these effects in serial recall.

Acoustic Stimulation↗
PubMed2000

Is daily mortality associated specifically with fine particles? Data reconstruction and replication of analyses.

In 1996, Schwartz, Dockery, and Neas reported that daily mortality was more strongly associated with concentrations of PM2.5 than with concentrations of larger particles (coarse mass [CM]) in six U.S. cities ("original paper"/"original analyses"). Because of the public policy implications of the findings and the uniqueness of the concentration data, we undertook a reanalysis of these results. This paper presents results of the reconstruction of these data and replication of the original analyses using the reconstructed data. The original investigators provided particulate air pollution data for this paper. Daily weather and daily counts of total and cause-specific deaths were reconstructed from original public records. The reconstructed particulate air pollution and weather data were consistent with the summaries presented in the original paper. Daily counts of deaths in the reconstructed data set were lower than in the original paper because of restrictions on residence and place of death. The reconstruction process identified an administrative change in county codes that led to higher numbers of deaths in St. Louis. Despite these differences in daily counts of deaths, the estimated effects of particulate air pollution from the reconstructed dataset, using analytic methods as described in the original paper, produced combined effect estimates essentially equivalent to the originally published results. For example, the estimated association of a 10 micrograms/m3 increase in 2-day mean particulate air pollution on total mortality was 1.3% (95% confidence interval [CI] 0.9-1.7%, t = 6.53) for PM2.5 based on the reconstructed dataset, compared to the originally reported association of 1.5% (95% CI 1.1-1.9%, t = 7.41). For coarse particles, the estimated association from the reconstructed dataset was 0.4% (95% CI -0.2-0.9%, t = 1.43) compared to the originally reported association of 0.4% (95% CI -0.1-1.0%, t = 1.48). These results from the reconstructed data suggest that the original results reported by Schwartz, Dockery, and Neas were essentially replicated.

Adolescent↗
PubMed2001

Demonstrating effectiveness of passive radon-resistant new construction.

Fifty percent of homes tested for radon in Rock Island County, IL, have radon levels above the U.S. Environmental Protection Agency (EPA) action guideline of 4 picoCuries per liter (pCi/L) of air. Therefore, the county is classified by the EPA as Zone 1 on the EPA's Map of Radon Potential. Radon-resistant new construction (RRNC) strategies for new homes are recommended by the EPA in Zone 1 areas. One city in the county, East Moline, reduced the cost of building permits for contractors volunteering to build new homes incorporating modified passive RRNC. Forty-six of 124 new homes built with passive RRNC in the city were tested during this study. Only 27 of the homes tested were below 4-pCi/L, justifying the importance of testing the system to ensure levels are below the action guideline. To provide additional support to an argument in favor of changing city building codes to the required RRNC, 23 of the homes were also tested with the systems deactivated. After systems were deactivated, 73% of the homes had radon levels above the action guideline. Four homes were sampled for bioaerosols to evaluate if passive RRNC might impact other indicators of poor indoor air quality (IAQ). The results of the research will be discussed here.

Air Pollutants, Radioactive↗
PubMed1998

Hydroxyl group of insulin A19Tyr is essential for receptor binding: studies on (A19Phe)insulin.

One mutant proinsulin gene was constructed through PCR with the code of A19Tyr changed into that of Phe. The mutant proinsulin, (A19Phe)-lysproinsulin (F19KPI) was expressed in E. coli and purified. After trypsin and carboxypeptidase B cleavage and Resource Q separation, (A19Phe)-human insulin (F19HI) was obtained. With native insulin as standard, activity assay and structural analysis were carried out. It was found that the conformation of F19HI is very similar to that of native insulin according to the data from native PAGE, reverse-phase FPLC and circular dichroism spectrum, which are also in agreement with the result of radioimmune assay. F19HI retains almost full immune activity, but displays only 13.3% of receptor binding activity. These results suggest that the hydroxyl group of insulin A19Tyr is essential for receptor binding.

Circular Dichroism↗
PubMed2004

Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function: potential role in neuropathogenesis.

Neurodegeneration and dementia caused by human immunodeficiency virus type 1 (HIV-1) infection of the brain are common complications of acquired immunodeficiency syndrome (AIDS). Introduction of highly active antiretroviral therapy (HAART) reduced the incidence of HIV-1-associated dementia, but so far had no effect on the high frequency of milder neurological disorders caused by HIV-1. This indicates that some neuropathogenic processes persist during limited HIV-1 replication in the central nervous system (CNS). The authors are evaluating the hypothesis that interaction of HIV-1 with astrocytes, which bind HIV-1 but support limited productive HIV-1 infection, may contribute to these processes by disrupting astrocyte functions that are important for neuronal activity or survival. Using laser-capture microdissection on brain tissue samples from HIV-1-infected individuals, we found that HIV-1 DNA can be detected in up to 1% of cortical and basal ganglia astrocytes, thus confirming HIV-1 infection in astrocytes from symptomatic patients. Using rapid subtraction hybridization, the authors cloned and identified 25 messenger RNAs in primary human fetal astrocytes either up-regulated or down-regulated by native HIV-1 infection or exposure to gp120 in vitro. Extending this approach to gene microarray analysis using Affymetrix U133A/B gene chips, the authors determined that HIV-1 alters globally and significantly the overall program of gene expression in astrocytes, including changes in transcripts coding for cytokines, G-coupled protein receptors, transcription factors, and others. Focusing on a specific astrocyte function relevant to neuropathogenesis, the authors showed that exposure of astrocytes to HIV-1 or gp120 in vitro impairs the ability of the cells to transport L-glutamate and the authors related this defect to transcriptional inhibition of the EAAT2 glutamate transporter gene. These findings define new pathways through which HIV-1 may contribute to neuropathogenesis under conditions of limited virus replication in the brain.

AIDS Dementia Complex↗
PubMed1989

Molecular cloning and sequence analysis of the Chlamydomonas gene coding for radial spoke protein 3: flagellar mutation pf-14 is an ochre allele.

Chlamydomonas reinhardtii flagellar motility mutant pf-14 fails to assemble radial spokes because of a deficiency for assembly-competent radial spoke protein 3 (Huang, B., G. Piperno, Z. Ramanis, and D. J. L. Luck. 1981. J. Cell Biol. 88:80-88). Here, we raise an antiserum to protein 3 and use it to isolate the corresponding structural gene from an expression library. Southern blot analysis indicates that the gene is single copy and has not undergone major rearrangement in mutant pf-14 cells. Northern blot analysis suggests that wild-type amounts of an apparently normal 2.3-kb transcript accumulate in mutant cells during flagellar regeneration. When this mutant RNA is hybrid selected and translated in vitro, however, it produces a slightly truncated polypeptide 3 with an altered charge. The mutant protein 3 fails to assemble into pf-14 flagella and is maintained within a cytoplasmic pool of unassembled radial spoke polypeptides, as indicated by immunoblot analysis of proteins from whole cells and isolated axonemes using antisera to several radial spoke polypeptides. Interestingly, amounts of the mutant protein are greatly diminished relative to other spoke components. Complete genomic and cDNA nucleotide sequences were determined, and the pf-14 mutation was identified. It is a C-to-T transition near the 5' end of the protein coding region, which changes codon 21 to the ochre termination signal UAA. The size and charge of the mutant protein, and its reduced levels in cells, suggest that it is produced by relatively inefficient translational initiation as codon 42. The unphosphorylated isoform of radial spoke protein 3 is identified, and the sequence similarities between intervening sequences of the radial spoke protein 3 gene and a conserved intervening sequence of the two Chlamydomonas beta-tubulin genes (Youngblom, J., J. A. Schloss, and C. D. Silflow. 1984. Mol. Cell. Biol. 4:2686-2696) are reported.

Alleles↗
PubMed1995

Interferon-alpha 2 variants in the human genome.

Variants of human leukocyte interferon alpha 2 (IFN-alpha 2a, alpha 2b, and alpha 2c) differ from each other by changes in their coding regions at nucleotide positions 137 and 170. As a result of these nucleotide variations, the DNA sequences of the three variants can be distinguished by selective restriction enzyme analysis. Human genomic DNA obtained from over 28,000 normal healthy individuals was used as templates in the polymerase chain reaction (PCR) to amplify the human IFN-alpha 2 gene sequence. The resulting PCR products were analyzed with restriction nucleases to identify the specific IFN-alpha 2 variant sequences present in the genomic DNA of the population examined. The results show that IFN-alpha 2b was detected as the predominant species and IFN-alpha 2c as a very minor species (< 0.1%). The IFN-alpha 2a gene was not detected in this population.

Alleles↗
PubMed1996

Interferon-alpha 8b is the only variant of interferon-alpha 8 identified in a large human population.

Three variants of human interferon (IFN)-alpha 8a gene, that is, IFN-alpha 8b, and IFN-alpha 8c, have been reported previously. They differ from each other by changes in their coding region at nucleotide positions 359-360, 372, and 550. Human genomic DNA obtained from over 28,000 healthy blood donors and from 4 human cell lines was used in the polymerase chain reaction (PCR) designed for specific amplification of the IFN-alpha 8 gene fragments. The resulting PCR product was analyzed by (1) restriction endonuclease digestion, (2) DNA sequencing, and (3) allele-specific secondary PCR amplification. Only one sequence for IFN-alpha 8 was identified, and that was for IFN-alpha 8b. The sequences for IFN-alpha 8a and IFN-alpha 8c were not detected after PCR amplification either in the pooled leukocytes obtained from > 28,000 individuals or in cell lines tested. These data suggest that the naturally occurring variant or allele for IFN-alpha 8 in the population is IFN-alpha 8b. IFN-alpha 8a and IFN-alpha 8c variants were consistently below the level of detection of the assays and, if present at all in the population, are very rare.

Alleles↗