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Biomedical subjects

J Williamson

Publications and source records attributed to J Williamson.

At least 19 recordsLinked to original sources
PubMed1999

Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q.

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of disorders characterized by insidiously progressive spastic weakness in the legs. Genetic loci for autosomal dominant HSP exist on chromosomes 2p, 14q, and 15q. These loci are excluded in 45% of autosomal dominant HSP kindreds, indicating the presence of additional loci for autosomal dominant HSP. We analyzed a Caucasian kindred with autosomal dominant HSP and identified tight linkage between the disorder and microsatellite markers on chromosome 8q (maximum two-point LOD score 5.51 at recombination fraction 0). Our results clearly establish the existence of a locus for autosomal dominant HSP on chromosome 8q23-24. Currently this locus spans 6.2 cM between D8S1804 and D8S1774 and includes several potential candidate genes. Identifying this novel HSP locus on chromosome 8q23-24 will facilitate discovery of this HSP gene, improve genetic counseling for families with linkage to this locus, and extend our ability to correlate clinical features with different HSP loci.

Adult↗
PubMed1998

The human polycomb group complex associates with pericentromeric heterochromatin to form a novel nuclear domain.

The Polycomb group (PcG) complex is a chromatin-associated multiprotein complex, involved in the stable repression of homeotic gene activity in Drosophila. Recently, a mammalian PcG complex has been identified with several PcG proteins implicated in the regulation of Hox gene expression. Although the mammalian PcG complex appears analogous to the complex in Drosophila, the molecular mechanisms and functions for the mammalian PcG complex remain unknown. Here we describe a detailed characterization of the human PcG complex in terms of cellular localization and chromosomal association. By using antibodies that specifically recognize three human PcG proteins- RING1, BMI1, and hPc2-we demonstrate in a number of human cell lines that the PcG complex forms a unique discrete nuclear structure that we term PcG bodies. PcG bodies are prominent novel nuclear structures with the larger PcG foci generally localized near the centromeres, as visualized with a kinetochore antibody marker. In both normal fetal and adult fibroblasts, PcG bodies are not randomly dispersed, but appear clustered into defined areas within the nucleus. We show in three different human cell lines that the PcG complex can tightly associate with large pericentromeric heterochromatin regions (1q12) on chromosome 1, and with related pericentromeric sequences on different chromosomes, providing evidence for a mammalian PcG-heterochromatin association. Furthermore, these heterochromatin-bound PcG complexes remain stably associated throughout mitosis, thereby allowing the potential inheritance of the PcG complex through successive cell divisions. We discuss these results in terms of the known function of the PcG complex as a transcriptional repression complex.

Cell Line↗
PubMed1998

Isolation and characterization of mouse minisatellites.

Minisatellites provide the most informative system for analyzing processes of tandem repeat turnover in humans. However, little is known about minisatellites and the mechanisms by which they mutate in other species. To this end, we have isolated and characterized 76 endogenous mouse VNTRs. Fifty-one loci have been localized on mouse chromosomes and, unlike in humans, show no clustering in proterminal regions. Sequence analysis of 25 loci revealed the majority to be authentic minisatellites with GC-rich repeat units ranging from 14 to 47 bp in length. We have further characterized 3 of the most polymorphic loci both in Mus musculus subspecies and in inbred strains by using minisatellite variant repeat mapping (MVR) by PCR to gain insight into allelic diversity and turnover processes. MVR data suggest that mouse minisatellites mutate mainly by intra-allelic nonpolar events at a rate well below 10(-3) per gamete, in contrast to the high-frequency complex meiotic gene conversion-like events seen in humans. These results may indicate a fundamental difference in mechanisms of minisatellite mutation and genome turnover between mice and humans.

Alleles↗
PubMed1998

A novel unstable mouse VNTR family expanded from SINE B1 elements.

Human hypervariable minisatellites provide highly informative loci for analyzing processes of tandem repeat turnover, but little is known about mechanisms of instability in other species. We have therefore screened the mouse genome for analogous VNTR loci. One of the probes we isolated, MMS10, detects a highly variable rodent-specific family of multiple loci derived by expansion of a common GGCAGA repeat unit from within a subset of B1 short interspersed elements. The mean germline mutation rate for loci detected by MMS10 was estimated at 1.7% per offspring band, though analysis of individual loci showed substantial variation in germinal instability apparently related to repeat array size. This MMS10 family of expanded hexanucleotide repeat loci provides a novel resource for investigating mechanisms of tandem repeat turnover in the mouse and an efficient means for monitoring germline mutations induced by external agents such as ionizing radiation.

Animals↗
PubMed1998

The human homologue of the ninjurin gene maps to the candidate region of hereditary sensory neuropathy type I (HSNI).

The human ninjurin gene was isolated from a cDNA library enriched for transcripts from band 9q22. A 1.2-kb message was detected for ninjurin in all human tissues studied. The full-length sequence codes for a putative 152-amino-acid protein with 89% identity to the rat ninjurin protein. The mouse homologue was isolated and showed 98% amino acid identity to the rat protein. Mapping by FISH localized mouse ninjurin to mouse chromosome 13, a region that shows synteny with human chromosome 9q22. Genomic characterization of the human gene revealed four exons covering less than 10 kb. The map position of the human gene is between the genetic markers D9S196 and D9S197 on human chromosome band 9q22. This places the gene within the candidate regions for the degenerative neurological disorder hereditary sensory neuropathy type I and the cancer predisposition syndrome multiple self-healing squamous epitheliomata.

Amino Acid Sequence↗
PubMed1998

The ubiquitin-homology gene PIC1: characterization of mouse (Pic1) and human (UBL1) genes and pseudogenes.

The human ubiquitin-homology domain protein PIC1 interacts with the acute promyelocytic leukemia protein PML, and both proteins form part of the large, nuclear, multiprotein complexes known as PML nuclear bodies. The normal punctate immunohistochemical staining pattern of these complexes is disrupted by viral infection or interferon treatment and in blast cells from patients with acute promyelocytic leukemia. We have characterized the murine homologue of PIC1 and have found that the predicted amino acid sequences of the mouse and human proteins are identical. High levels of Pic1 mRNA were detected in a range of mouse tissues. Pic1 genomic clones were isolated, and the organization of the gene was determined. Two processed Pic1 pseudogenes were also isolated and characterized. Through FISH, the chromosomal localizations of the mouse Pic1 gene and the two pseudogenes were determined. Human PIC1 (HGMW-approved symbol UBL1)-related sequences were isolated from human genomic DNA and were shown to represent processed pseudogenes. The role of PIC1 in a variety of cellular processes is discussed.

3T3 Cells↗
PubMed1998

The prevalence and impact of self-reported hip fracture in elderly community-dwelling women: the Women's Health and Aging Study.

To estimate the prevalence and impact of self-reported hip fracture in elderly women an age-stratified random sample of 3841 community-dwelling women aged 65 years and above were interviewed to determine the occurrence of 13 chronic conditions and difficulty performing 15 tasks. Associations were examined using multiple logistic regression analysis. The weighted prevalence of hip fracture was 4.7 per 100. Prevalence increased with increasing age from 2.9 per 100 in women aged 65-74 years to 12.6 per 100 in women aged 85 years and above, and was higher in white women than black women. Women with hip fracture were significantly more likely to report concomitant Parkinson's disease (age-adjusted odds ratio [aOR] = 2.8) and stroke (aOR = 1.8). After adjustment for potential confounding variables, women with hip fracture were significantly more likely to report difficulty performing 11 activities that map into domains of mobility/exercise tolerance, self-care tasks and higher functioning domains. Hip fracture is common among elderly community-dwelling women and is associated with difficulty in performing activities of daily living.

Activities of Daily Living↗
PubMed1998

Kinetic model of folate metabolism in nonpregnant women consuming [2H2]folic acid: isotopic labeling of urinary folate and the catabolite para-acetamidobenzoylglutamate indicates slow, intake-dependent, turnover of folate pools.

In a 10-wk study of folate metabolism in nonpregnant women (21-27 y, n -6 per group), subjects were fed a diet containing approximately 68 nmol/d (30 microg/d) folate from food. The remainder of the ingested folate was provided as folic acid in apple juice (as nonlabeled during wk 1-2, as [2H2]folic acid during wk 3-10) to yield a constant intake of 454, 680 or 907 nmol/d (200, 300 or 400 microg/d). Isotopic enrichment of total urinary folate and the primary catabolite para-acetamidobenzoylglutamate (ApABG) was determined. Isotopic enrichment of ApABG served as an indicator of labeling of tissue folates. A kinetic model consisting of fast- and slow-turnover nonsaturable pools and a saturable slow-turnover pool, with provisions for urinary and fecal excretion, catabolism and enterohepatic circulation, yielded a close fit to the data. Mean residence times for total body folate were 212, 169 and 124 d for folate intakes of 454, 680, and 907 nmol/d, respectively. The model predicted that variation in folate intake over this range had little effect on the mass of the large saturable folate pool; however, the fast-turnover nonsaturable pools increased in proportion to folate intake, whereas the slow nonsaturable pool also tended to increase. This model will aid in evaluation of folate turnover and in predicting kinetic consequences of physiologic conditions associated with altered folate requirements.

Adult↗
PubMed1998

Urinary excretion of [2H4]folate by nonpregnant women following a single oral dose of [2H4]folic acid is a functional index of folate nutritional status.

In a 10-wk study with nonpregnant women (21-27 y, n = 5-6 per group), subjects were fed a diet containing approximately 68 nmol/d (30 microg/d) folate from food that was supplemented with folic acid in apple juice to yield a constant intake of 454, 680 or 907 nmol/d (200, 300 or 400 microg/d) to evaluate folate status and long-term in vivo kinetics. Reported here is an additional phase of this protocol conducted to determine the relationship between short-term urinary excretion after a single isotopically labeled dose and various measures of folate nutritional status. It was hypothesized that urinary excretion from a single [glutamate-2H4]folic acid ([2H4]folic acid) dose would increase in proportion to folate nutritional status due to saturable cellular uptake and retention processes along with saturation of renal reabsorption. Each subject was given 1.13 micromol (500 microg) of [2H4]folic acid orally on the morning of d 70 of the study, followed by a complete 24-h urine collection. Urine was analyzed to determine the isotopic enrichment of urinary folate by gas chromatography-mass spectrometry and the concentration of urinary folate by HPLC. Urinary excretion of [2H4]folate was greatest at the 907 nmol/d intake and was positively correlated with serum folate concentration but was not correlated with erythrocyte folate. Excretion of [2H4]folate tended to be greatest when plasma homocysteine concentrations were low (<8 micromol/L), although this relation was not significant. These results suggest that 24-h urinary excretion after a single oral dose of isotopically labeled folate is a functional indicator of folate nutritional status that complements other measures of folate nutriture.

Adult↗
PubMed1998

Assessing condom use practices. Implications for evaluating method and user effectiveness.

BACKGROUND: Consistent and correct condom use remains important to human immunodeficiency virus (HIV) prevention. Although many studies evaluate consistent condom use, few examine how condoms are used during intercourse. GOALS: Assess how user practices affect exposure to risks of pregnancy and infection during condom use. STUDY DESIGN: A cross-sectional survey on condom behaviors in the past month was conducted among 98 male students attending two Georgia universities. RESULTS: Altogether, 35 of 270 total condom uses (13.0%, 95% confidence interval, 7.4-18.5) resulted in potential exposure to sexually transmitted disease and/or HIV infection or pregnancy. Both consistent and inconsistent users were similarly likely to report potential exposures during condom use. CONCLUSION: These findings suggest condom problems occur among both consistent and inconsistent users. Future studies of condom effectiveness must distinguish whether condoms were used both consistently and correctly.

Adolescent↗
PubMed1998

Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma.

Infection with Mycoplasma pneumoniae has been shown to exacerbate asthma in humans. However, the role of M. pneumoniae in the pathogenesis of chronic asthma has not been defined. Eighteen asthmatics with chronic, stable asthma and 11 nonasthmatic control subjects underwent evaluation of the upper and lower airways and serologic analysis to determine the presence of M. pneumoniae, Chlamydia pneumoniae, and seven respiratory viruses through culture, enzyme-linked immunoassay (EIA) and polymerase chain reaction (PCR). M. pneumoniae was detected by PCR in 10 of 18 asthmatics and one of 11 control subjects (p = 0.02). In nine of the 10 patients, the organism was detected in bronchoalveolar lavage or bronchial biopsies. Seven of 18 asthmatics and one of 11 control subjects were also positive for M. fermentans and M. genitalium by PCR. All patients' cultures, EIAs, and serology were negative for M. pneumoniae. All PCR and cultures were negative for C. pneumoniae, and all EIAs for respiratory viruses were negative in all subjects. Nine asthmatics and one control subject exhibited positive serology for C. pneumoniae (p = 0.05). M. pneumoniae was present in the lower airways of chronic, stable asthmatics with greater frequency than control subjects, and may play a role in the pathogenesis of chronic asthma.

Adult↗
PubMed1997

Thalidomide: lack of mutagenic activity across phyla and genetic endpoints.

The human and rabbit teratogen thalidomide has been tested for mutagenicity in a wide range of assays, ranging from bacterial gene mutation assays conducted in vitro to in vivo cytogenetic assays conducted using rabbits, and including a variety of human-derived tissues. Thalidomide was not mutagenic to 6 strains of Salmonella when tested both in the presence and absence of Aroclor-induced rat liver S9 mix. This inactivity was confirmed in strains TA98 and TA100 using a 1-h pre-incubation assay protocol with the same S9 mix (10% S9), and additionally, in strain TA98 using 3 concentrations of S9 (4%, 10% and 30% S9 in S9 mix). Thalidomide was not clastogenic either to cultured human lymphocytes (whole blood cultures, minus S9 mix) or to Chinese hamster ovary (CHO) cells treated in vitro. Further, no cytotoxicity was observed in purified human lymphocytes when exposed to thalidomide up to the limit of its solubility in the medium in the presence and absence of liver S9 from Aroclor-induced pregnant rabbit. The CHO assays were conducted without metabolic activation and in the presence of a variety of sources of auxiliary metabolic activation (PB/beta NP-induced rat liver S9 mix, pooled male and female human liver S9 mix, uninduced and Aroclor-induced pregnant rabbit liver S9 mix and foetal rabbit S9 mix). Thalidomide did not induce micronuclei in isolated human lymphocytes (minus S9 mix) and it was non-mutagenic to mouse lymphoma L5178Y TK+/- cells when tested to the limits of its solubility in the culture medium (+/- S9 mix). No indication of recombinogenic or clastogenic activity was observed for thalidomide when tested in Drosophila. In addition, it failed to induce chromosome aberrations in grasshopper neuroblasts when tested in the presence and absence of Aroclor-induced rat liver S9 mix. Some unusual chromosome morphologies were observed in the grasshopper cytogenetic preparations indicating a potential of thalidomide to interact with chromosomal proteins. However, this potential was not evident in the human lymphocyte micronucleus assay, and thalidomide was apparently not reactive to the proteins of the mouse skin, as it gave negative results in a mouse local lymph node assay for skin sensitizing agents. Thalidomide was inactive in bone marrow micronucleus assays conducted using males and females from two strains of mice, and female New Zealand white rabbits. It is concluded that thalidomide is neither a mutagen nor an aneugen. This conclusion is discussed within the context of the results of earlier mutagenicity studies, the recent claim that thalidomide may be a heritable germ cell mutagen to humans, and the current interest in thalidomide for the treatment of immune system-related diseases.

Abnormalities, Drug-Induced↗
PubMed1997

Gene structure, cDNA sequence, and expression of murine Bak, a proapoptotic Bcl-2 family member.

To facilitate the creation of Bak knockout mice and the further analysis of this Bcl-2 family member, we have isolated and sequenced the complete mouse Bak cDNA. The cDNA is 2 kb long and shares an overall nucleotide identity to the human Bak cDNA of 62%. The mouse Bak protein is 208 amino acids long with a predicted molecular weight of 23 kDa. The mouse Bak mRNA could be detected in all mouse tissues examined. In addition we mapped the murine bak gene. It consists of six exons spanning about 10 kb on chromosome 17B. The 5' region of the murine bak gene is unmethylated on the dinucleotide CpG in the area around exon 1. Furthermore, it contains potential binding sites for transcription factors such as Sp1 and c-Myb.

Amino Acid Sequence↗
PubMed1997

Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo.

The voltage activated K+ channel (Kv1.3) has recently been identified as the molecule that sets the resting membrane potential of peripheral human T lymphoid cells. In vitro studies indicate that blockage of Kv1.3 inhibits T cell activation, suggesting that Kv1.3 may be a target for immunosuppression. However, despite the in vitro evidence, there has been no in vivo demonstration that blockade of Kv1.3 will attenuate an immune response. The difficulty is due to species differences, as the channel does not set the membrane potential in rodent peripheral T cells. In this study, we show that the channel is present on peripheral T cells of miniswine. Using the peptidyl Kv1.3 inhibitor, margatoxin, we demonstrate that Kv1.3 also regulates the resting membrane potential, and that blockade of Kv1.3 inhibits, in vivo, both a delayed-type hypersensitivity reaction and an Ab response to an allogeneic challenge. In addition, prolonged Kv1.3 blockade causes reduced thymic cellularity and inhibits the thymic development of T cell subsets. These results provide in vivo evidence that Kv1.3 is a novel target for immunomodulation.

Animals↗