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Biomedical subjects

H Williams

Publications and source records attributed to H Williams.

At least 109 records · Page 6Linked to original sources
PubMed1997

Compression of nucleotide databases for fast searching.

MOTIVATION: International sequencing efforts are creating huge nucleotide databases, which are used in searching applications to locate sequences homologous to a query sequence. In such applications, it is desirable that databases are stored compactly, that sequences can be accessed independently of the order in which they were stored, and that data can be rapidly retrieved from secondary storage, since disk costs are often the bottleneck in searching. RESULTS: We present a purpose-built direct coding scheme for fast retrieval and compression of genomic nucleotide data. The scheme is lossless, readily integrated with sequence search tools, and does not require a model. Direct coding gives good compression and allows faster retrieval than with either uncompressed data or data compressed by other methods, thus yielding significant improvements in search times for high-speed homology search tools.

Algorithms↗
PubMed1997

Worldwide variations in prevalence of symptoms of allergic rhinoconjunctivitis in children: the International Study of Asthma and Allergies in Childhood (ISAAC).

BACKGROUND: As part of the International Study of Asthma and Allergies in Childhood (ISAAC), prevalence surveys were conducted among representative samples of school children from locations in Europe, Asia, Africa, Australia, North and South America. SUBJECTS: 257,800 children aged 6-7 years from 91 centres in 38 countries, and 463,801 children aged 13-14 years from 155 centres in 56 countries. METHODS: Written symptom questionnaires were translated from English into the local language for self-completion by the 13-14-year-olds and completion by the parents of the 6-7-year-olds. Rhinitis was described as a problem with sneezing, or a runny, or blocked nose when you (your child) DID NOT have a cold or the flu. Additional questions were asked about rhinitis associated with itchy-watery eyes, interference with activities and a history of hay fever ever. RESULTS: The prevalence of rhinitis with itchy-watery eyes ("rhinoconjunctivitis") in the past year varied across centres from 0.8% to 14.9% in the 6-7-year-olds and from 1.4% to 39.7% in the 13-14-year-olds. Within each age group, the global pattern was broadly consistent across each of the symptom categories. In centres of higher prevalence there was great variability in the proportion of rhinoconjunctivitis labelled as hay fever. The lowest prevalences of rhinoconjunctivitis were found in parts of eastern Europe, south and central Asia. High prevalences were reported from centres in several regions. CONCLUSION: These results suggest substantial worldwide variations in the prevalence and labelling of symptoms of allergic rhinoconjunctivitis which require further study. These differences, if real, may offer important clues to environmental influences on allergy.

Adolescent↗
PubMed1997

Correlation between self-reported cocaine use and urine toxicology in an inner-city prenatal population.

To determine the prevalence of recent cocaine use and the accuracy of self-reported use, the results of a urine assay for the major cocaine metabolite benzoylecgonine were compared with self-reported cocaine use in an inner-city prenatal population offered routine voluntary urine toxicology screening at the time of registration for prenatal care. During a 1-year period, 6866 women registered for prenatal care and 5200 (76%) consented to urine assays for cocaine metabolites. Of the women consenting to urine assays, 253 (5%) had positive assays for benzoylecgonine. Women with positive assays were significantly more likely than those with negative assays to be older (mean [SD] 27 [5] versus 23 [6] years), black, single, and unemployed. In addition, women with positive assays were significantly more likely to be multiparous, report > two sexual partners in the previous year, and acknowledge a history of a sexually transmitted disease (STD). Forty-seven percent of women with positive assays acknowledged cocaine use in the 6 months prior to sampling. Women with positive assays who denied cocaine use were significantly more likely than those who admitted use to be younger (mean [SD] 26 [5] versus 28 [4] years), to report > or = two sexual partners in the past year, and acknowledge a history of an STD. This analysis revealed a poor correlation between self-reported cocaine use and the results of urine assays for cocaine metabolites among women seeking prenatal care in an inner-city institution.

Cocaine↗
PubMed1996

Chronic recurrent multifocal osteomyelitis: spinal involvement and radiological appearances.

We report a case of chronic recurrent multifocal osteomyelitis which presented as back pain in a 14-yr-old male. The full distribution of the spinal lesions was determined by MRI, which proved to be more sensitive than other imaging modalities. After 1 yr, in spite of a good symptomatic response to corticosteroid therapy, new MRI abnormalities had developed.

Adolescent↗
PubMed1996

Linkage of rheumatoid arthritis to the candidate gene NRAMP1 on 2q35.

The macrophage resistance gene NRAMP1 regulates priming/activation of macrophages for enhanced TNF alpha, IL 1 beta, and MHC class II expression. Since all of these functions are of potential importance in the induction or maintenance or both of autoimmune disease, samples from the Arthritis and Rheumatism Council's repository of multicase rheumatoid arthritis families were typed for a dinucleotide repeat in the NRAMP1 promoter region and four other 2q34 (TNP1) or 2q35 (IL8R, VIL1, DES) marker genes. Identity by descent (IBD) sib pair analysis using a three locus haplotype NRAMP1-IL8RB-VIL1, or NRAMP1 alone, provided preliminary evidence (maximum lod score = 1.01, p = 0.024) for a gene in this region contributing to suceptibility to rheumatoid arthritis. Candidacy for NRAMP1 as the disease susceptibility gene was supported by a significant bias (p = 0.048) towards transmission of the NRAMP1 promoter region allele 3 in affected offspring.

Arthritis, Rheumatoid↗
PubMed1996

Proteoglycan-degrading activity of human stromelysin-1 and leukocyte elastase in rabbit joints. Quantitation of proteoglycan and a stromelysin-induced HABR fragment of aggrecan in synovial fluid and cartilage.

The objective of this study was to compare the specificity and potency of recombinant human SLN-1 (rhSLN) and human leukocyte elastase (HLE) as proteoglycan (PG)-degrading enzymes after intraarticular injection into rabbits. Another objective was to evaluate the elicitation of a rhSLN-induced hyaluronan-binding region (HABR) fragment from rabbit aggrecan in joints using a polyclonal antiserum (anti-FVDIPEN) against the synthetic peptide, Phe-Val-Asp-Ile-Pro-Glu-Asn (FVDIPEN). The intraarticular injection of either activated rhSLN or HLE resulted in enzyme-specific quantitative release of PG fragments into synovial fluid. Based on the criteria used herein, HLE appears to be a more potent PG-degrading enzyme than SLN. Intraarticular injection of rhSLN also resulted in time- and dose-dependent release of a new HABR fragment of aggrecan (HABR-FMDIPEN) into both articular cartilage and synovial fluid. HABR-FVDIPEN is likely to be a good marker of matrix metalloproteinase (MMP)-induced degradation of aggrecan.

Aggrecans↗
PubMed1996

Management of substance misusers on the general hospital ward.

Since a high prevalence of physical morbidity is associated with substance misuse, drug misusers are frequently admitted to general hospitals. Medical staff often perceive drug misusers as a particularly difficult patient group, feeling that they lack the knowledge and skill to deal with them adequately without specialist support. We review the common physical complications of substance misuse likely to be encountered in a general hospital, and provide comprehensive guidelines for the assessment and management of drug dependence in this setting.

Hospitalization↗
PubMed1995

Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis.

Recent studies have shown that mucocutaneous leishmaniasis (MCL), a severe and debilitating form of American cutaneous leishmaniasis (ACL) caused by Leishmania braziliensis infection, is accompanied by high circulating levels of tumor necrosis factor (TNF)-alpha. Analysis of TNF polymorphisms in Venezuelan ACL patients and endemic unaffected controls demonstrates a high relative risk (RR) of 7.5 (P < 0.001) of MCL disease in homozygotes for allele 2 of a polymorphism in intron 2 of the TNF-beta gene, especially in females (RR = 9.5; P < 0.001) compared with males (RR = 4; P < 0.05). A significantly higher frequency (P < 0.05) of allele 2 at the -308-basepair TNF-alpha gene polymorphism was also observed in MCL patients (0.18) compared with endemic control subjects (0.069), again associated with a high relative risk of disease (RR = 3.5; P < 0.05) even in the heterozygous condition. Because both the TNF-alpha and TNF-beta polymorphisms have previously been linked with functional differences in TNF-alpha levels, these data suggest that susceptibility to the mucocutaneous form of disease may be directly associated with regulatory polymorphisms affecting TNF-alpha production.

Adolescent↗
PubMed1995

Quantification of a matrix metalloproteinase-generated aggrecan G1 fragment using monospecific anti-peptide serum.

Several members of the matrix metalloproteinase family have been reported to cleave aggrecan in the interglobular domain between Asn-341 and Phe-342. An antiserum was prepared against a peptide conjugate corresponding to the C-terminal sequence of the matrix metalloproteinase-generated aggrecan G1 fragment (Phe335-Val-Asp-Ile-Pro-Glu-Asn341). A quantitative radioimmunoassay, with a limit of detection of about 80 pM, was developed using this antiserum. This antiserum requires the free carboxyl group of the C-terminal asparagine for optimal recognition. If the C-terminal asparagine is excised from the sequence, replaced with closely related amino acids, or extended across the matrix metalloproteinase cleavage site, there is a 40-10,000-fold loss in detection. Using peptides cleaved from the N-terminus, it was determined that the antiserum requires the entire Phe-Val-Asp-Ile-Pro-Glu-Asn sequence for optimal recognition. The radioimmunoassay detects matrix metalloproteinase-generated G1 fragments with similar sensitivity to the Phe-Val-Asp-Ile-Pro-Glu-Asn peptide, but it does not recognize intact aggrecan. Immunoreactive aggrecan G1 fragments of molecular mass 50 kDa are generated by the matrix metalloproteinases stromelysin and gelatinase A. In contrast, under identical conditions, the closely related metalloproteinases, gelatinase B and collagenase, as well as cathepsin G, cathepsin B and human leucocyte elastase, did not generate a G1 fragment recognized by the antiserum. The anti-Phe-Val-Asp-Ile-Pro-Glu-Asn serum detects stromelysin-generated aggrecan G1 fragments from mouse, guinea pig, rabbit and human, indicating that the detection is not species-specific. This antiserum and radio-immunoassay should be useful for quantifying and characterizing matrix metalloproteinase-generated aggrecan G1 fragments in articular cartilage and synovial fluids from humans and various animal models of articular-cartilage destruction.

Aggrecans↗
PubMed1995

An approach in the assessment of pacing hemodynamics: a comparison of VVI and DDD.

Previous methods for assessment of pacemaker hemodynamics have been limited to a rigid hospital environment. An alternative is the ambulatory ventricular function monitor (C-VEST) that, with a single injection of technetium-99m, permits the continuous measurement of relative ejection fraction (EF) and cardiac output (CO) during the activities of daily living. A study of reproducibility and a comparison of dual chamber (DDD) and fixed rate ventricular (VVI) pacing are presented. Reproducibility was assessed in six patients (4 males; mean age 58, range 27-78 years) with a mean EF of 48.5% (range 34%-62%) and DDD pacemakers, implanted for conduction abnormalities. In addition, 11 patients (7 males; mean age 55.5, range 34-75 years) with a mean EF of 48.5% (range 34%-65%), chronic complete heart block, and DDD pacemakers were used for the comparative study. After an initial multigated scan, the monitor was positioned over the left ventricle and kept in place with the plastic C-VEST. The patients undergoing the reproducibility study performed three shuttle walking tests with 20 minutes of rest in between. The patients in the comparative study were randomized to either VVI or DDD mode and performed one shuttle walking test in each pacing mode. The results confirmed that the C-VEST produces reproducible results with no significant difference in peak CO between the three shuttle walks. In addition, it confirmed previous hemodynamic studies showing that DDD pacing was superior to VVI pacing both at rest (P < 0.004) and at exercise (P < 0.002). These findings show the C-VEST to be an extremely useful tool for the hemodynamic assessment of pacemaker patients.

Adult↗
PubMed1995

The effect of simultaneous intravenous administration of nitroglycerin and heparin on partial thromboplastin time.

The purpose of this study was to determine whether intravenous nitroglycerin, when infused simultaneously through the same tubing with heparin, alters the anticoagulant effect of heparin as evidenced by partial thromboplastin time (PTT) values. A time series, cross-over design was used. The study included patients admitted to the Coronary Care Unit with a diagnosis of unstable angina. Patients were randomly assigned to one of two treatment groups: (1) heparin/nitroglycerin infused in the same site or (2) heparin/nitroglycerin infused in separate sites. After 18 hours, treatments were reversed. PTT results were measured seven times per subject. Ninety-eight subjects, 70 males and 28 females, participated. Mean age was 62.4 +/- 9 years. Using repeated measures analysis of variance, there was no change in the patients' PTTs (p = 0.47). Prior to this study, research was divided on whether nitroglycerin interferes with heparin's activity. This study indicates no significant difference in PTT in subjects receiving these infusions via separate or the same intravenous sites.

Adult↗
PubMed1995

Genomic organization and sequence of the human NRAMP gene: identification and mapping of a promoter region polymorphism.

BACKGROUND: Murine Nramp is a candidate for the macrophage resistance gene Ity/Lsh/Bcg. Sequence analysis of human NRAMP was undertaken to determine its role in man. MATERIALS AND METHODS: A yeast artificial chromosome carrying NRAMP was subcloned and positive clones sequenced. The transcriptional start site was mapped using 5' RACE PCR. Polymorphic variants were amplified by PCR. Linkage analysis was used to map NRAMP. RESULTS: NRAMP spans 12kb and has 15 exons encoding a 550 amino acid protein showing 85% identity (92% similarity) with Nramp. Two conserved PKC sites occur in exon 2 encoding the Pro/Ser rich SH3 binding domain, and in exon 3. Striking sequence similarities (57 and 53%) were observed with yeast mitochondrial proteins, SMF1 and SMF2, especially within putative functional domains: exon 6 encoding the second transmembrane spanning domain, site of the murine susceptibility mutation; and exon 11 encoding a conserved transport motif. No mutations comparable to the murine susceptibility mutation were found. The transcriptional initiation site mapped 148 bp 5' of the translational initiation codon. 440bp of 5' flanking sequence contained putative promoter region elements: 6 interferon-gamma response elements, 3 W-elements, 3 NF kappa B binding sites and 1 AP-1 site. Nine purine-rich GGAA core motifs for the myeloid-specific PU.1 transcription factor were identified, two combining with imperfect AP1-like sites to create PEA3 motifs. TATA, GC and CCAAT boxes were absent. A possible enhancer element containing the Z-DNA forming dinucleotide repeat t(gt),ac(gt),ac(gt),g was polymorphic (4 alleles; n = 4,9,10,11), and was used to map NRAMP to 2q35. CONCLUSIONS: This analysis provides important resources to study the role of NRAMP in human disease.

Alleles↗
PubMed1995

Enhanced preservation of the auditory nerve following cochlear perfusion with nerve growth factors.

Survival of auditory neurons in the cochlea is thought to be an important factor in the success of cochlear implantations. Damage to the cochlear end-organ often produces loss of dendrites in the osseous spiral lamina. The authors have established a method that delivers water soluble pharmacologic agents to the cochlea using a mini osmotic pump with a polyethylene cannula that is inserted into the scala tympani via cochleostomy. The cannula is filled with an ototoxic agent, neomycin, that destroys the end-organ over the first 24 hours after insertion. Nerve growth factor (NGF), or a control substance, is placed in the pump reservoir and is pumped into the cochlea over a 2-week period. In this study, auditory nerve fibers in the osseous spiral lamina were counted in the apical, middle, and basal turns of the cochlea in 16 guinea pigs. At each location, fiber counts were significantly higher when neomycin was followed by perfusion with NGF, than when it was followed by infusion with control substances. The study demonstrates that NGF confers some protection against ototoxic induced degeneration of the auditory nerve in vivo.

Animals↗
PubMed1995

An extended study: protective effects of nerve growth factor in neomycin-induced auditory neural degeneration.

Intracochlear survival of auditory neurons is thought to be a factor contributing to the success of cochlear implantations. Damage to the cochlear end-organ is frequently associated with loss of neurites in the osseous spiral lamina. The authors have previously reported a model for long-term intracochlear administration of pharmacologic agents using a technique and device analogous to a cochlear implant. These studies suggest that nerve growth factor (NGF) protects the auditory nerve from the immediate neurotoxic effects of neomycin. The intent of the present investigation is to determine whether NGF can protect auditory neural elements from neomycin-induced degeneration after several weeks have elapsed between the neomycin perfusion and the administration of NGF. Neomycin was infused over 24 hours through an indwelling, intracochlear cannula attached to a mini osmotic pump to unilaterally destroy the cochlear end-organ. The pump perfused the cochlea with artificial perilymph for 2 weeks. Then, the pump reservoirs were surgically replaced; the new reservoirs delivered either NGF or artificial perilymph for an additional 2 weeks. Spiral ganglion cell densities were measured along Rosenthal's canal in the basal, middle, and apical cochlear turns. This investigation revealed that NGF prevented auditory nerve degeneration over the 2-week period, when compared to controls, and that the protective effect was greatest in the neural elements closest to the source of NGF.

Animals↗
PubMed1995

Verlukast (MK-0679) conjugation with glutathione by rat liver and kidney cytosols and excretion in the bile.

Verlukast (MK-0679) is a potent leukotriene D4 antagonist that was under development for the treatment of bronchial asthma. A previously uncharacterized metabolite of verlukast was formed in incubations using rat liver cytosol fortified with glutathione (GSH). The metabolite was detected by HPLC and characterized by UV spectroscopy (photodiode array detection after HPLC) and capillary HPLC continuous flow-liquid secondary-ion mass spectrometry. After a large-scale incubation and isolation, it was further characterized by 500 MHz proton NMR. The metabolite is a 1,4-Michael addition product in which GSH has added to position 12 of the styryl quinoline double bond of verlukast. There is no apparent stereoselectivity because a mixture of the two possible isomers, in equal amounts, was observed by NMR. Although there was spontaneous chemical addition of GSH to verlukast (0.18 nmol/min), the reaction was shown to be enzyme-catalyzed in studies using three different preparations of rat liver cytosol at pH 7.4. Using Lineweaver-Burk analysis of experiments in which the effect of verlukast concentration on the rate of conjugation was studied, the apparent KM and Vmax were determined to be 107 +/- 22 microM (SD, N=3) and 0.66 +/- 0.21 nmol/min/mg protein, respectively. In similar studies with GSH as the variable substrate, the apparent KM and Vmax were 2.32 +/- 0.68 mM and 0.69 +/- 0.14 nmol/min/mg protein, respectively. Incubations with kidney cytosol produced the GSH, cysteinylglycine, and cysteine conjugates of verlukast. In bile collected from rats dosed intravenously with 50 mg/kg of verlukast, approximately 80% of the dose was recovered up to 4 hr postdose. The GSH conjugate accounted for 16.5% of the dose. The cysteinylglycine, cysteine, and N-acetylcysteine conjugates were observed and together accounted for 7.5%. Verlukast accounted for 14.5%, and the remainder of the metabolites (40.5%) were oxidation or acyl glucuronide metabolites.

Animals↗