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Biomedical subjects

J Ireland

Publications and source records attributed to J Ireland.

At least 37 records · Page 2Linked to original sources
PubMed1999

Characterization of single-nucleotide polymorphisms in coding regions of human genes.

A major goal in human genetics is to understand the role of common genetic variants in susceptibility to common diseases. This will require characterizing the nature of gene variation in human populations, assembling an extensive catalogue of single-nucleotide polymorphisms (SNPs) in candidate genes and performing association studies for particular diseases. At present, our knowledge of human gene variation remains rudimentary. Here we describe a systematic survey of SNPs in the coding regions of human genes. We identified SNPs in 106 genes relevant to cardiovascular disease, endocrinology and neuropsychiatry by screening an average of 114 independent alleles using 2 independent screening methods. To ensure high accuracy, all reported SNPs were confirmed by DNA sequencing. We identified 560 SNPs, including 392 coding-region SNPs (cSNPs) divided roughly equally between those causing synonymous and non-synonymous changes. We observed different rates of polymorphism among classes of sites within genes (non-coding, degenerate and non-degenerate) as well as between genes. The cSNPs most likely to influence disease, those that alter the amino acid sequence of the encoded protein, are found at a lower rate and with lower allele frequencies than silent substitutions. This likely reflects selection acting against deleterious alleles during human evolution. The lower allele frequency of missense cSNPs has implications for the compilation of a comprehensive catalogue, as well as for the subsequent application to disease association.

Alleles↗
PubMed1999

Failed adoptive immunity transfer: reactivation or reinfection?

A 26-year-old female bone marrow transplant (BMT) recipient was hepatitis B surface antigen (HBsAg) and hepatitis B e antibody (HBeAb) positive. The donor, her human leucocyte antigen (HLA)-compatible sister, was HBsAg negative but hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) positive. Twelve weeks post-BMT the patient became HBsAg negative, as determined using a monoclonal antibody-based assay. At 16 weeks post-BMT, HBsAg became undetectable by monoclonal and polyclonal immunoassay with seroconversion to HBsAb; however, at 24 weeks post-BMT the patient again became HBsAg positive. Both the recipient and the donor were retrospectively tested by hepatitis B virus (HBV) polymerase chain reaction (PCR) and found to be positive. The recipient displayed variants at amino acids 4 and 47 of the surface (S) gene prior to BMT. These mutations were not detected 32 weeks post-BMT when the S gene sequence was identical to that of an adr prototype. The donor was found to have four unique amino acid substitutions at positions 30, 98, 101 and 210 of the S gene. However, in vitro-expressed HBsAg from the donor was detected by commercial kits and an immunofluorescence assay, indicating that antigenic alteration did not explain HBsAg negativity. This donor highlights the value of PCR as the gold standard test for current HBV infection. It also demonstrates that discordance between two commercial HBsAg assays may not always be caused by antigenic variants. The second episode of hepatitis may theoretically have been caused by reactivation, selection of an escape mutant by HBsAb, reinfection or recombination. We suggest it was reactivation because none of the donor variants was seen in the recipient post-BMT.

Adoptive Transfer↗
PubMed1999

The topical microbicide PRO 2000 protects against genital herpes infection in a mouse model.

Vaginal gel formulations containing the naphthalene sulfonate polymer PRO 2000 are being developed as topical microbicides to protect against infection with sexually transmitted disease (STD) pathogens. A mouse model was used to determine whether PRO 2000 could protect against genital herpes in vivo. Animals received a single intravaginal application of 15 microL of a 10% PRO 2000 aqueous solution or a 4.0% or 0.5% PRO 2000 vaginal gel formulation 20 s prior to intravaginal challenge with 4.0 log10 pfu of herpes simplex virus type 2. Treatment with the 4.0% gel provided complete protection against infection; treatment with the 0.5% gel or 10% solution provided 81% and 80% protection, respectively. Furthermore, the 4% gel provided significant protection even when viral challenge was delayed until 60 min after treatment. This is the first report to show that PRO 2000 can protect against infection with an STD pathogen in vivo.

Administration, Topical↗
PubMed1998

PMA/ionomycin induces Ig kappa 3' enhancer activity which is in part mediated by a unique NFAT transcription complex.

The Ig kappa 3' enhancer is required for high levels of Ig kappa gene expression. We now show that kappa 3' enhancer function increases five- to eightfold after stimulation of primary murine B cells with phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin. In the presence of cyclosporin A this induction is almost halved, suggesting that transcription factors of the NFAT family contribute to kappa 3' enhancer induction. Indeed, we identify a novel NFAT binding site which is required for full enhancer function. We find that this site is transcriptionally active in stimulated B cells, T cells and fibroblasts and that both PMA and ionomycin are required for maximal induction. Time course analysis of the components of the protein-DNA complex in primary lymphocytes reveals that both NFATp and NFATc are present in the complex after 15 min, while only NFATc is detectable after 4 h. This suggests that NFATc plays the dominant role in controlling long-term responses of this transcription factor family. Furthermore, JunB, JunD, FosB and cFos form part of the DNA-protein complex in Bal-17 B cells. Complex formation as well as transcriptional activity can also be induced by crosslinking of surface Ig. We have, thus, identified a unique NFAT complex in B cells that contributes to Ig kappa gene expression.

Animals↗
PubMed1998

Derivation of a homesickness scale.

A 33-item measure of homesickness (the Homesickness Questionnaire, HQ) was derived from features of grief modified for the circumstance of separation from home. In three samples of year 1 students (N = 264) during their first year at university, total HQ scores were highly correlated with a single-item measure of homesickness used in previous studies, and 28 items showed significant differences between subgroups divided on the basis of the single-item scores. Previous findings that homesick students show more health and psychological symptoms, and cognitive failures, were supported by further comparisons between the two groups, and a meta-analysis of four studies. Factor analysis of the HQ indicated two factors, disliking the university, and attachment to the home, which are consistent with both the separation and strain models of homesickness. Correlations with other variables, and sex differences in the factor scores, further supported the distinction between these two aspects of homesickness. Women showed higher levels of intrusive thinking about the homesickness, but this was mediated by their higher scores on the attachment factor of the HQ. There was no sex difference in avoidant responses to homesickness.

Adaptation, Psychological↗
PubMed1998

Lung function in South African children with cystic fibrosis.

OBJECTIVE: To determine the pattern of lung function in stable cystic fibrosis (CF) patients and to investigate the relationship of abnormal lung function to demographic variables, CF genotype and pulmonary colonisation with Pseudomonas aeruginosa (PA). DESIGN: A descriptive study done at the CF clinic at Red Cross War Memorial Children's Hospital in Cape Town. METHODS: Data were recorded and pulmonary function testing (PFT) was performed in 42 CF patients. RESULTS: 29 patients (69%) had mild disease, while 11 (26%) and 2 (5%) had moderate and severe disease respectively. Twenty-four patients (57%) demonstrated lower airway obstruction (LAO). Patients with moderate or severe disease were significantly older than those with mild disease (13.3 (3.7) years (mean (SD)) compared with 11.1 (3.0) years (t = 2.1; P = 0.04). PA colonisation status differed significantly with the pattern of lung function (chi 2 = 6.6; P = 0.04) and severity of lung disease (chi 2 = 12.6; P = 0.002). Nine (35%) of the 26 patients tested before and after bronchodilator therapy showed a positive response. CONCLUSION: The majority of patients had mildly impaired or normal lung function, with LAO predominating. A minority of patients were bronchodilator-responsive. PA colonisation may be associated with the development of abnormal lung function and more severe pulmonary disease.

Adolescent↗
PubMed1996

Absorption and presystemic metabolism of selegiline hydrochloride at different regions in the gastrointestinal tract in healthy males.

PURPOSE: The absorption and disposition of selegiline (SEL) and its metabolites N-desmethylselegiline (DMS), L-methamphetamine (MET), and L-amphetamine (AMP) were assessed in 8 healthy male volunteers at proximal and distal regions of the intestine relative to oral administration (in the stomach) to determine if intestinal site dependence contributed to the erratic oral absorption of selegiline hydrochloride which is manifest as low and variable bioavailability. METHODS: An open-label, four-way crossover, single dose pharmacokinetic study comparing the bioavailability of 10 mg selegiline hydrochloride administered to healthy young males as a solution by the oral route (in the stomach) and by a nasoenteric tube to the following three sites: duodenum, jejunum and terminal ileum was conducted. Infusions were administered over a 1 minute interval and a two week washout was observed between treatments. Samples were taken over 96 hours and analyzed by LC/MS/MS. RESULTS: Selegiline exposure was greatest following administration to the stomach (approximately 150% > duodenum or jejunum) and least in the terminal ileum (approximately 33% less than duodenum or jejunum). Duodenal and jejunal sites were equivocal based on selegiline absorption and subsequent metabolism. While both AMP and MET exposure was equivalent at all dosing sites, DMS exposure was less (approximately 18%) at the terminal ileum. CONCLUSIONS: The oral absorption of selegiline is neither permeability-limited or intestinal site-dependent. Stomach absorption may bypass presystemic metabolism. The reduced DMS exposure at the terminal ileum is consistent with the theorized presystemic formation of DMS via luminal P450 enzymes and the density of these enzymes in the duodenum and jejunum relative to the ileum. AMP and MET metabolites were insensitive to dosing site consistent with their hepatic formation. The true magnitude of these effects would require multiple dosing as single dose pharmacokinetics do not predict the extent of multiple dose selegiline exposure.

Administration, Oral↗
PubMed1995

Repression of the immunoglobulin heavy chain 3' enhancer by helix-loop-helix protein Id3 via a functionally important E47/E12 binding site: implications for developmental control of enhancer function.

The activity of the immunoglobulin 3' enhancer is restricted to the late stages of B lymphoid development. Here we further examine the molecular basis for the temporally restricted activity of the B-lymphoid IgH 3' enhancer. We demonstrate that a binding site (E5 site) for the E47 and/or E12 proteins is functionally important for enhancer activity. The multimerized E5 site acts as a B cell-specific enhancer and, when assayed in COS cells, can be transactivated by E47/E12 proteins. This transactivation in COS cells, as well as the activity of the full length 3' enhancer in plasma cells, can be repressed by overexpression of the dominant negative nuclear regulator Id3. When examining the tissue distribution of Id3 in murine cell lines, we find that Id3 is expressed throughout the pre-B and B cell stages, but is down-regulated at the plasma cell stage. Thus, Id3 may contribute to the temporal regulation of the IgH 3' enhancer.

Animals↗
PubMed1994

Activation of the immunoglobulin kappa 3' enhancer in pre-B cells correlates with the suppression of a nuclear factor binding to a sequence flanking the active core.

Both the kappa intron and the kappa 3' enhancer are required for high levels of immunoglobulin kappa gene expression. The activity of both enhancer elements can be induced by LPS in pre-B cells. While the LPS induction of the kappa intron enhancer is mediated by NF-kappa B, this factor is not responsible for activation of the 3' enhancer. Dissection of the 3' enhancer has shown that in pre-B cells the activity of the kappa 3' enhancer is repressed by a region flanking an active core element. We have now scanned this flanking region for nuclear factor binding sites and have identified sites for B-cell specific E47/E12-like proteins and two ubiquitous nuclear proteins. Furthermore, we have identified a nuclear factor in pre-B cells whose binding activity is suppressed in response to LPS. In its tissue-distribution and binding specificity this factor appears to be identical to the lymphoid specific protein LEF-1. The position of the LEF-1 binding site within the 3' enhancer and its response to LPS raise the possibility that LEF-1 may be the target for a second pathway able to mediate LPS induction of immunoglobulin kappa gene transcription.

Animals↗
PubMed1993

Meniscal nodule.

Explore the source record for details and available documents.

Adult↗
PubMed1993

Robust and inexpensive equipment design for polymerase chain reaction detection of sequence mutations. Cystic fibrosis in a mother and 2 children analysed.

Every polymerase chain reaction (PCR) requires use of a temperature cycler for about 3 hours. Since there are many diagnostic tests using this technology, it is important that robust but inexpensive machinery is available. Such a stand-alone machine has been designed and used to analyse an interesting family in which a mother and her 2 children were diagnosed as having cystic fibrosis.

Adult↗
PubMed1990

Utilisation of outpatient services at Red Cross War Memorial Children's Hospital, Cape Town.

The demand for outpatient services continues to grow at Red Cross War Memorial Children's Hospital (RCCH). To determine current utilisation patterns, we conducted a 2-week survey in the outpatient department (OPD). In addition, we reviewed the RCCH Annual Reports for the period 1961-1988. Annual outpatient attendances have increased from around 42,000 in 1957 to their highest level ever; nearly 350,000 in 1988. This steady rise in outpatient attendance was stemmed during the 1970s by the expansion of health services in the greater Cape Town area, in particular the introduction of day hospitals. In general, blacks are utilising the OPD as a primary community hospital for the treatment of infectious and environmentally induced diseases. In contrast, the white outpatient profile is more characteristic of a tertiary referral centre, with a higher proportion of specialist clinic attendances. The utilisation patterns for coloured children are intermediate. Analysis of the residential address of patients and their presenting diagnoses indicates an urgent demand for primary health care services in the most recently settled and poorest suburbs of Cape Town, many of which are remote from the hospital.

Black or African American↗
PubMed1990

Bilateral arthrography of the wrist.

In order to determine the true significance of a positive arthrogram in the investigation of wrist pain, a prospective trial was carried out in 60 patients, using the opposite asymptomatic wrist as a control. Of the 46 patients with positive findings in the symptomatic wrist, 34 (74%), had positive arthrograms in the opposite, asymptomatic, wrist. As a result of this, we conclude that a unilateral arthrogram is of little diagnostic value and we recommend the use of the opposite, asymptomatic, wrist as a control.

Adolescent↗
PubMed1990

Clinical trial of 'off diet' older phenylketonurics with a new phenylalanine-free product.

Ten PKU subjects were treated with Product 196 for one year. Product 196 is a special phenylalanine-free dietary supplement consisting primarily of essential amino acids, carbohydrate, Vitamin C and some minerals, made by Scientific Hospital Supplies Limited, Liverpool, England. It is intended for persons with phenylketonuria who are not consuming a phenylalanine-restricted diet. During the year that the 10 subjects were on the product, they remained asymptomatic, maintained their weight and appeared healthy. Subjective behavioural improvement was noted in six but no significant changes in intelligence were noted.

Adolescent↗