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J Worthington

Publications and source records attributed to J Worthington.

At least 19 recordsLinked to original sources
PubMed1998

Integrated microsatellite markers suitable for genetic studies of cytokine genes.

A panel of 13 highly informative dinucleotide repeats which are genetic markers for 17 cytokine genes and receptors is described. The marker panel is designed for use in fluorescence based semi-automated genotyping, with primers designed and labelled such that all 13 markers can be analysed in a single lane of a gel. Cytokine and cytokine receptors have a potential role in many diseases and pathological processes. Evidence suggests that cytokine production in vivo is influenced by polymorphisms within regulatory sequences of these genes. Genetic investigation of disease genes often requires genotyping of very large numbers of individuals. This panel of markers will, therefore, provide a useful tool to those wishing to undertake family-based linkage analysis studies of cytokine genes or large-scale association studies.

Alleles↗
PubMed1997

Variation in emergency department use of cervical spine radiography for alert, stable trauma patients.

OBJECTIVE: To, assess the emergency department use of cervical spine radiography for alert, stable adult trauma patients in terms of utilization, yield for injury and variation in practices among hospitals and physicians. DESIGN: Retrospective survey of health records. SETTING: Emergency departments of 6 teaching and 2 community hospitals in Ontario and British Columbia. PATIENTS: Consecutive alert, stable adult trauma patients seen with potential cervical spine injury between July 1, 1994, and June 30, 1995. MAIN OUTCOME MEASURES: Total number of eligible patients, referral for cervical spine radiography (overall, by hospital and by physician), presence of cervical spine injury, patient characteristics and hospitals associated with use of radiography. RESULTS: Of 6855 eligible patients, cervical spine radiography was ordered for 3979 (58.0%). Only 60 (0.9%) patients were found to have an acute cervical spine injury (fracture, dislocation or ligamentous instability); 98.5% of the radiographic films were negative for any significant abnormality. The demographic and clinical characteristics of the patients were similar across the 8 hospitals, and no cervical spine injuries were missed. Significant variation was found among the 8 hospitals in the rate of ordering radiography (p < 0.0001), from a low of 37.0% to a high of 72.5%. After possible differences in case severity and patient characteristics at each hospital were controlled for, logistic regression analysis revealed that 6 of the hospitals were significantly associated with the use of radiography. At 7 hospitals, there was significant variation in the rate of ordering radiography among the attending emergency physicians (p < 0.05), from a low of 15.6% to a high of 91.5%. CONCLUSIONS: Despite considerable variation among institutions and individual physicians in the ordering of cervical spine radiography for alert, stable trauma patients with similar characteristics, no cervical spine injuries were missed. The number of radiographic films showing signs of abnormality was extremely low at all hospitals. The findings suggest that cervical spine radiography could be used more efficiently, possibly with the help of a clinical decision rule.

Adolescent↗
PubMed1997

Multipoint analysis of quantitative traits.

Complete multipoint analysis as implemented by MAPMAKER/SIBS was used to identify the chromosomal regions with the strongest evidence of linkage. Three different quantitative sib-pair methods were compared. For each trait the maximum lod/Z score was used to implicate a chromosomal region. For trait Q5, chromosome 5, the analysis was repeated in a second data set to test for replication of the result from the first data set. The initial screen was carried out using complete parental information and the first sibling pair from each nuclear family. The effect of removing the parental genotypes and the use of multiple independent sibs was examined in the second data set for Q5, chromosome 5.

Chromosome Mapping↗
PubMed1997

Allelic markers close to prolactin are associated with HLA-DRB1 susceptibility alleles among women with rheumatoid arthritis and systemic lupus erythematosus.

OBJECTIVE: To investigate linkage disequilibrium between HLA-DRB1 disease susceptibility alleles and microsatellite markers close to the prolactin gene, among women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and normal controls. METHODS: DNA from 89 women with RA, 76 women with SLE, and 94 controls was typed for HLA-DRB1 status and D6S422 and D6S285, 2 highly polymorphic microsatellite markers close to the prolactin gene. RA patients were stratified by DRB1*0401 status, and SLE patients were stratified by *0301 status. RESULTS: There was an excess frequency of D6S422*1 among SLE patients with DRB1*0301 (odds ratio [OR] 3.1). The frequency of this allele was also slightly in excess among RA patients with DRB1*0401 (OR 1.9). D6S285*5 was also in excess among female RA patients with DRB1*0401 (OR 3.5), and was slightly increased among female SLE patients with DRB1*0301. None of these alleles were found to be increased among *0401-positive or *0301-positive controls. CONCLUSION: These data indicate that there may be linkage disequilibrium between HLA-DRB1 alleles and microsatellite marker alleles close to the prolactin gene among women with RA and SLE. This suggests the possibility of extended haplotypes encoding for HLA-DRB1 susceptibility and high prolactin production, which contribute to susceptibility to both RA and SLE.

Alleles↗
PubMed1997

Variation in ED use of computed tomography for patients with minor head injury.

STUDY OBJECTIVE: To determine the frequency of utilization, yield for brain injury, incidence of missed injury, and variation in the use of computed tomography (CT) for ED patients with minor head injury. METHODS: This retrospective health records survey was conducted over a 12-month period in the EDs at seven Canadian teaching institutions. Included in this review were adult patients who sustained acute minor head injury, defined as witnessed loss of consciousness or amnesia and a Glasgow Coma Scale score of 13 or greater. Data were collected by research assistants who were trained to select cases and abstract data in a standardized fashion according to a resource manual. Subsequently, patient eligibility was reviewed by the study coordinator and principal investigator. RESULTS: Of the 1,699 patients seen, 521 (30.7%) were referred for CT, and 418 (79.8%) of these scans were negative for any type of brain injury. Overall, 105 (6.2%) of these patients sustained acute brain injury, including 9 (.5%) with an epidural hematoma Cochran's Q test for homogeneity demonstrated significant variation between the seven centers for rate of ordering CT (P < .0001), from a low of 15.9% to a high of 70.4%. All five cases of "missed" hematoma occurred at the institutions with the highest and third highest rates of CT use. After controlling for possible differences in case severity and patient characteristics at each hospital, logistic regression analysis revealed that five of seven hospitals were significantly associated with the use of CT (respected odds ratios [OR], .4, .5, .5, 3.2, and 4.7). Three of the centers (two with the highest ordering rates) showed significant heterogeneity in the ordering of CT among their attending staff physicians, from a low of 6.5% to a high of 80.0%. CONCLUSION: There was considerable variation among institutions and individual physicians in the ordering of CT for patients with minor head injury. Although emergency physicians were selective when ordering CT, the yield of radiography was very low at all hospitals. None of the cases of "missed" intracranial hematoma came from the lowest ordering institutions, indicating that patients may be managed safely with a selective approach to CT use. These findings suggest great potential for more standardized and efficient use of CT of the head, possibly through the use of a clinical decision rule.

Adolescent↗
PubMed1997

TNF microsatellite a2, b3 and d2 alleles are associated with systemic lupus erythematosus.

We have investigated TNF microsatellite polymorphisms in SLE and their association with both HLA class II alleles and disease expression. A total of 91 Caucasoid SLE and 109 matched Caucasoid controls were recruited for this study. TNF microsatellites a, b and d were typed using fluorescent based semi-automated gene scanning. TNF a2, b3 and d2 allele frequencies were significantly increased in the SLE group compared to controls. These alleles were found to be part of an extended HLA-DRB1*0301 haplotype and have previously been associated with high TNF-alpha production. When the SLE group was analyzed according to presentation of certain clinical features, photosensitivity and Raynaud's phenomenon, the frequency of these alleles (TNF a2, b3 and d2) were also significantly increased. No significant increase in the allele frequencies of TNF a2, b3 and d2 was demonstrated in the group of patients with renal involvement. These data suggest that TNF microsatellite alleles are not independent of HLA associations in SLE and may be important in the expression of certain clinical features in SLE.

Alleles↗
PubMed1997

Happy families.

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Ethics, Medical↗
PubMed1997

Investigation of candidate disease susceptibility genes in rheumatoid arthritis: principles and strategies.

It has been estimated that a number of non-HLA susceptibility loci exist in rheumatoid arthritis (RA), each making relatively small contributions (lambda s < 2). Previous approaches for whole genome screening are unlikely to be sufficiently sensitive to detect such loci. As the pathology of RA already indicates several molecules that may be of potential importance in disease susceptibility, we propose an alternative approach, targeting candidate genes directly. Highly polymorphic dinucleotide markers within a candidate gene sequence or close to the gene can be used as markers, and the selection of the most appropriate markers is discussed. RA sibling pair families from the Arthritis and Rheumatism Council National Repository (n = 200) are used in linkage analysis studies. The data generated are analyzed using sib pair analysis methods to examine evidence of linkage. The interpretation of such results is also discussed, in particular, minimizing the possibility of type I errors, and the interpretation of negative results.

Arthritis, Rheumatoid↗
PubMed1997

The sensitivity of different analytical methods to detect disease susceptibility genes in rheumatoid arthritis sibling pair families.

Our aim was to compare the sensitivity of 4 analytical methods to detect linkage to a known disease susceptibility locus, HLA-DRB1, in 100 rheumatoid arthritis sibling pair families with incomplete parental genotype information. Genotypes for the HLA-DRB1 and HLA-A loci were analyzed using (1) identity-by-descent (IBD), considering inheritance of maternal and paternal alleles separately; (2) maximum likelihood score-IBD (MLS-IBD), which infers missing parental genotypes; (3) identity-by-state (IBS), which does not require parental genotypes; and (4) transmission disequilibrium test (TDT), which uses affected offspring with a heterozygous parent. Due to the small number of informative meoisis for HLA-DRB1, the IBD analysis was not significant for linkage (p = 0.014). HLA-A was more informative (p = 0.0002). The MLS-IBD method for HLA-DRB1 (p = 0.00004) and HLA-A (p < or = 0.00001) was significant. Using IBS both loci gave highly significant evidence of linkage, (p < < 0.00001). The TDT detected HLA-DRB1*0401 as the allele associated with RA; no HLA-A allele was associated. Thus, sib pair families with limited parental genotypes can be used to detect disease susceptibility loci, but when selecting the method of analysis the informativeness of the markers should be taken into account.

Arthritis, Rheumatoid↗
PubMed1997

Tumor necrosis factor microsatellite haplotypes are different in male and female patients with RA.

We investigated whether tumor necrosis factor (TNF) microsatellite polymorphisms are associated with sex and age at disease onset in rheumatoid arthritis (RA). A case-control study was used to compare the frequencies of TNF microsatellite alleles in 181 Caucasian RA cases and 251 controls. TNF microsatellite genotyping was performed using fluorescent based polymerase chain reaction (PCR) techniques and HLA-DR typing using PCR based sequence specific oligonucleotide probing. The association of TNF microsatellite alleles a6, b5, and d4 with RA was confirmed. These polymorphisms were more frequent in female patients. Male patients with RA with young age at onset had a different TNF microsatellite profile, TNFa2, b1, and c2 being the most frequent. TNF microsatellite polymorphisms are different in male and female patients with RA. This difference was more obvious in patients stratified according to age at onset. Sex and age at onset should be considered in studies of genetic factors in RA.

Adult↗
PubMed1997

Linkage and association studies of the natural resistance associated macrophage protein 1 (NRAMP1) locus in rheumatoid arthritis.

OBJECTIVE: To determine if there is any evidence of linkage between the natural resistance associated macrophage protein gene, NRAMP1, and rheumatoid arthritis (RA). METHODS: Two dinucleotide markers, D2S1471, a highly polymorphic marker within 160 kb of NRAMP1, and a less polymorphic marker in the promoter region of NRAMP1, have been analyzed in 115 affected sib-pair RA families (35 with 2 parents, 18 with one parent) from the Arthritis and Rheumatism Council (ARC) National Repository and an additional 85 probands from the ARC National Twin Study and 96 controls. Individuals were typed for both markers by fluorescence based semiautomated polymerase chain reaction analysis. RESULTS: No evidence of increased allele sharing in affected sib-pairs was obtained using identity by descent (IBD), identity by state, and maximum likelihood score (MLS) analysis for the whole data set. A significant increase in allele sharing was observed with marker D2S1471 (LOD 0.74; p 0.05) in the HLA discordant subgroup using IBD and MLS-IBD. No significant differences in allele frequencies were observed for any markers in the association study. CONCLUSION: In a subset of sib-pairs that shared one or zero HLA haplotypes, LOD scores suggestive of linkage were observed. This suggests a role for NRAMP1 polymorphism in a subset of patients who do not possess HLA susceptibility alleles.

Alleles↗
PubMed1997

Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus.

OBJECTIVE: To investigate interleukin 10 (IL-10) gene promoter polymorphisms in systemic lupus erythematosus (SLE) and its clinical subsets. METHODS: DNA from 76 Caucasian patients with SLE and 119 controls as genotyped for 3 defined dimorphic polymorphisms (G or A at position -1082, C or T at position -819, C or A at position -592) in the promoter region of the IL-10 gene, using the polymerase chain reaction to amplify the IL-10 gene promoter and oligonucleotide probes specific for each allelic sequence. The frequency of genotypes was compared between patients with SLE and controls, and between clinical subsets of patients with the disease. RESULTS: There was no significant change in the allele frequency of the three IL-10 gene promoter dimorphic polymorphisms in the SLE group compared with controls. However, when subgrouped according to autoantibody status and clinical features, IL-10 -1082*G, -819*C, and -592*C alleles were increased in patients possessing Ro autoantibodies and those with renal involvement. These alleles are in preferential allelic association, namely GCC, ACC, and ATA haplotypes, and the GCC haplotype was increased in these patient subgroups. CONCLUSION: Polymorphisms within the IL-10 gene promoter that are associated with high IL-10 levels may be important in the development of certain clinical features in SLE.

Adolescent↗
PubMed1996

Are both genetic and reproductive associations with rheumatoid arthritis linked to prolactin?

The risk of rheumatoid arthritis (RA) seems to be associated with reduced fecundity and with breastfeeding; these apparently contradictory risk factors can be explained by their association with high prolactin concentrations. The only consistent genetic association with RA is for genes encoded in the HLA complex, particularly HLA DR4. We have identified some data indicating that the effects of breastfeeding and nulliparity are modified by HLA DR4 status, suggesting an interaction between genetic and reproductive risk factors in the aetiology of RA. The prolactin gene is in close proximity to the HLA region on the short arm of chromosome six. We therefore propose the hypothesis that the associations between DR4 and reproductive risk factors in RA are due to linkage disequilibrium between DR4 and an abnormally regulated prolactin gene polymorphism.

Arthritis, Rheumatoid↗
PubMed1996

Association of tumor necrosis factor microsatellite polymorphisms with HLA-DRB1*04-bearing haplotypes in rheumatoid arthritis patients.

OBJECTIVE: To investigate 1) tumor necrosis factor (TNF) microsatellite allele frequencies in rheumatoid arthritis (RA), and 2) associations between TNF microsatellites and RA-associated HLA specificities in order to build up extended HLA haplotypes. METHODS: Eighty-five caucasoid patients with RA and 109 healthy caucasoid controls were typed for TNF microsatellites a-d using fluorescent-labeled primers and semiautomated genotyping. A further 56 RA patients who were selected for having certain HLA-DRB1 types were also typed for these TNF microsatellites. Linkage disequilibria between TNF and HLA alleles were calculated, and extended haplotypes were established. RESULTS: The TNFa6 allele frequency was significantly increased in the RA patients compared with the controls (P = 0.0019, odds ratio [OR] 2.5, 95% confidence interval [95% CI] 1.3-4.6), an increase that was further evident in patients who were HLA-DRB1*0401 homozygous (P = 0.0003, OR 7.3, 95% CI 2.2-24.4). This increase was found to be due to association with HLA-DRB1*0401. No TNF microsatellite allele was found to be associated with HLA-DRB1*0404. Three HLA extended haplotypes were identified in the RA group: 1) HLA-DRB1*0401;TNFd4;TNFa6;TNFb5;HLA-B44; HLA-Cw5;HLA-A2, 2) HLA-DRB1*0301;TNFd2; TNFa2;TNFb3;HLA-B8;HLA-Cw7;HLA-A1, and 3) TNFd5;TNFc2;TNFa2;TNFb1;HLA-B62;HLA-Cw3. CONCLUSION: TNF microsatellites found to be associated with RA do not appear to be independent of class II HLA associations.

Alleles↗
PubMed1996

Prevalence of panic in patients referred for pulmonary function testing at a major medical center.

OBJECTIVE: The authors examined the prevalence and correlates of panic disorder in a group of patients who were referred for pulmonary function testing. METHOD: Patients (N = 115) were screened for the presence of panic attacks and panic disorder with a self-report questionnaire; a subgroup (N = 25) received structured diagnostic assessment. RESULTS: Of the 115 patients, 41% (N = 47) reported panic attacks and 17% (N = 20) met screening criteria for panic disorder. From the confirmed rate of panic disorder among the subgroup who received structured diagnostic assessment, the overall prevalence rate of panic disorder was estimated to be 11% and included six of the nine patients (67%) who had a diagnosis of chronic obstructive pulmonary disease. There were no significant differences between patients with and without panic in the severity of pulmonary function abnormalities or in the response to bronchodilators. However, patients with panic attacks were significantly more likely to report dyspnea at rest and irritable bowel symptoms and tended to report difficulty swallowing. CONCLUSIONS: This study suggests that panic disorder and subsyndromal panic are relatively common and may be unrecognized and inadequately treated in patients who present with respiratory symptoms.

Airway Obstruction↗
PubMed1996

Fluoxetine treatment of anger attacks: a replication study.

"Anger attacks" are outbursts of anger which are accompanied by intense autonomic arousal and are clearly inappropriate to the situation in which they occur. The Anger Attacks Questionnaire, designed to assess these attacks, was administered to 164 consecutive patients (78 men and 86 women; mean age, 40.5 +/- 11.0 years) diagnosed as having major depression with the Structured Clinical Interview for DSM-III-R. These patients were treated openly with fluoxetine, 20 mg/day for 8 weeks, and the prevalence of anger attacks was assessed before and after treatment. At baseline, 64 (39%) (26 men and 38 women) of these patients reported having anger attacks according to our criteria. Forty-one (64%) of the 64 depressed patients with anger attacks at baseline did not report anger attacks following fluoxetine treatment, while 7 (7%) of the 100 patients who did not have anger attacks at baseline reported these attacks following treatment, with this difference being statistically significant (chi 2 = 22.7, p < .0005).

Adolescent↗