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Biomedical subjects

P Stuart

Publications and source records attributed to P Stuart.

At least 19 recordsLinked to original sources
PubMed2005

Analysis of RUNX1 binding site and RAPTOR polymorphisms in psoriasis: no evidence for association despite adequate power and evidence for linkage.

BACKGROUND: A previous study identified two peaks of allelic association between psoriasis and single nucleotide polymorphisms (SNPs) mapping to distal chromosome 17q, including a disease associated SNP that leads to loss of a RUNX1 transcription factor binding site, and additional SNPs in the third intron of the RAPTOR gene. Another study found an association with SNPs in the RAPTOR gene, but not with the RUNX1 binding site polymorphism. METHODS: In an effort to confirm these observations, we genotyped 579 pedigrees containing 1285 affected individuals for three SNPs immediately flanking and including the RUNX1 binding site, and for three SNPs in the RAPTOR gene. RESULTS: Here we report further evidence for linkage to distal chromosome 17q, with a linkage peak mapping 1.7 cM distal to the RUNX1 binding site (logarithm of the odds 2.26 to 2.73, depending upon statistic used). However, we found no evidence for association to individual SNPs or haplotypes in either of the previously identified peaks of association. Power analysis demonstrated 80% power to detect significant association at genotype relative risks of 1.2 (additive and multiplicative models) to 1.5 (dominant and recessive models) for the RUNX1 binding site, and 1.3 to 1.4 for the RAPTOR locus under all models except dominant. CONCLUSIONS: Our data provide no support for the previously identified RUNX1 binding site or for the RAPTOR locus as genetic determinants of psoriasis, despite evidence for linkage of psoriasis to distal chromosome 17q.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Preoperative fasting for preventing perioperative complications in children.

BACKGROUND: Children, like adults, are required to fast before general anaesthesia with the aim of reducing the volume and acidity of their stomach contents. It is thought that fasting reduces the risk of regurgitation and aspiration of gastric contents during surgery. Recent developments have encouraged a shift from the standard 'nil-by-mouth-from-midnight' fasting policy to more relaxed regimens. Practice has been slow to change due to questions relating to the duration of a total fast, the type and amount of intake permitted. OBJECTIVES: To systematically assess the effects of different fasting regimens (duration, type and volume of permitted intake) and the impact on perioperative complications and patient wellbeing (aspiration, regurgitation, related morbidity, thirst, hunger, pain, comfort, behaviour, nausea and vomiting) in children. SEARCH STRATEGY: We searched Cochrane Wounds Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL, the National Research Register, relevant conference proceedings and article reference lists and contacted experts. SELECTION CRITERIA: Randomised and quasi randomised controlled trials of preoperative fasting regimens for children were identified. DATA COLLECTION AND ANALYSIS: Data extraction and trial quality assessment was conducted independently by two authors. Trial authors were contacted for additional information including adverse events. MAIN RESULTS: Forty-three randomised controlled comparisons (from 23 trials) involving 2350 children considered to be at normal risk of regurgitation or aspiration during anaesthesia. Only one incidence of aspiration and regurgitation was reported. Children permitted fluids up to 120 minutes preoperatively were not found to experience higher gastric volumes or lower gastric pH values than those who fasted. The children permitted fluids were also less thirsty and hungry, better behaved and more comfortable than those who fasted. Clear fluids preoperatively did not result in a clinically important difference in the children's gastric volume or pH. Evidence relating to the preoperative intake of milk was sparse. The volume of fluid permitted during the preoperative period did not appear to impact on children's intraoperative gastric volume or pH contents. AUTHORS' CONCLUSIONS: There is no evidence that children who are not permitted oral fluids for more than six hours preoperatively benefit in terms of intraoperative gastric volume and pH over children permitted unlimited fluids up to two hours preoperatively. Children permitted fluids have a more comfortable preoperative experience in terms of thirst and hunger. This evidence applies only to children who are considered to be at normal risk of aspiration/regurgitation during anaesthesia.

Adolescent↗
PubMed2005

The efficacy of structured assessment and analgesia provision in the paediatric emergency department.

OBJECTIVES: To ascertain if the use of a structured pain assessment tool and nurse initiated oral analgesia protocols improve uptake and time to analgesia for children presenting to the emergency department with minor or moderate musculoskeletal injuries. METHODS: Three groups of children with peripheral limb injuries were examined to identify the rates of analgesia provision and time from attendance to analgesia provision. These groups corresponded to an initial group with no pain scoring and physician initiated analgesia, a second group with pain scoring at triage then physician initiated analgesia, and a third group with pain scoring and nurse initiated analgesia. RESULTS: The mean time to analgesia in the initial group was 138 minutes. After initiation of triage pain assessment the mean time to analgesia was 93 minutes, there was no statistical difference between these two groups. After the introduction of nurse initiated analgesia, the time to analgesia fell to a mean of 46 minutes. The rate of analgesia provision was initially 20.5% while after the initiation of triage pain assessment the provision rate was 23%. After the initiation of nurse initiated analgesia the analgesia provision rate significantly rose to 34% of attendances. CONCLUSIONS: The use of a nurse initiated, oral analgesia protocol for treatment of children with mild to moderate injury can significantly increase analgesia provision rates and decrease time to provision of analgesia.

Acetaminophen↗
PubMed2005

Pilot study of a paediatric emergency department oral rehydration protocol.

OBJECTIVE: To ascertain if the use of a paediatric oral rehydration protocol in the emergency department changed rates of admission, total time spent in hospital, total time spent in the emergency department, or number of unscheduled returns to the emergency department. METHODS: A two month time period was analysed before and then after the adoption of an oral rehydration protocol for children presenting to the emergency department with symptoms suggestive of gastroenteritis. The rates of admission, total time spent in hospital, total time spent in the emergency department, and the rate of unscheduled returns were analysed using Fisher's exact and Wilcoxon testing for non-parametric data. RESULTS: The adoption of a paediatric rehydration protocol was associated with a significant reduction in admission rates (before = 22.5%, after 5.1%; p = 0.048) and mean total hospital time (before = 7 hours 54 minutes, after = 2 hours 17 minutes; p = 0.017). There was no significant difference in time spent in the emergency department (before = 1 hour 25 minutes, after 1 hour 35 minutes, p = 0.3). The number of unscheduled returns did not change significantly (p = 0.3). CONCLUSION: Adoption of a paediatric rehydration protocol significantly reduces admission rates and total time spent in hospital for children presenting to the emergency department with symptoms of gastroenteritis. The mean time spent in the actual emergency department does not significantly increase. The rate of unscheduled returns does not change.

Adolescent↗
PubMed2005

Pressurised metered dose inhalers with spacers versus nebulisers for beta-agonist delivery in acute asthma in children in the emergency department.

OBJECTIVES: Wet nebulisers are widely used for beta-2 agonist delivery in Australasian emergency departments (ED). An increasing body of work suggests that pressurised metered dose inhalers with spacers (pMDI-S) are as effective. This study aims to investigate the effect on admission rates, total time in the ED, and total time in hospital after initiation of routine pMDI-S treatment for mild to moderate asthma in children presenting to the ED. METHODS: Children with a discharge diagnosis of asthma were identified over sequential 3 month time periods. In the first period, wet nebuliser treatment was routine and in the subsequent trial period pMDI-S treatment was instituted as routine. Admissions rates, total time in hospital, and total time in the ED were recorded for each group. RESULTS: Admission rates fell significantly from 31% to 20.6% after routine use of pMDI-S treatment. There was a non-significant trend to an increase in total ED and total hospital times. CONCLUSION: Introduction of routine pMDI-S treatment in the paediatric ED results in a significant drop in admission rates but no significant change in total hospital times or total ED times.

Acute Disease↗
PubMed2005

Capillary versus venous bedside blood glucose estimations.

OBJECTIVES: To determine the mean difference and correlation between capillary and venous bedside glucose estimation in comparison to laboratory blood glucose analysis in emergency department (ED) patients. METHODS: Blood glucose levels were synchronously analysed using a bedside blood glucometer on capillary and venous derived samples from consenting ED patients aged >12 years. The venous sample was sent for comparative testing using a laboratory based multichannel analyser. Mean difference and correlation coefficients were determined. RESULTS: A total of 20 subjects (aged 13-88 years) were enrolled, with 100% data capture. The mean laboratory glucose was 7.075 mmol/l. The mean capillary blood glucose was 7.66 mmol/l (mean difference compared with mean laboratory glucose 0.58 mmol/l; 95% confidence interval 0.3 to 0.9). The mean venous derived blood glucometer glucose was 7.99 mmol/l (mean difference compared with mean laboratory glucose 0.91 mmol/l; 95% CI 0.6 to 1.2). The correlation coefficient for the laboratory blood glucose versus the capillary blood glucometer glucose was 0.97 mmol/l (p<0.001). The correlation coefficient for the laboratory blood glucose and the venous blood glucometer glucose was 0.96 (p<0.001). Variation occurred between the glucometer and the laboratory blood glucose results. CONCLUSIONS: There is a small but significant difference in the blood glucose results analysed on a bedside glucometer when the samples are taken from capillary or venous sources. Although good correlation is the norm between venous and capillary derived samples, caution must be exercised in accepting the results as equivalent or using either as substitutes for a laboratory blood glucose result.

Adolescent↗
PubMed2003

Preoperative fasting for adults to prevent perioperative complications.

BACKGROUND: Fasting before general anaesthesia aims to reduce the volume and acidity of stomach contents during surgery, thus reducing the risk of regurgitation/aspiration. Recent guidelines have recommended a shift in fasting policy from the standard 'nil by mouth from midnight' approach to more relaxed policies which permit a period of restricted fluid intake up to a few hours before surgery. The evidence underpinning these guidelines however, was scattered across a range of journals, in a variety of languages, used a variety of outcome measures and methodologies to evaluate fasting regimens that differed in duration and the type and volume of intake permitted during a restricted fasting period. Practice has been slow to change. OBJECTIVES: To systematically review the effect of different preoperative fasting regimens (duration, type and volume of permitted intake) on perioperative complications and patient wellbeing (including aspiration, regurgitation and related morbidity, thirst, hunger, pain, nausea, vomiting, anxiety) in different adult populations. SEARCH STRATEGY: Electronic databases, conference proceedings and reference lists from relevant articles were searched for studies of preoperative fasting in August 2003 and experts in the area were consulted. SELECTION CRITERIA: Randomised controlled trials which compared the effect on postoperative complications of different preoperative fasting regimens on adults were included. DATA COLLECTION AND ANALYSIS: Details of the eligible studies were independently extracted by two reviewers and where relevant information was unavailable from the text attempts were made to contact the authors. MAIN RESULTS: Thirty eight randomised controlled comparisons (made within 22 trials) were identified. Most were based on 'healthy' adult participants who were not considered to be at increased risk of regurgitation or aspiration during anaesthesia. Few trials reported the incidence of aspiration/regurgitation or related morbidity but relied on indirect measures of patient safety i.e. intra-operative gastric volume and pH. There was no evidence that the volume or pH of participants' gastric contents differed significantly depending on whether the groups were permitted a shortened preoperative fluid fast or continued a standard fast. Fluids evaluated included water, coffee, fruit juice, clear fluids and other drinks (e.g. isotonic drink, carbohydrate drink). Participants given a drink of water preoperatively were found to have a significantly lower volume of gastric contents than the groups that followed a standard fasting regimen. This difference was modest and clinically insignificant. There was no indication that the volume of fluid permitted during the preoperative period (i.e. low or high) resulted in a difference in outcomes from those participants that followed a standard fast. Few trials specifically investigated the preoperative fasting regimen for patient populations considered to be at increased risk during anaesthesia of regurgitation/aspiration and related morbidity. REVIEWER'S CONCLUSIONS: There was no evidence to suggest a shortened fluid fast results in an increased risk of aspiration, regurgitation or related morbidity compared with the standard 'nil by mouth from midnight' fasting policy. Permitting patients to drink water preoperatively resulted in significantly lower gastric volumes. Clinicians should be encouraged to appraise this evidence for themselves and when necessary adjust any remaining standard fasting policies (nil-by-mouth from midnight) for patients that are not considered 'at-risk' during anaesthesia.

Adult↗
PubMed2001

The genetics of psoriasis 2001: the odyssey continues.

Accumulating evidence indicates that psoriasis is a multifactorial disorder caused by the concerted action of multiple disease genes in a single individual, triggered by environmental factors. Some of these genes control the severity of multiple diseases by regulating inflammation and immunity (severity genes), whereas others are unique to psoriasis. Various combinations of these genes can occur even within a single family, accounting in large measure for the many clinical manifestations of psoriasis. The disease-causing variants (alleles) of these genes probably arose early in the history of modern humans. As a result, psoriasis disease alleles are common in the general population, have a worldwide distribution, and often share the same ancestral chromosome with neutral alleles at adjacent loci. This phenomenon, called linkage disequilibrium, explains why psoriasis is strongly associated with HLA-Cw6 worldwide, although HLA-Cw6 is unlikely to be the disease allele. Many unaffected individuals carry 1 or more disease alleles, but lack other genetic and/or environmental factors necessary to produce disease. This explains why psoriasis develops in only about 10% of HLA-Cw6-positive individuals, and why genome-wide linkage scans for psoriasis and other multifactorial genetic disorders have not been uniformly successful. The Human Genome Project is rapidly generating a catalog of human DNA sequence variations. This resource has already allowed precise linkage disequilibrium mapping of the major histocompatibility complex psoriasis gene to just beyond HLA-C, toward HLA-A. This gene is likely to be identified soon. Further development and use of linkage disequilibrium resources will provide a powerful tool for the identification of the remaining psoriasis genes.

Genetic Heterogeneity↗
PubMed2001

S100A2 coding sequence polymorphism: characterization and lack of association with psoriasis.

Psoriasis is a chronic inflammatory skin disease with a strong genetic component. Linkage studies have identified several susceptibility loci for psoriasis including a region on chromosome 1q21 termed the 'epidermal differentiation complex'. At least 20 genes involved in epidermal differentiation and proliferation have been mapped to this region including S100A2, a gene known to be over-expressed in psoriasis lesions. In the course of cloning and sequencing several S100A2 cDNAs, we identified an A/G (Asn62Ser) polymorphism at nucleotide 185 of the S100A2 coding region. To determine whether this polymorphism is associated with psoriasis, we tested DNA from 38 unrelated normal and 40 unrelated psoriatic individuals. The 185G allele was present in 148 of the 156 chromosomes analysed, giving an allele frequency of 94.9%. All of the remaining chromosomes carried 185A. There was no significant difference in the allele distribution between normal and psoriatic individuals (normals 72G, 4A; psoriatics 76G, 4A; P = 1.00 by Fisher's exact test). Our data explain conflicting results in the literature regarding the sequence of S100A2 but provide no support for a direct causal role for S100A2 in psoriasis.

Adolescent↗
PubMed2000

Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C.

Recent genome scans have established the presence of a major psoriasis-susceptibility locus in the human leukocyte antigen (HLA) complex on chromosome 6p21.3. To narrow the interval for candidate gene testing, we performed a linkage-disequilibrium analysis of 339 families, with the use of 62 physically mapped microsatellite markers spanning the major histocompatibility complex (MHC). As detected by use of the transmission/disequilibrium test (TDT), individual markers yielded significant linkage disequilibrium across most of the MHC. However, the strongest evidence for marker-trait disequilibrium was found in an approximately 300-kb region extending from the MICA gene to the corneodesmosin gene. Maximum-likelihood haplotypes were constructed across the entire MHC in the original sample and across a 1.2-Mb region of the central MHC in an expanded sample containing 139 additional families. Short (two- to five-marker) haplotypes were subjected to the TDT using a "moving-window" strategy that reduced the variability of TDT P values relative to the single-locus results. Furthermore, the expanded sample yielded a sharp peak of evidence for linkage disequilibrium that spanned approximately 170 kb and that was centered 100 kb telomeric to HLA-C. The 1.2-Mb interval was further dissected by means of recombinant ancestral haplotype analysis. This analysis identified risk haplotype 1 (RH1), which is a 60-kb fragment of ancestral haplotype 57.1, on all identifiable HLA risk haplotypes. One of these haplotypes exhibits significant linkage disequilibrium with psoriasis but does not carry Cw6, which is the HLA allele most strongly associated with the disease. These results demonstrate that RH1 is highly likely to carry the disease allele at PSORS1, and they exclude HLA-C and corneodesmosin with a high degree of confidence.

Alleles↗
PubMed1999

Linkage disequilibrium analysis of familial psoriasis: identification of multiple disease-associated MHC haplotypes.

Although psoriasis vulgaris (PsV) is strongly associated with certain human leukocyte antigens, the pathogenetic nature of these associations remains elusive. The objectives of this study were: (i) to determine whether HLA loci directly determine susceptibility or merely serve as markers for the susceptibility allele; and (ii) to identify additional disease-associated haplotypes. By applying maximum likelihood linkage disequilibrium analysis (LDA) in cases vs. controls, we found the susceptibility gene to be more strongly associated with specific HLA haplotypes than with their component alleles. Stronger linkage disequilibrium between PsV and HLA alleles was detected at HLA-C and HLA-B than at DRB1 and DQB1. Parametric linkage analysis accounting for marker-trait disequilibrium in psoriasis vulgaris pedigrees yielded most significant results for a locus close to HLA-B and -C. Furthermore, we found that susceptibility is linked to at least three different ancestral HLA haplotypes; among them, HLA-Cw7-B8-DRB1*0301-DQB1*02 is linked to PsV for the first time. These results identify a major PsV susceptibility locus in the immediate vicinity of, but distinct from HLA-B or HLA-C, and suggest that multiple disease alleles have arisen during human evolution.

Alleles↗
PubMed1998

Linkage analysis of human leukocyte antigen (HLA) markers in familial psoriasis: strong disequilibrium effects provide evidence for a major determinant in the HLA-B/-C region.

Although psoriasis is strongly associated with certain human leukocyte antigens (HLAs), evidence for linkage to HLA markers has been limited. The objectives of this study were (1) to provide more definitive evidence for linkage of psoriasis to HLA markers in multiplex families; (2) to compare the major HLA risk alleles in these families with those determined by previous case-control studies; and (3) to localize the gene more precisely. By applying the transmission/disequilibrium test (TDT) and parametric linkage analysis, we found evidence for linkage of psoriasis to HLA-C, -B, -DR, and -DQ, with HLA-B and -C yielding the most-significant results. Linkage was detectable by parametric methods only when marker-trait disequilibrium was considered. Case-control association tests and the TDT identified alleles belonging to the EH57.1 ancestral haplotype as the major risk alleles in our sample. Among individuals carrying recombinant ancestral haplotypes involving EH57. 1, the class I markers were retained selectively among affecteds four times more often than among unaffecteds; among the few affected individuals carrying only the class II alleles from the ancestral haplotype, all but one also carried Cw6. These data show that familial and "sporadic" psoriasis share the same risk alleles. They also illustrate that substantial parametric linkage information can be extracted by accounting for linkage disequilibrium. Finally, they strongly suggest that a major susceptibility gene resides near HLA-C.

Adult↗
PubMed1997

Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.

In a 12.5 cM genome-wide scan for psoriasis susceptibility loci, recombination-based tests revealed linkage to the HLA region (Zmax = 3.52), as well as suggestive linkage to two novel regions: chromosome 16q (60-83.1 cM from pter, Zmax = 2.50), and chromosome 20p (7.5-25 cM from pter, Zmax = 2.62). All three regions yielded P values < or = 0.01 by non-parametric analysis. Recombination-based and allele sharing methods also confirmed a previous report of a dominant susceptibility locus on distal chromosome 17q (108.2 cM from pter, Zmax = 2.09, GENEHUNTER P = 0.0056). We could not confirm a previously reported locus on distal chromosome 4q; however, a broad region of unclear significance was identified proximal to this proposed locus (153.6-178.4 cM from pter, Zmax = 1.01). Taken together with our recent results demonstrating linkage to HLA-B and -C, this genome-wide scan identifies a psoriasis susceptibility locus at HLA, confirms linkage to 17q, and recommends two novel genomic regions for further scrutiny. One of these regions (16q) overlaps with a recently-identified susceptibility locus for Crohn's disease. Psoriasis is much more common in patients with Crohn's disease than in controls, suggesting that an immunomodulatory locus capable of influencing both diseases may reside in this region.

Adult↗
PubMed1997

Design and construction of a hybrid immunoglobulin domain with properties of both heavy and light chain variable regions.

The complementarity-determining regions (CDRs) of a human kappa light chain were replaced with CDRs from a murine gamma-1 heavy chain and, by use of molecular modeling, key heavy chain framework residues were identified and thus included to preserve the native conformation of the heavy chain CDRs. Co-expression of this hybrid human kappa chain (V[HB]C[L]) with a human kappa chain counterpart (V[L]C[L], engineered to contain murine light chain CDRs) resulted in the secretion of high levels of a heterodimeric protein (V[HB]C[L]::V[L]C[L]) termed 'kappabody'. This protein also had equivalent affinity for antigen as the Fab' of the parent murine IgG1. High-level secretion was also observed for the hybrid chain as homodimers (V[HB]C[L]::V[HB]C[L]), which is not observed for chimeric chains consisting of a heavy chain variable region and light chain constant region, i.e. V[H]C[L] homodimers or single chains are not secreted. This indicates that regions within the variable domain, required for secretion of light chains, reside outside of the hypervariable regions (CDRs) and that the heavy chain CDRs and supporting residues do not prevent secretion. These results demonstrate the possibility of designing small, single-domain molecules possessing a given binding activity which may be secreted at high levels from mammalian cells.

Amino Acid Sequence↗
PubMed1994

Moderate hypoglycemia impairs the function of the inferior colliculus in the awake rat.

To assess the effect of acute hypoglycemia on the brain stem auditory pathway, we implanted electrodes into the inferior colliculus (IC) and subsequently recorded auditory-evoked potentials from the IC (ICEP) and brain stem (BAEP) in normal awake rats during euglycemic and hypoglycemic hyperinsulinemia (2 hours). Latencies of the ICEP and peak V of the BAEP were significantly prolonged by hypoglycemia (approximately 2.7 mmol/L). The change in the BAEP was principally between peak III and peak V. suggesting an effect in or near the IC. ICEP and BAEP latencies did not change during euglycemic hyperinsulinemia. We conclude that the function of the IC is very sensitive to episodes of moderate hypoglycemia. These data provide direct evidence that the scope of adverse central nervous system effects resulting from hypoglycemia extends beyond cognitive centers to include the brain stem.

Acute Disease↗
PubMed1993

Comparison of anticoagulant control among patients attending general practice and a hospital anticoagulant clinic.

Management of patients receiving oral anticoagulant therapy was assessed in general practice and a dedicated hospital anticoagulant clinic. The demographic characteristics of patients in both groups were similar, as were the indications for anticoagulation therapy and the duration of treatment. General practice patients were reviewed significantly more frequently, with a median interval of 16 days compared with 42 days for hospital patients (P < 0.001). Twenty four per cent of general practice visits and 26% of hospital attendances resulted in an alteration to the warfarin dosage. Overall, 52% of general practice thrombotest results lay within the ranges recommended by the British Society for Haematology, compared with 45% of hospital results (P < 0.001). There was no difference in the rate of complications in general practice and the hospital clinic. In this study, the anticoagulant control achieved in a general practice setting was superior to that in a dedicated hospital outpatient clinic, although control was far from ideal in either setting.

Aged↗