Biomedical subjects

O Smith

Publications and source records attributed to O Smith.

At least 19 recordsLinked to original sources

PubMed2006

Acetylcholine neuroprotection against glutamate-induced excitotoxicity in adult pig retinal ganglion cells is partially mediated through alpha4 nAChRs.

In the mammalian retina, excess glutamate release has been shown to be involved in retinal ganglion cell (RGC) death associated with various diseases. Recent studies have determined that activation of alpha7 nicotinic acetylcholine receptors (nAChRs) partially protect isolated RGCs from glutamate-induced excitotoxicity. In this study, we further classify the types of nAChRs involved in neuroprotection against glutamate-induced excitotoxicity using isolated adult pig RGCs. Cells were isolated with a modified two-step immunoselective panning technique designed to isolate RGCs from other retinal neurons. Once isolated, nAChR subunits were identified using a combination of pharmacological and immunocytochemical techniques. In cell culture experiments, a variety of alpha4 nAChR specific agonists were found to have a partial neuroprotective against glutamate-induced excitotoxicity. This neuroprotection was abolished in the presence of the alpha4 nAChR antagonist, dihydro-beta-erythroidine (DHbetaE). Immunocytochemical results localized several nAChR subunits on isolated adult pig RGCs; in particular alpha4, alpha7 and beta2 nAChR subunits. Large RGCs exclusively immunostained with antibodies against alpha7 nAChR subunits whereas alpha4 and beta2 subunits exclusively immunostained only small RGCs. Double label experiments provided evidence that alpha4 and beta2 subunits co-localize on small RGCs. Knowledge of the receptor subtypes responsible for neuroprotection may lead to treatments associated with glutamate-induced excitotoxicity.

Acetylcholine↗

PubMed2006

Wilms' tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring.

Wilms' tumor gene 1 (WT1) is overexpressed in the majority (70-90%) of acute leukemias and has been identified as an independent adverse prognostic factor, a convenient minimal residual disease (MRD) marker and potential therapeutic target in acute leukemia. We examined WT1 expression patterns in childhood acute lymphoblastic leukemia (ALL), where its clinical implication remains unclear. Using a real-time quantitative PCR designed according to Europe Against Cancer Program recommendations, we evaluated WT1 expression in 125 consecutively enrolled patients with childhood ALL (106 BCP-ALL, 19 T-ALL) and compared it with physiologic WT1 expression in normal and regenerating bone marrow (BM). In childhood B-cell precursor (BCP)-ALL, we detected a wide range of WT1 levels (5 logs) with a median WT1 expression close to that of normal BM. WT1 expression in childhood T-ALL was significantly higher than in BCP-ALL (P<0.001). Patients with MLL-AF4 translocation showed high WT1 overexpression (P<0.01) compared to patients with other or no chromosomal aberrations. Older children (> or =10 years) expressed higher WT1 levels than children under 10 years of age (P<0.001), while there was no difference in WT1 expression in patients with peripheral blood leukocyte count (WBC) > or =50 x 10(9)/l and lower. Analysis of relapsed cases (14/125) indicated that an abnormal increase or decrease in WT1 expression was associated with a significantly increased risk of relapse (P=0.0006), and this prognostic impact of WT1 was independent of other main risk factors (P=0.0012). In summary, our study suggests that WT1 expression in childhood ALL is very variable and much lower than in AML or adult ALL. WT1, thus, will not be a useful marker for MRD detection in childhood ALL, however, it does represent a potential independent risk factor in childhood ALL. Interestingly, a proportion of childhood ALL patients express WT1 at levels below the normal physiological BM WT1 expression, and this reduced WT1 expression appears to be associated with a higher risk of relapse.

Adolescent↗

PubMed2006

Circulating levels of beta2-glycoprotein I in thrombotic disorders and in inflammation.

Beta2-glycoprotein I (beta2GPI) is a plasma protein suspected to have a role in inhibition of thrombosis. This suspicion is reinforced by the observation that beta2GPI is the major target for autoantibodies in the antiphospholipid syndrome. However, little is known about its circulating levels in common thrombotic diseases or inflammation. We measured beta2GPI levels in 344 healthy controls, 58 normal pregnancies, 102 patients with non-haemorrhagic stroke, 121 patients with acute coronary syndrome and 200 patients with elevated C-reactive protein (CRP). In healthy individuals, we found a strong positive correlation between age and beta2GPI concentration (r = 0.274, P < 0.001) and that beta2GPI levels fall significantly after the eighth week of pregnancy (P = 0.002). We also found significantly reduced levels of beta2GPI in patients with stroke and in elderly patients with myocardial syndrome (P = 0.013 and 0.043). However, in neither group did beta2GPI levels change in the following six months, suggesting that the reduced levels were not a transient post-event phenomenon. In patients with inflammation, beta2GPI levels showed a significant negative correlation with CRP (r = -0.284, P < 0.001) and positively correlated with albumin and transferrin (r = 0.372 and 0.453, respectively with P < 0.001 for both). Furthermore, the largest reduction in beta2GPI levels occurred in patients with the highest CRP values (P < 0.001).

Adult↗

PubMed2005

Preferential transmission and association of the -403 G --> A promoter RANTES polymorphism with atopic asthma.

Asthma is a complex inherited disease. The study was undertaken to identify the association of RANTES promoter polymorphisms with atopy and asthma using family-based association tests (FBATs) and generation-specific case-control analyses. We identified 154 nuclear families (453 individuals) in whom we established RANTES promoter status using the RFLP-PCR method. Of the two known promoter polymorphisms -403G/A and -28C/G, only the former appeared with a clinically relevant frequency. A total of 61 families were eligible for assessment of transmission of the allele with asthma and atopy by the pedigree disequilibrium test (PDT). Overall, allele frequency for -403A was 38.3% and 84 of 89 (94.3%) alleles were transmitted with physician diagnosed asthma (PDA) (P=0.001). All 89 children with atopy received the mutant allele, which was more than expected following Mendelian Laws of transmission (P=0.0001). In 303 unrelated parents, significant associations of the mutant allele were for atopy with or without asthma (P=0.001). In 150 unrelated children, significant associations were for atopy alone (P=0.001) and asthma (P=0.001). No associations were found for bronchial hyper-responsiveness (BHR). The -403 G --> A is transmitted with atopy and atopic asthma, although its contribution appears to relate more to atopy than asthma and BHR.

Adolescent↗

PubMed2005

Recessive congenital methaemoglobinaemia: functional characterization of the novel D239G mutation in the NADH-binding lobe of cytochrome b5 reductase.

Type I recessive congenital methaemoglobinaemia (RCM), caused by the reduced form of nicotinamide adenine dinucleotide (NADH)-cytochrome b(5) reductase (cytb(5)r) deficiency, manifests clinically as cyanosis without neurological dysfunction. Two mutations, E255- and G291D, have been identified in the NADH-binding lobe of cytb(5)r in previously reported patients, and we have detected a further novel mutation, D239G, in this lobe in two unrelated Irish families. Although one family belongs to the genetically isolated Traveller Community, which separated from the general Irish population during the 1845-48 famine, the D239G mutation was present on the same haplotype in both families. Three known cytb(5)r mutations were also identified, including the R159- mutation, which causes loss of the entire NADH-binding lobe and had previously been reported in an individual with type II RCM. Characterization of the three NADH-binding lobe mutants using a heterologous expression system revealed that all three variants retained stoichiometric levels of flavin adenine dinucleotide with spectroscopic and thermodynamic properties comparable with those of native cytb(5)r. In contrast to the E255- and G291D variants, the novel D239G mutation had no adverse impact on protein thermostability. The D239G mutation perturbed substrate binding, causing both decreased specificity for NADH and increased specificity for NADPH. Thus cytb(5)r deficient patients who are heterozygous for an NADH-binding lobe mutation can exhibit the clinically less severe type I phenotype, even in association with heterozygous deletion of the NADH-binding lobe.

Adolescent↗

PubMed2005

Long-term outcomes of restorative proctocolectomy for Crohn's disease and indeterminate colitis.

INTRODUCTION: The present study aims to evaluate the short-term and long-term outcomes of patients undergoing restorative proctocolectomy (RPC) for Crohn's disease (CD) and Indeterminate colitis (IC) and to identify factors associated with adverse outcomes. METHODS: A descriptive study of 52 patients with CD or IC from a total of 1652 patients undergoing primary or salvage RPC in a single tertiary referral centre between 1978 and 2003. Primary outcomes were ileal pouch failure (excision or indefinite diversion), adverse events and functional outcomes (bowel frequency, urgency and continence). RESULTS: Patients with IC or IC favouring ulcerative colitis (Group 1, n = 26) had a pouch failure rate of 11.5%vs 57.5% for patients with CD or IC favouring CD (Group 2, n = 26). Pouch salvage surgery was undertaken in 15 patients with a 13.3% failure rate. Patients in Group 2 were 2.6 times more likely (95% CI: 0.96-7. No significant differences were evident between CD and IC patients with regards to pelvic sepsis (19.2%vs 15.4%), anastomotic stricture (23.1%vs 21.7%), small bowel obstruction (26.9%vs 26.9%) or pouchitis (15.4%vs 11.5%). The 24-h bowel frequency (7.5 vs 8), faecal urgency, daytime or night time incontinence were similar between patients with CD or IC..17) to develop a pouch-related fistula than patients in Group 1. DISCUSSION: Crohn's disease and to a great extent indeterminate colitis favouring CD were both associated with high failure rates and postoperative pouch-related fistula rates. Despite these problems, functional outcomes for patients with CD or IC were similar. Patients with IC should remain candidates for RPC but careful pre-operative assessment is advised to exclude clinical signs favouring the diagnosis of CD. The complications associated with failure are extensive and the option of reconstructive surgery in patients with CD should be questioned.

Adolescent↗

PubMed2002

Total knee arthroplasty in patients with severe haemophilia.

We reviewed the perioperative records of haemophiliac patients who underwent total knee replacement (TKR) over the period 1990-1999 and followed up the surviving patients. Nine knees were replaced in eight patients. Seven of the nine patients did not require blood transfusion. Mean perioperative haemoglobin drop was 2.9 g/dl. There were no significant complications. All surviving patients (eight TKRs) were reviewed clinically using a standard scoring system. The mean follow-up period was 51 months. All patients scored excellent (>90/100) in the functional category. The frequency of haemarthroses fell significantly from the rate experienced prior to TKR, and pain scores were zero.

Adult↗

PubMed2001