Search

This chapter reflects upon the blended learning approach involving the delivery of a work-based, competency-focused programme in higher education. Based on their experience, the authors present the various approaches taken to deliver an optimal blended model for this programme type in the domain of Hearing Aid Audiology. Synchronous and asynchronous online learning are appraised and strategies to encourage learner engagement are explored. Advantages and limitations of the blended approach are considered, including the external factors which can influence outcomes in blended programmes. The chapter also discusses how the rapid, unplanned, upskilling of a high percentage of academic staff to deliver online programmes during the Covid-19 global pandemic has resulted in a cohort of highly experienced academics now proficient in online delivery. This upskilling has contributed to more efficient online delivery in the post-pandemic era. The impact of this upskilling of both the learners (through increased digital literacy) and academics has created an educational ecosystem with more universities embarking on the delivery of blended learning programmes or fully online programmes. This positive outcome in the post-pandemic era may have an impact on the future delivery of programmes in the WBL space, adopting a blended learning approach, and incorporating online learning.

PurposeThis study investigates a blended learning model which incorporates online learning for a competency-focused, work-based learning (WBL) programme within allied healthcare. The case-study is centred on hearing aid audiology.Design/methodology/approachThe study evaluated the feedback received through a tripartite group of stakeholders (learners, academic staff and employers).FindingsResults showed that although there was universal support for blended learning, incorporating online learning, each stakeholder contributed different perspectives. The authors identified that in terms of curriculum design, a comprehensive analysis of the holistic perspective across all stakeholders is essential to ascertain the suitability of this learning mode for WBL. The study may provide the basis of a preparatory framework for the development of a generic, competency-focused model that can be applied across allied healthcare WBL programmes.Originality/valueAlthough previous studies of WBL have been reported, to the knowledge of the authors, there is no current reference in the literature to studies that examine thematic areas relevant to all three stakeholders across a programme of this nature in hearing aid audiology.

Anal fistulae are abnormal hollow connections between the wall of the anal canal and the perianal skin around the anus that have remained a burden on the medical sector for centuries. The complexity of this disease is attributed to a number of factors such as the degree of associated sphincter muscle, concomitant illnesses, existence of multiple fistulous tracts and the number of previous interventions. Persistence of a complex anal fistula can cause a decline in patient's physical quality of life as well as impact on the psychological status of patients who often suffer from anxiety and depression. Surgical intervention remains the gold standard for treatment, however; the risk of incontinence and high recurrence potential has led to interest into developing alternative treatment approaches such as the use of biologics, bioactives and biomaterials. One potential reason for these varied outcomes could be the multifactorial interplay between genetic, immune-related, environmental, and microbial persistence factors on tissue regeneration. Recent observations have proposed that adverse inflammatory mediators may contribute more than microbial factors. The moderate to high success rates of biotechnological advances (mesenchymal stem cells and biomaterial scaffolds) show promise as therapies for the amelioration of adverse persistent factors while facilitating a means to closing the fistula tract. The purpose of this review is to outline recent advances in biologics and combination therapies to treat persistent factors associated with complex anal fistula.

Cronobacter species have adapted to survive harsh conditions, particularly in the food manufacture environment, and can cause life-threatening infections in susceptible hosts. These opportunistic pathogens employ a multitude of mechanisms to aid their virulence throughout three key stages: environmental persistence, infection strategy, and systemic persistence in the human host. Environmental persistence is aided by the formation of biofilms, development of subpopulations, and high tolerance to environmental stressors. Successful infection in the human host involves several mechanisms such as protein secretion, motility, quorum sensing, colonisation, and translocation. Survival inside the host is achieved via competitive acquisition and utilization of minerals and metabolites respectively, coupled with host immune system evasion and antimicrobial resistance (AMR) mechanisms. Across the globe, Cronobacter sakazakii is associated with often fatal systemic infections in populations including neonates, infants, the elderly and the immunocompromised. By providing insight into the mechanisms of virulence utilised by this pathogen across these three stages, this review identifies current gaps in the literature. Further research into these virulence mechanisms is required to inform novel mitigation measures to improve global food safety with regards to this food-borne pathogen. info:eu-repo/semantics/acceptedVersion

Complex anal fistulae remain a challenge for the medical sector as conventional treatments put patients at risk of incontinence. Clinicians and researchers have become interested in the application of bioresorbable materials, as a means of avoiding invasive procedures and/or secondary procedures. Advances in polymer chemistry and processing techniques, the range of biomaterial medical devices has expanded since first implemented in the early 1990’s. Clinical evaluation of biomaterial-based medical devices initially generated great enthusiasm, however; subsequent studies observed low – moderate success rates. The next generation of biomaterial-based devices focus on addressing the principles of fistulae treatment, these include: novel device design and the incorporation of bioactives and biologics. This review focuses on the biomaterials utilized, the form of medical device developed and the recent inclusion of dual-purpose scaffolds for complex anal fistulae treatments. yes

Biomedical polymers are an integral component in a wide range of medical devices because of their many desirable properties. However, extensive use of polymer materials in medical devices has been associated with an increasing incidence of patient infections. Efforts to address this issue have included incorporating antimicrobial additives to develop novel antimicrobial polymeric materials. Silver, with its high toxicity towards bacteria, oligodynamic effect and good thermal stability, has been employed as an additive for polymeric medical devices. In the present study, commercially available elemental (Biogate) and ionic (Ultrafresh 16) silver additives were incorporated into a Polyamide 11 (PA 11) matrix using a compression press. These polymer composites were evaluated for their antimicrobial and ion-release properties. Elemental silver composites were shown to retain their antimicrobial properties for extended periods and actively released silver ions for 84 days; whereas ionic silver composites lost their ion-release activity and, therefore, their antibacterial activity after 56 days. Bacterial log reduction units of 3.87 for ionic silver and 2.41 for elemental silver were identified within 24 h, when tested in accordance with the ISO 22196 test standard; this indicates that ionic silver is more efficient for short-term applications than elemental silver.

Direct incorporation of antimicrobial additive into the polymer matrix is a cost effective approach for the development of polymer/metal antimicrobial composites. Application of these antimicrobial composite systems for manufacturing medical devices addresses the issue of device related infections. In the present study, commercially available inorganic copper based additive, Plasticopper, was incorporated into a Polyamide 11(PA 11) matrix during the polymer processing stage. These polymer composites were evaluated for their morphological, mechanical, antimicrobial and ion release properties. Isothermal crystallisation studies showed that the copper additive acted as a nucleating agent and promoted faster crystallisation. Short term mechanical studies confirmed that the incorporation of copper has reinforcing effect on the composites with 5 and 10% copper loadings and did not adversely affect the short-term mechanical performance of the polymer composites. These composite systems were shown to be active against Escherichia coli ATCC 8739 with > 99.99% reduction in bacterial population. Corresponding ion release profiles for these composites indicated long term antimicrobial activity.

New antibiotics are urgently required by human medicine as pathogens emerge with developed resistance to almost all antibiotic classes. Pioneering approaches, methodologies and technologies have facilitated a new era in antimicrobial discovery. Innovative culturing techniques such as iChip and co-culturing methods which use 'helper' strains to produce bioactive molecules have had notable success. Exploiting antibiotic resistance to identify antibacterial producers performed in tandem with diagnostic PCR based identification approaches has identified novel candidates. Employing powerful metagenomic mining and metabolomic tools has identified the antibiotic'ome, highlighting new antibiotics from underexplored environments and silent gene clusters enabling researchers to mine for scaffolds with both a novel mechanism of action and also few clinically established resistance determinants. Modern biotechnological approaches are delivering but will require support from government initiatives together with changes in regulation to pave the way for valuable, efficacious, highly targeted, pathogen specific antimicrobial therapies.

D-amino acids are responsible for cell wall re-modelling in Staphylococcus and are capable of inhibition and mature biofilm disassembly. Staphylococcus aureus and Staphylococcus epidermidis are recognised as recurrent nosocomial pathogens and a common cause of biofilm-associated infections. The combination of amino acids used in the study consisted of d- and l- isomers of tyrosine, methionine, tryptophan and phenylalanine. A semiquantitative microplate crystal violet assay was used to assess the effect of amino acids on biofilm development. Biofilm viability staining using fluorescent microscopy was performed to assess the effect of the amino acid mixtures on biofilm development on submerged surfaces. None of the amino acids when tested individually or as a mixture could reduce biofilm formation. However, at the highest concentration tested 25 mmol 1−1 equimolar D-amino acid mixture of tryptophan, phenylalanine, tyrosine and methionine caused a considerable biofilm inhibition in three Staphylococcus strains. Microscopy analysis showed that initial surface attachment remained unaffected at 25 mmol 1−1 mixture of d-amino acids but bacteria did not proceed to form mature biofilms. This suggests inhibition of protein synthesis or a lack of polysaccharide extracellular adhesin formation as no aggregates were observed. The reported bioactivity of D-amino acid on biofilm development and disassembly has been conflictual. It has been established that D-amino acids are incorporated in the bacterial cell wall suggesting they play a role in the complexity of biofilm lifecycle. However, our study indicates that they play no direct role in the inhibition of biofilm formation in Staphylococcus.

Streptococcus mutans is the major cariogenic organism associated with Dental Caries, a widespread chronic disease of the oral cavity (Muras et al. 2018). It is associated with oral biofilm formation, production of organic acids, and has the capacity to out-compete non-cariogenic commensal species (Lemos et al. 2013). Recent studies carried out on fatty acids demonstrated effective antimicrobial activity against S. mutans (Hughes, 2014). This study will evaluate the activity of lipids on S. mutans biofilm formation and proposes that dietary constituents may be used as a natural therapy to maintain oral hygiene. Clinical isolate S. mutans 3014 D5929 was exposed to various concentrations of lipid for 24 h. Crystal violet assay was performed for quantification of biofilm biomass. Fluorescent microscopy using SYTO® 9 and Alexa Fluor® 647-labelled dextran conjugate was performed to visualise biofilm formation pre- and post-exposure to MCO. Biofilm biomass was reduced for all lipid concentrations. Fluorescent microscopy indicated a significant reduction in bacterial cell number and a lack of structural biofilm upon exposure to fatty acid mixtures when compared to control. The research demonstrated that lipid does have S. mutans based antimicrobial and antibiofilm capabilities.

Introduction Following the observed success of a herbal cocktail in controlling and eliminating acute respiratory infections in a group of approximately sixty, 1–3 year old equines, it was decided to test ten of the herbs individually for antibacterial activity, using in vitro methodology. Methods Hydroethanolic extracts of defined concentration for each of the ten herbs were sourced from a licensed supplier in the UK. Positive and negative controls were included in the study. A quantitative suspension test for the evaluation of bactericidal activity of chemical disinfectants and antiseptics according to British Standard BS EN 1276:2009 was used to assess the anti-microbial activity of ten neat herbal tinctures. Results Bactericidal activity is described as the capability of a product to produce at least a 5 log10 reduction in specified test organisms within 5 minutes when the disinfectant is tested at its intended use dilution(s). The performance of each neat herbal tincture in this study was assessed only under moderate to heavy (dirty) soiling conditions. Commiphora molmol, Inula helenium, and Thymus vulgaris showed antimicrobial activity against all three test strains of bacteria, and over the entire dilution range (10−1 to 10−7). Baptisia tinctoria, Echinacea pupurea, Marribium vulgare, and Salvia officinalis, showed maximum antimicrobial activity only to two of the three test organisms. The tinctures of Galium aperine and Glechoma hederacea showed zero to very low antimicrobial activity against the three test organisms. Conclusion A herbal formulation containing a blend of the ten tested herbs constitutes a powerful antimicrobial cocktail.

Photo-polymerized polyethylene glycol dimethacrylate (PEGDMA) scaffolds were synthesized using two macromolecular monomers of 750 and 550 number average molecular weight. Variation in chain length of macromolecular monomers visibly influenced viscoelastic properties of the compositions, exhibiting an increase in shear storage and loss modulus in PEGDMA 750 hydrogels. Furthermore, water content in the pre-polymerization mixture was a main factor determining physical appearance of the samples, where increase in water content resulted in polymerization induced phase separation, demonstrated by opaqueness of preparations containing 60 and 75% (w/w) of H2O. In addition to this, swelling, gel fraction, compression and rheological measurements are found to be influenced by the amount of water incorporated in the hydrogels, resulting in the increased distance between polymer chains within the network. Furthermore this resulted in an apparent decrease in viscoelastic and mechanical properties of compositions, as well as in lowering their crosslinking density and compressive strength. Preliminary cytotoxicity results show no toxicity of the samples with approximately 80% cell viability after 24 h exposure of MC3T3-E1 Subclone 4 cells to the hydrogels, thus indicating that these materials could be potentially applied in the biomedical arena.

Aims Antimicrobial resistance poses a significant global healthcare predicament. An attractive approach to the dilemma of drug-resistant bacteria is the development and use of agents that interfere with the ability of pathogens to adhere to human tissue. The influence of sweet whey protein concentrate (SWPC), and selected hydrolysates of this material, on host-pathogen interactions of Cronobacter sakazakii (ATCC 29544) was investigated. Methods and Results CaCo-2 cell line was selected as a suitable model for the human intestinal epithelium. C. sakazakii ATCC 29544 was identified as the strain with the highest adhesion efficiency. SWPC reduced its association by 80% (p 95% (p < 0.001). SWPC enzymatically modified with lipase, trypsin and pepsin had variable effects on these behaviours with the most significant effect exhibited with the lipase treatment. SWPC produced an almost total inhibition of translocation of C. sakazakii across a CaCo-2 cell monolayer. Lipase and pepsin treated SWPC also reduced translocation by 75% and 90% respectively. However, trypsin treatment nullified the effect SWPC had on translocation. The presence of viable bacterial cells and SWPC both increased expression of IL-8 following Cronobacter invasion into CaCo-2 cells. Conclusions Factors governing adherence, invasion and translocation of Cronobacter spp. to human intestinal cells are multi-factorial and digested milk products exhibit varying effects dependant on their enzyme modification and protein lipid content. Significance and Impact of the Study These findings contribute to our, as yet, incomplete understanding of Cronobacter pathogenesis, and suggest that SWPC in whole and enzymatically hydrolysed forms, may provide a cost-effective source of bioactive materials with inhibitory effects on bacterial virulence. This article is protected by copyright. All rights reserved.

Cronobacter spp. are emerging opportunistic pathogens commonly associated with the feeding of powdered infant formula (PIF). This study aimed to investigate the ability of C.sakazakii (ATCC 29544) to survive heat injury in laboratory growth medium and powdered infant formula (PIF) in comparison to Escherichia coli (ATCC 25922) and other selected Cronobacter strains. As part of this work the thin agar layer (TAL) method for the recovery of heat-injured foodborne pathogens was evaluated for use with C.sakazakii (ATCC 29544) and E.coli (ATCC 25922). We report that heat treatment at 55°C for 10 minutes had no significant effect (P > 0.05) on C.sakazakii (ATCC 29544) viability in peptone or PIF. Significant differences in survival of Cronobacter strains after this heat treatment were identified indicating that heat tolerance in this genus may be strain dependent. PIF did not enhance survival of this organism in comparison to other media. Results indicate that a decrease in temperature of 5°C from the recommended 70°C for the reconstitution of PIF was sufficient to produce a significant increase in survival of C.sakazakii (ATCC 29544). Reconstituted PIF stored at room temperature was shown to support the survival and proliferation of this pathogen indicating that temperature abuse during PIF preparation and storage may significantly increase the risk of disease caused by these opportunistic pathogens.

Summary Low folate status may be a consequence of suboptimal intake, transport or cellular utilization of folate and, together with elevated homocysteine, is a recognized risk factor or marker for several human pathologies. As folate transport across cell membranes is mediated in part by the reduced folate carrier (RFC1), variants within SLC19A1, the gene that encodes RFC1, may influence disease risk via an effect on folate and/or homocysteine levels. The present study was undertaken to assess the association between the SLC19A1 c.80G>A polymorphism and folate/homocysteine concentrations in healthy young adults from Northern Ireland. The SLC19A1 c.80G>A polymorphism was not strongly associated with either serum folate or homocysteine concentrations in either men or women. However, in women, but not in men, this polymorphism explained 5% of the variation in red blood cell (RBC) folate levels (P= 0.02). Relative to women with the SLC19A1 c.80GG genotype, women with the GA and AA genotypes had higher RBC folate concentrations. Consequently, compared to women with the SLC19A1 c.80GA and AA genotypes, women who are homozygous for the 80G allele may be at increased risk of having a child affected with a neural tube defect and of developing pathologies that have been associated with folate insufficiency, such as cardiovascular disease.

Warfarin sodium is a vitamin K antagonist that is plagued by large variability in patient response, including higher dose requirements among African Americans. Polymorphisms in the gene encoding apolipoprotein E (APOE) may partly explain this variability by altering transport of vitamin K to the liver. In a prospective cohort study of 232 individuals (52.2% Caucasian and 47.8% African American) initiating warfarin therapy, the weekly maintenance dose was significantly higher for African Americans than for Caucasians (mean 42.9 versus mean 36.9 mg, P=0.018), and the epsilon4 allele was more common among African Americans (37.8 versus 26.4% for Caucasians). In multivariable analyses, the presence of the epsilon4 allele was associated with a statistically significantly higher warfarin dose among African Americans (median 45.0 mg in epsilon4 carriers versus 35.0 mg in non-epsilon4 carriers, P=0.014) but not Caucasians (38.1 versus 35.0 mg, P=0.60). In addition, warfarin maintenance dose increased among African Americans according to genotype previously associated with differential hepatic chylomicron clearance (epsilon2/epsilon2 or epsilon2/epsilon3: 30.0 mg; epsilon3/epsilon3: 35.0 mg; epsilon3/epsilon4 or epsilon4/epsilon4: 45.0 mg; P=0.012), although the epsilon4/epsilon4 genotype was rare and not clearly associated with higher doses. The association of APOE with warfarin dosing was independent of CYP2C9 and VKORC1 polymorphisms. APOE polymorphisms thus may be important determinants of warfarin maintenance dose and could explain at least some of the observed racial differences in dose requirements.

Preliminary studies suggested that age at onset (AAO) may help to define homogeneous bipolar affective disorder (BPAD) subtypes. This candidate symptom approach might be useful to identify vulnerability genes. Thus, the probability of detecting major disease-causing genes might be increased by focusing on families with early-onset BPAD type I probands. This study was conducted as part of the European Collaborative Study of Early Onset BPAD (France, Germany, Ireland, Scotland, Switzerland, England, Slovenia). We performed a genome-wide search with 384 microsatellite markers using non parametric linkage analysis in 87 sib-pairs ascertained through an early-onset BPAD type I proband (age at onset of 21 years or below). Non parametric multi-point analysis suggested eight regions of linkage with p-values

Monocyte chemoattractant protein-1 (MCP-1), encoded by the CCL2 gene, plays an important role in the initiation and progression of atherosclerosis. Ea.hy 926 endothelial cells grown under low folate conditions (LO cells) synthesize more MCP-1 mRNA and secrete more MCP-1 protein than folate-replete control cells (HI cells). We investigated the mechanisms underlying the modulation of MCP-1 expression by long-term "folate stress".CCL2 transcription, assessed using promoter-reporter assays, is up-regulated in LO cells relative to HI cells, whereas MCP-1 mRNA stability is unchanged. This quantitative transcriptional bias under chronic low folate conditions is not attributable to differences in active NF-kappaB, but is associated with elevated levels of both total p38 and phospho-p38 that are detectable by Western immunoblotting. Transient, acute methotrexate-mediated folate depletion or exposure to high concentrations of homocysteine (Hcy) had no effect on MCP-1 synthesis by Ea.hy 926 cells. The p38 inhibitor SB-203580 abolished the excess MCP-1 production by LO cells. The quantitative transcriptional bias of CCL2 in LO cells was retained following massive induction by TNF-alpha.During long-term folate stress, p38 is the primary determinant of CCL2 transcription. Long-term folate insufficiency "primes" Ea.hy 926 endothelial cells to have a quantitatively more vigorous response to cytokine-mediated inflammatory stress.

The objective of this study was to determine whether warfarin dosing algorithms developed for Caucasians and African Americans on the basis of clinical, environmental, and genetic factors will perform better than an empirical starting dose of 5 mg/day. From April 2002 through December 2005, 259 subjects (Caucasians and African Americans) who started using warfarin were prospectively followed until they reached maintenance dose. The Caucasian algorithm included 11 variables (R(2) = 0.43). This model (which predicted 51% of the doses to within 1 mg of the observed dose) performed better than 5 mg/day (which predicted 29% of the doses to within 5 +/- 1 mg). The African-American algorithm included 10 variables (R(2) = 0.28). This model predicted 37% of the doses to within 1 mg of the observed dose, representing a small improvement compared with 5 mg/day (which predicted 34% of the doses to within 1 mg of 5 mg/day). These results were similar to the results we obtained from testing other published algorithms. The dosing algorithms explained

The objective of this study was to determine whether two vitamin K epoxide reductase complex 1 (VKORC1) polymorphisms contribute to the variability in warfarin response, particularly in African Americans. The effect of the VKORC1 1173C/T and -1639G/A polymorphisms was examined in a prospective cohort study of 338 warfarin users. Subjects carrying an 1173T allele had a lower warfarin maintenance dose compared with subjects with the CC genotype in African Americans (-12.10 mg/week+/-4.93; P=0.02) and Caucasians (-14.41 mg/week+/-3.28; P0.001). Before reaching maintenance dose, only Caucasians with the T allele had significantly increased risk of international normalized ratio3 (odds ratio=3.10; 95% confidence interval: 1.73-5.55) compared with Caucasians with the CC genotype. Polymorphisms in the VKORC1 gene are associated with warfarin maintenance dose requirements among both African Americans and Caucasians. However, these polymorphisms may not be as useful in predicting over-anticoagulation among African Americans.

Introduction: Warfarin is a widely prescribed, efficacious oral anticoagulant. S-warfarin, the more active form, is metabolized by the cytochrome P450 (CYP)2C9 enzyme. The aim was to evaluate the influence of two CYP2C9 functional polymorphisms (*2 and *3) on warfarin dose in African–Americans, an unstudied population and Caucasians, and also to assess the effect of these polymorphisms on anticoagulation response after accounting for nongenetic factors and genetic factors that might also impact the dose–response relationship of warfarin. Patients and methods: A prospective cohort of 362 patients with a target international normalized ratio of between 2.0 and 3.0 were genotyped. Warfarin sensitivity stratified by genotype was investigated using univariate and multivariate analyses. Results: The maintenance dose of warfarin was significantly related to genotype (p

Objective To compare the incidence and extent of coronary artery calcification (CAC) as measured by electron beam computed tomography (EBCT) in patients with systemic lupus erythematosus (SLE) and controls, and to identify variables associated with CAC in patients with SLE. Methods Female patients with SLE and matched controls were recruited; EBCT of the coronary arteries was performed, and laboratory values (including the homocysteine concentration, the lipid level, the high-sensitivity C-reactive protein [hsCRP] concentration, the glomerular filtration rate [GFR], and the level of soluble CD154 [sCD154]) were determined. For patients, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index and the SLE Disease Activity Index scores were recorded. Tests of association between the CAC score and the above-mentioned variables were performed. Results The incidence of CAC was higher in patients with SLE than in controls (P = 0.009), and patients had a higher mean raw CAC (rCAC) score (87.9 versus 9.6 in controls; P = 0.02). In particular, more CAC-positive patients than CAC-positive controls had rCAC scores above the 75th percentile (P = 0.003). Among both patients and controls, those with CAC were ∼10 years older than those without CAC. In addition to age, a significant determinant of positive CAC status in both groups was the number of cardiovascular risk factors. In patients with SLE, CAC was associated with a higher homocysteine concentration, a lower GFR, and longer disease duration. In controls, the total cholesterol level correlated positively with CAC. When multivariate logistic regression methods were applied to candidate explanatory variables, homocysteine concentration, age, and disease duration (but not the levels of sCD154 or hsCRP) contributed significantly to CAC status. The methylenetetrahydrofolate reductase C677T genotype was not a predictor of hyperhomocysteinemia or CAC status. Conclusion Among patients with SLE, the homocysteine concentration, the GFR, age, and disease duration were associated with CAC. CAC occurred more frequently and was more extensive in patients with SLE than in controls, suggesting that EBCT could be used to detect premature atherosclerosis in the former group. An elevated homocysteine concentration might identify patients with SLE who are likely to have premature atherosclerosis and who would benefit from evaluation of CAC by EBCT.

Using a collection of Irish sib-pair nuclear families, we previously obtained modest evidence of linkage implicating 14q22-24 in bipolar disorder (BPD). To follow-up on this preliminary finding, an extended linkage analysis was performed which employed thirteen microsatellite markers, spanning a total distance of 85 cM on 14q. Effectively, P-values

PUBLISHED, Substantial evidence suggests that a low folate/high homocysteine phenotype is pathogenic. We analyzed the impact of the thymidylate synthase (TYMS) 3UTR ins/del polymorphism on folate and homocysteine levels and assessed the relationship between the TYMS 3UTR ins/del polymorphism and key genetic and lifestyle variables. Among non-smokers only, the TYMS 3UTR ins/del polymorphism was significantly associated with red blood cell folate (RBC folate; P=0.002) and homocysteine (P=0.03) concentrations. Median RBC folate concentration was much higher for TYMS 3UTR del/del subjects (434 g/l) compared with either ins/ins (282 g/l) or ins/del (298 g/l) subjects. The median homocysteine concentration for del/del homozygotes was considerably lower compared with either ins/ins homozygotes or ins/del heterozygotes. A possible additive effect for the impact of the TYMS 3UTR del/del and MTHFR 677CC genotypes on RBC folate concentration was also observed. Our findings suggest that the TYMS 3UTR del/del genotype is a significant determinant of elevated RBC folate concentration in a non-smoking population of northwestern European adults and that this genotype confers protection against diseases for which a low folate/high homocysteine phenotype appears to be an etiologic component., This work was supported by NIH grant AR47663 and in part by NIH grants HD39195 and HD39081. Support for the Young Hearts Project was provided by the British Heart Foundation and the Wellcome Trust.

Oestrogen, a sex steroid hormone, has long been hypothesized to be involved in alterations to pathways involved in neurotransmission, and therefore may be involved in neuropsychiatric conditions including bipolar disorder. Indeed, certain depressive disorders in women have been found to be associated with low levels of oestrogen and can be much improved by the administration of this hormone. As the effects of oestrogen are most probably mediated through the oestrogen receptors (ER alpha and ER beta), the genes encoding these receptors may be possible candidates for association studies with bipolar disorder and other neuropsychiatric disorders. A number of studies, including previous results from this group, have reported modest evidence of linkage between both bipolar disorder and schizophrenia and a region of chromosome 14 (q22-q24), where the ER beta gene has been localized. In the present study, a sample of 102 Irish parent-proband trios were genotyped for a single nucleotide polymorphism within the ER beta gene (3' untranslated region, A1730G). However, the transmission/disequilibrium test failed to reveal evidence of a distortion in allele transmission to bipolar I (BPI) probands.