Agents and spectres: Life-space on a medium secure forensic psychiatric unit.

Medium secure forensic psychiatric units are unique environments within the broader 'post asylum' landscape of mental health services. Length of stay is much greater, a recovery-focused care system is much more difficult to implement, and there is a paucity of suitable "step-down" services. The aim of this study was to examine how forensic psychiatric environments contribute to the shaping of recovery, by examining key features such as social interactions and agency. Here, we report on the findings from patients participating in a qualitative-visual study. This analysis forms part of larger study on staff and patient experiences of secure hospital space. In this paper, the analytical focus is directed towards two key elements of recovery - agency and relationality, using the concept of 'topology' and 'life-space', developed by the social psychologist Kurt Lewin. First, we explore how patients have relative freedom to move within institutional spaces, yet lack relational space. Secondly, we explore how life-space is expanded or compressed by the manner in which the patient's present life in hospital is connected or disconnected from their past or pending future. Finally, we discuss the implications of these findings for a recovery model within secure forensic settings, focused on personalisation and expanded life-space.

Protein Separation and Hemocompatibility of Nitride Membranes in Microfluidic Filtration Systems.

Improving the health outcomes for end-stage renal Disease (ESRD) patients on hemodialysis (HD) requires new technologies for wearable HD such as a highly efficient membrane that can achieve standard toxic clearance rates in small device footprints. Our group has developed nanoporous silicon nitride (NPN) membranes which are 100 to 1000 times thinner than conventional membranes and are orders-ofmagnitude more efficient for dialysis. Counter flow dialysis separation experiments were performed to measure urea clearance while microdialysis experiments were performed in a stirred beaker to measure the separation of cytochrome-c and albumin. Hemodialysis experiments testing for platelet activation as well as protein adhesion were performed. Devices for the counter flow experiments were constructed with polydimethylsiloxane (PDMS) and a NPN membrane chip. The counter flow devices reduced the urea by as much as 20%. The microdialysis experiments showed a diffusion of ~ 60% for the cytochrome-c while clearing ~ 20% of the Albumin. Initial hemocompatibility studies show that the NPN membrane surface is less prone to both protein adhesion and platelet activation when compared to positive control (glass).

Genetic and phenotypic overlap of specific obsessive-compulsive and attention-deficit/hyperactive subtypes with Tourette syndrome.

BACKGROUND: The unique phenotypic and genetic aspects of obsessive-compulsive (OCD) and attention-deficit/hyperactivity disorder (ADHD) among individuals with Tourette syndrome (TS) are not well characterized. Here, we examine symptom patterns and heritability of OCD and ADHD in TS families. METHOD: OCD and ADHD symptom patterns were examined in TS patients and their family members (N = 3494) using exploratory factor analyses (EFA) for OCD and ADHD symptoms separately, followed by latent class analyses (LCA) of the resulting OCD and ADHD factor sum scores jointly; heritability and clinical relevance of the resulting factors and classes were assessed. RESULTS: EFA yielded a 2-factor model for ADHD and an 8-factor model for OCD. Both ADHD factors (inattentive and hyperactive/impulsive symptoms) were genetically related to TS, ADHD, and OCD. The doubts, contamination, need for sameness, and superstitions factors were genetically related to OCD, but not ADHD or TS; symmetry/exactness and fear-of-harm were associated with TS and OCD while hoarding was associated with ADHD and OCD. In contrast, aggressive urges were genetically associated with TS, OCD, and ADHD. LCA revealed a three-class solution: few OCD/ADHD symptoms (LC1), OCD & ADHD symptoms (LC2), and symmetry/exactness, hoarding, and ADHD symptoms (LC3). LC2 had the highest psychiatric comorbidity rates (⩾50% for all disorders). CONCLUSIONS: Symmetry/exactness, aggressive urges, fear-of-harm, and hoarding show complex genetic relationships with TS, OCD, and ADHD, and, rather than being specific subtypes of OCD, transcend traditional diagnostic boundaries, perhaps representing an underlying vulnerability (e.g. failure of top-down cognitive control) common to all three disorders.

The genetic architecture of pediatric cognitive abilities in the Philadelphia Neurodevelopmental Cohort.

The objective of this analysis was to examine the genetic architecture of diverse cognitive abilities in children and adolescents, including the magnitude of common genetic effects and patterns of shared and unique genetic influences. Subjects included 3689 members of the Philadelphia Neurodevelopmental Cohort, a general population sample comprising those aged 8-21 years who completed an extensive battery of cognitive tests. We used genome-wide complex trait analysis to estimate the SNP-based heritability of each domain, as well as the genetic correlation between all domains that showed significant genetic influence. Several of the individual domains suggested strong influence of common genetic variants (for example, reading ability, h(2)g=0.43, P=4e-06; emotion identification, h(2)g=0.36, P=1e-05; verbal memory, h(2)g=0.24, P=0.005). The genetic correlations highlighted trait domains that are candidates for joint interrogation in future genetic studies (for example, language reasoning and spatial reasoning, r(g)=0.72, P=0.007). These results can be used to structure future genetic and neuropsychiatric investigations of diverse cognitive abilities.

Genome-wide association study of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Efficiency of molar distalization with the XBow appliance related to second molar eruption stage.

To quantitatively evaluate on lateral cephalograms horizontal, vertical, and angular changes in the position of the maxillary first molar based on the presence and absence of erupted maxillary second molars when it is distalized with the XBow appliance. In this retrospective study, a total of 102 consecutively treated cases were assessed. Lateral cephalograms were obtained at the start and after completion of active treatment with the XBow appliance. In one group of patients, distal movement of the maxillary first molars was performed before the eruption of maxillary second molars; in the other group of patients, both first and second maxillary molars were simultaneously moved distally. All cephalograms were superimposed on palatal plane using the method of best-fit. In order to compare the mean horizontal, vertical, and angular changes in molar position between the treatment groups and gender, a multivariate analysis of covariance (MANCOVA) was performed with the pre-treatment class II severity used as a covariate. Regression analysis was also performed to further explore any possible relationships between the predictor variables and the quantity and quality of distalization. A MANCOVA revealed that the eruption stage of the maxillary second molar did not have a significant effect on the change in position of the maxillary first molar after treatment with a XBow appliance. When distalizing maxillary first molars with a XBow appliance, there is no difference in the amount of distalization in patients with erupted and unerupted maxillary second molars.

A latent modeling approach to genotype-phenotype relationships: maternal problem behavior clusters, prenatal smoking, and MAOA genotype.

This study illustrates the application of a latent modeling approach to genotype-phenotype relationships and gene × environment interactions, using a novel, multidimensional model of adult female problem behavior, including maternal prenatal smoking. The gene of interest is the monoamine oxidase A (MAOA) gene which has been well studied in relation to antisocial behavior. Participants were adult women (N = 192) who were sampled from a prospective pregnancy cohort of non-Hispanic, white individuals recruited from a neighborhood health clinic. Structural equation modeling was used to model a female problem behavior phenotype, which included conduct problems, substance use, impulsive-sensation seeking, interpersonal aggression, and prenatal smoking. All of the female problem behavior dimensions clustered together strongly, with the exception of prenatal smoking. A main effect of MAOA genotype and a MAOA × physical maltreatment interaction were detected with the Conduct Problems factor. Our phenotypic model showed that prenatal smoking is not simply a marker of other maternal problem behaviors. The risk variant in the MAOA main effect and interaction analyses was the high activity MAOA genotype, which is discrepant from consensus findings in male samples. This result contributes to an emerging literature on sex-specific interaction effects for MAOA.

The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data.

The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13,835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ∼0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.

The mechanistic basis for sexual dysfunction in male transforming growth factor beta1 null mutant mice.

The cytokine transforming growth factor beta1 (TGFB1) is implicated in male sexual function. Previous behavioral studies show that Tgfb1 null mutant mice mount and display limited intromission behavior with receptive females but are unable to complete successful copulation. The studies presented here explore the physiologic basis for sexual dysfunction in Tgfb1 null mutant males. Scanning electron microscopy revealed that the surface of the penis in Tgfb1 null mutant males was abnormally coated in superficial keratinized epithelial cells. There was a significant reduction in protrusion of penile spines through the superficial tissue in Tgfb1 null mutant mice; in some mice, the spines were almost completely embedded. Histologic analysis revealed reduced skin thickness in the penis of Tgfb1 null mutant males. Nerve fibers, endothelial cells, smooth muscle actin, macrophages, and neuronal and inducible nitric oxide synthase were present in similar abundance and location in Tgfb1 null mutant mice compared with wild-type controls; however, an increase in collagen I deposition was detected. Behavioral studies revealed that Tgfb1 null mutant males undergo spontaneous noncontact erections, albeit at a reduced rate compared with control mice, and engage in less frequent genital grooming activity. These studies suggest that Tgfb1 null mutation may adversely influence copulatory behavior through effects on both altered structural integrity of the penile skin and impaired tissue compliance leading to erectile dysfunction.

Integration and decontamination of Bacillus cereus in Pseudomonas fluorescens biofilms.

AIMS: The hypothesis that surrogate planktonic pathogens (Bacillus cereus and polystyrene microspheres) could be integrated in biofilms and protected from decontamination was tested. METHODS AND RESULTS: Pseudomonas fluorescens biofilms were grown on polyvinyl chloride coupons in annular reactors under low nutrient conditions. After biofilm growth, B. cereus spores and polystyrene microspheres (an abiotic control) were introduced separately. Shear stress at the biofilm surface was varied between 0.15 and 1.5 N m(-2). The amount of surrogate pathogens introduced ranged from approximately 10(5) CFU ml(-1) to 10(10 )spheres ml(-1). The quantity of surrogate pathogens integrated in the biofilm was proportional to the amount introduced. In 14 of the 16 cases, 0.4-3.0% of the spores or spheres introduced were measured in the biofilms. The other two cases had 10% and 21% of the spores detected. Data suggested that the spores germinated in the system. The amount of surrogate pathogens detected in the biofilms was higher in the mid-shear range. Chlorine treatment reduced the quantity of both surrogate pathogens and biofilm organisms. In one experiment, the biofilms and B. cereus recovered when the chlorine treatment was terminated. CONCLUSIONS: Planktonic surrogate pathogens can be integrated in biofilms and protected from chlorination decontamination. SIGNIFICANCE AND IMPACT OF THE STUDY: This knowledge assists in understanding the impact of biofilms on harbouring potential pathogens in drinking-water systems and protecting the pathogens from decontamination.

Caspase-activated DNase (CAD)-independent oligonucleosomal DNA fragmentation in chronic myeloid leukaemia cells; a requirement for serine protease and Mn2+-dependent acidic endonuclease activity.

We have previously reported that the pro-apoptotic pyrrolobenzoxazepine, PBOX-6, induces apoptosis in chronic myelogenous leukaemia (CML) cells which is accompanied by oligonucleosomal DNA fragmentation. In this study we show that PBOX-6-induced oligonucleosomal DNA fragmentation occurs in the absence of caspase and CAD activation in CML cells. Dissection of the signalling pathway has revealed that induction of apoptosis requires the upstream activation of a trypsin-like serine protease that promotes the phosphorylation and inactivation of anti-apoptotic Bcl-2. In addition, in this system chymotrypsin-like serine proteases are dispensable for high molecular weight DNA fragmentation, however are required for the activation of a relatively small manganese-dependent acidic endonuclease that is responsible for oligonucleosomal fragmentation of DNA. Furthermore, we demonstrate mitochondrial involvement during PBOX-6-induced apoptosis and suggest the existence of unidentified mitochondrial effectors of apoptosis.

Malondialdehyde and measures of antioxidant activity in subjects from the Belfast Elderly Longitudinal Free-living Aging Study.

Glutathione and glutathione peroxidase activity are important components in the complex body defense against oxidative damage. In this study, we have measured malondialdehyde (MDA) as a marker of oxidative stress, the antioxidant glutathione (GSH), and activity of the antioxidant enzyme (GSHPx), in a cohort of free-living elderly subjects from the Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST), hypothesizing that free-living Senieur-approximated nonagenarians might demonstrate enhanced antioxidant defense mechanisms. The main finding in the BELFAST octo/nonagenarians was that plasma antioxidant glutathione increased in nonagenarian compared with septo/octogenarian subjects (P =.015), whereas conversely antioxidant glutathione peroxidase activity fell in the nonagenarian group (P <.0001). In the same subject group, malondialdehyde, a measure of lipid peroxidation, showed no change across the age groups (P =.73). These results might overall represent a situation in which elderly survivors in the BELFAST study have evolved a sort of free radical/antioxidant equilibrium as a mechanism of successful aging.

The social phobia diagnostic questionnaire: preliminary validation of a new self-report diagnostic measure of social phobia.

BACKGROUND: The development and validation of the Social Phobia Diagnostic Questionnaire (SPDQ), a new self-report diagnostic instrument for social phobia is described in three separate studies. STUDY 1: The participants were 125 undergraduates seeking help for an anxiety disorder of whom 60 had social phobia. Receiver operating characteristics (ROC) analysis was conducted comparing SPDQ diagnoses and clinician-based Anxiety Disorder Interview Schedule-IV (ADIS-IV) diagnoses of social phobia. Diagnoses made by the SPDQ showed an 85% specificity, an 82% sensitivity and kappa agreement with the ADIS-IV of 0.66. STUDY 2: The participants were 462 undergraduates who completed the SPDQ and a battery of additional questionnaires. The SPDQ had good internal consistency (alpha=0.95), good split-half reliability (r=0.90) and strong convergent and discriminant validity. STUDY 3: The participants were 145 undergraduates who completed the SPDQ at two time points separated by 2 weeks as well as several additional questionnaires. Scores on the SAD, FNE and SISST of SPDQ categorized undergraduates were also compared to scores on these measures from 35 clinical community participants to determine the clinical validity of the SPDQ. The SPDQ had strong 2-week test-retest reliability and good convergent and discriminant validity. Undergraduates diagnosed with social phobia by the SPDQ were not significantly different on the SAD, FNE and SISST from the socially phobic community sample, but both groups had significantly higher scores than undergraduates identified by the SPDQ as not meeting criteria for social phobia, demonstrating clinical validity of the SPDQ. CONCLUSIONS: These three studies provide preliminary evidence of the strong psychometric properties of the SPDQ as a measure to identify socially phobic participants.

Individuals with cystic fibrosis do not display impaired endothelial function or evidence of oxidative damage in endothelial cells exposed to serum.

Heightened systemic oxidative stress is increasingly recognized as a feature of cystic fibrosis (CF). The consequences of long-term exposure to free radical attack include a predisposition to diseases such as cancer and atherosclerosis. An increased incidence of malignancy among adult patients with CF has been reported, but the absence of atherosclerotic disease is well described. The aim of the present study was to assess endothelial function in vivo and relate this to the potential of serum from patients with CF to induce oxidative-mediated damage in cultured human endothelial cells. A group of 11 CF patients was matched with a group of healthy volunteers with regard to age and sex. Endothelial function was assessed as endothelium-dependent and -independent vasodilation by measuring forearm blood flow in response to infused acetylcholine and sodium nitroprusside respectively. Confluent monolayers of cultured human endothelial cells were exposed to serum from CF patients and control subjects. Following exposure, cell death was assessed by lactate dehydrogenase release, and the degree of lipid peroxidation in the membrane was assessed by measuring the content of lipid hydroperoxides, malondialdehyde and 4-hydroxynonenal. Endothelial monolayers exposed to serum from CF patients released significantly less lactate dehydrogenase following exposure than those exposed to serum from healthy controls (1.8% and 3.0% respectively; mean difference -1.2%; 95% confidence intervals -1.9% to -0.1%; P<0.05) and contained significantly less 4-hydroxynonenal (0.75 and 3.41 micromol/g of protein respectively; mean difference -2.66 micromol/g; 95% confidence intervals -5.10 to -0.22 micromol/g; P<0.05). There was no significant difference between patients and controls in the extent of serum-induced membrane peroxidation, as assessed by malondialdehyde or lipid hydroperoxides, or in endothelial function, as assessed by forearm blood flow. In conclusion, despite evidence for heightened systemic oxidative stress in CF, patients displayed no impairment of endothelial function, and their serum caused significantly less damage to human endothelial cells than that from matched controls.

Breath isoprene in patients with heart failure.

BACKGROUND: Chronic heart failure (CHF) is characterised by increased vascular resistance. This increased after load on the left ventricle contributes to the vicious cycle that leads to progression of myocardial failure, multiple organ failure and death. There is evidence for increased oxidative stress in heart failure, which will influence the myocardium but also peripheral vasculature endothelium. AIMS: The aim of the present study was to examine the production of isoprene, reputed to reflect oxidative stress, in patients with CHF compared to control subjects. METHODS: Twelve patients with CHF and thirty-one healthy control subjects free from heart disease were studied. Breath was collected via a two-way non-re-breathing valve into a 60-l gas collection bag. A sample of ambient air was collected at the same time. A measured aliquot of patient breath and ambient air (approx. 1.5 l) was adsorbed onto a gas adsorption tube packed with poropak-Q. Isoprene was measured using GC/MS and the production rate calculated. All samples of breath were collected at 10.00 h after subjects had been sitting at rest for 15 min. RESULTS: Breath isoprene production in subjects with CHF was significantly reduced compared to controls 83(23) vs. 168(20) pmol min(-1) kg(-1). CONCLUSION: Breath isoprene does not directly reflect oxidative stress in CHF.

Increased oxidative stress in Alzheimer's disease as assessed with 4-hydroxynonenal but not malondialdehyde.

Oxidative stress is thought to play a major role in the pathogenesis of Alzheimer's disease (AD). Although there is strong post-mortem and experimental evidence of oxidative damage occurring in AD brains, the use of markers in the peripheral circulation to show oxidative stress is less convincing. We examined plasma from AD patients for markers of increased oxidative stress. We report elevated levels of 4-hydroxy-nonenal (4-HNE) in AD patients compared to controls (median 20.6, IQR 6.0-25.2 vs. 7.8, 3.3-14.5 micomol/l, respectively; p=0.001) but not malondialdehyde (MDA), and lower levels of ascorbate in AD plasma when compared to age-matched controls (9.9, 6.0-33.7 vs. 24.2, 13.9-48.6 micromol/l; p<0.05). Levels of 4-HNE in AD patients were inversely related to ascorbate (r=-0.337; p=0.07) and Folstein Mini-Mental State Examination (MMSE) (r=-0.474; p=0.015). The concentration of protein sulphydryls, free-radical scavengers, was directly related to the MMSE result (r=0.427; p=0.03). Increased production of 4-HNE indicates increased oxidative stress (lipid peroxidation), which is not evident using the more common marker MDA. This elevation of 4-HNE was related to the degree of cognitive impairment (MMSE).

Experience with urine drug testing by the Correctional Service of Canada.

The Correctional Service of Canada implemented a urine drug-screening program over 10 years ago. The objective of this report is to describe the program and drug test results in this program for 1999. Offenders in Canadian federal correctional institutions and those living in the community on conditional release were subject to urine drug testing. Urine specimens were collected at correctional facilities and shipped by courier to MAXXAM Analytics Inc. laboratory. All urine specimens were analyzed for amphetamines, cannabinoids, cocaine metabolite (benzoylecgonine), opiates, phencyclidine, benzodiazepines, methyl phenidate, meperidine, pentazocine and fluoxetine by immunoassay screening (homogeneous EIA and ELISA assays) followed by GC-MS confirmation. Ethyl alcohol was analyzed when specifically requested. Alternative screening and confirmation methods with lower cut-off values were used, whenever urine specimens were dilute (creatinine <20mg/dl and specific gravity

The effect on endothelial function of vitamin C during methionine induced hyperhomocysteinaemia.

BACKGROUND: Manipulation of total homocysteine concentration with oral methionine is associated with impairment of endothelial-dependent vasodilation. This may be caused by increased oxidative stress. Vitamin C is an aqueous phase antioxidant vitamin and free radical scavenger. We hypothesised that if the impairment of endothelial function related to experimental hyperhomocysteinaemia was free radically mediated then co-administration of vitamin C should prevent this. METHODS: Ten healthy adults took part in this crossover study. Endothelial function was determined by measuring forearm blood flow (FBF) in response to intra-arterial infusion of acetylcholine (endothelial-dependent) and sodium nitroprusside (endothelial-independent). Subjects received methionine (100 mg/Kg) plus placebo tablets, methionine plus vitamin C (2 g orally) or placebo drink plus placebo tablets. Study drugs were administered at 9 am on each study date, a minimum of two weeks passed between each study. Homocysteine (tHcy) concentration was determined at baseline and after 4 hours. Endothelial function was determined at 4 hours. Responses to the vasoactive substances are expressed as the area under the curve of change in FBF from baseline. Data are mean plus 95% Confidence Intervals. RESULTS: Following oral methionine tHcy concentration increased significantly versus placebo. At this time endothelial-dependent responses were significantly reduced compared to placebo (31.2 units [22.1-40.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo). Endothelial-independent responses were unchanged. Co-administration of vitamin C did not alter the increase in homocysteine or prevent the impairment of endothelial-dependent responses (31.4 [19.5-43.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo) CONCLUSIONS: This study demonstrates that methionine increased tHcy with impairment of the endothelial-dependent vasomotor responses. Administration of vitamin C did not prevent this impairment and our results do not support the hypothesis that the endothelial impairment is mediated by adverse oxidative stress.

The effects of oral methionine and homocysteine on endothelial function.

BACKGROUND: Raised homocysteine is a risk factor for vascular disease. Homocysteine is formed from methionine, and dietary manipulation of homocysteine in primates and humans with oral methionine is associated with endothelial dysfunction. A cause-effect relation has not been clearly established. AIM: To study the effect of oral methionine and then oral homocysteine on endothelial function. METHODS: 22 healthy adults were recruited for two randomised crossover studies, each containing 11 subjects. Endothelial function was determined by measuring forearm blood flow in response to intra-arterial infusion of acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent). Subjects received methionine or placebo (study 1), or homocysteine or placebo (study 2). Methionine and homocysteine were determined at baseline and t = 4 hours. Endothelial function was determined at four hours. The responses to the vasoactive substances are expressed as the area under the curve of change in forearm blood flow from baseline. RESULTS: Study 1: plasma methionine and homocysteine concentrations increased significantly versus placebo. The increases were associated with a reduction of endothelium dependent responses (mean (95% confidence interval), arbitrary units), from 48.8 (95% CI 36.4 to 61.2) to 29.9 (95% CI 18.0 to 41.1), p < 0.04; endothelium independent responses were unchanged. Study 2: homocysteine concentration increased significantly while methionine remained unchanged. Endothelium dependent responses were reduced from 34.6 (95% CI 20.6 to 48.6) to 22.8 (95% CI 12.0 to 33.6), p < 0.03. CONCLUSIONS: Homocysteine and not methionine is responsible for the changes in endothelial function. This supports the hypothesis that homocysteine promotes atherosclerosis by inducing endothelial dysfunction.