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Diversity in terms of class, sexual identity and migration background among medical students in high income countries has increased greatly in recent decades. Some research into the experiences of these new groups of doctors has been performed. However, no previous research into the experiences of psychiatry residents specifically, is known. This qualitative study investigates how psychiatry residents, from these minoritized groups, experience their training regarding inclusion. Inclusion is defined as the degree to which one's needs for connection and for being valued in one's uniqueness, is satisfied. In-depth interviews with 16 psychiatry residents were conducted. These interviews were transcribed and coded using MaxQDA software. Initial themes that were constructed, were explored further in subsequent interviews and linked to literature. Finally, the developed themes were ordered in a model conceptualizing inclusion. Participants reported high belongingness within psychiatry training. Their experienced value in uniqueness, however, was generally quite low. Participants reported to experience little interest in and sensitivity for their perspectives and lived experiences from their co-workers. When faced with stigmatization and discrimination, participants reported lack of support from their colleagues. Assimilation was found to be the most frequently used coping strategy in dealing with diversity. Participants seemed to conform to the 'neutral' norm and experienced barriers in expressing themselves. Through this mechanism of assimilation, the added value that participants might bring with their unique knowledge and lived experiences was not used, both in patient care and in creating an inclusive climate within the organization. Moreover, assimilation is associated with psychological strain., (© 2023. The Author(s).)

Moe Kura is a longitudinal study focused on the role of sleep in the health and well-being of mothers and children in Aotearoa New Zealand (NZ). The leadership, design and conduct of the study is informed by Kaupapa Māori research principles and is positioned within a broader rights-based approach to health, recognising that inequities in health must be identified and understood to improve the health of wāhine Māori and tamariki. In late pregnancy 418 Māori women and 768 non-Māori women were recruited and data collected at four waves (35-37 weeks gestation, 4-6 weeks postpartum, 11-13 weeks postpartum and when the Moe Kura child was 3-4 years of age) with linkage to birth records and national administrative datasets and associated qualitative research. Findings demonstrate substantial inequities in sleep health, infant and maternal health, and maternal employment between Māori and non-Māori, along with the important role of sleep in perinatal health and maternal mental health outcomes. The research philosophy that underpins the study, the primary focus on women, and the detailed measurement of sleep during the childbearing years has provided new and important findings that contribute to intervention development and health policy for women and children in NZ., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Royal Society of New Zealand.)

Background   In recent years, diversity among therapists in terms of migratory background and openly expressed LGBTQ+ identity has increased. As a result, there are more often dyads in which the patient and therapist belong to the same minority. Aim   To illustrate how having a similar background can influence the therapeutic relationship. These illustrations can help practitioners reflect on how best make use of this similarity. Method   We describe two therapies where therapist and patient shared migratory background and a LGBTQ+ identity. Possible advantages and disadvantages of these similarities are discussed. Finally, we discuss the barriers that therapists can experience to introduce these themes in supervision and intervision. Results   In the case reports, both patients seemed to benefit from having a therapist from the same minority group, partly because he made the similarities in identity open to discussion. They felt that they were understood and were less afraid of negative reactions, which made them feel safe and supported to work on their own conflicts in this dyad. Conclusion   Discussing similarities in identity between therapist and patient can be of added value. With a shared migration background and LGBTQ+ identity, it seems that the same mechanisms often play a role.

Background: People with schizophrenia smoke about 5.6 times as much as people without the disease. This factor is a major but treatable cause of morbidity and mortality in this patient population. Nevertheless, health professionals make relatively little effort to discourage people from smoking or to give it up altogether.
AIM: To increase health professionals' knowledge about possible therapeutic interventions that can help people with schizophrenia to stop smoking.
METHOD: We studied the relevant literature.
RESULTS: Many people with schizophrenia do in fact want to give up smoking. However, many health professionals are reluctant to intervene because, as a result, people with schizophrenia might experience a deterioration in their mental state. We believe that people with schizophrenia who are determined to give up smoking need to receive a combination of pharmacotherapy and psychological support. This patient population requires a longer than normal period of treatment.
CONCLUSION: So far, a combination of bupropion, nicotine patches and psychological support has proved the most effective form of support for this target group consisting of people with schizophrenia.

Increased oxidative stress has been implicated in both the onset and the progression of diabetes mellitus and its complications. The development of easy to measure biomarkers of oxidative stress would, therefore, help in determining in a prospective manner the impact of glycemic control on oxidative stress and macrovascular disease in patients with diabetes. We report the development and validation of a novel method to directly measure the urinary concentrations of the conjugated metabolites of vitamin E (α-tocopherol) and investigate whether the oxidized metabolite α-tocopheronolactone (α-TL) could be used as a biomarker of oxidative stress in children with type 1 diabetes. A novel method using liquid chromatography-tandem mass spectrometry was developed and used to measure directly and rapidly the urinary concentrations of the glucuronidated and sulfated metabolites of α-tocopherol in 32 young patients with type 1 diabetes and age-matched controls. The mean concentrations of the glucuronidated and sulfated conjugates of α-TL were all highly significantly increased in the children with type 1 diabetes (p<0.001). The results suggest that the measurement of the urinary concentrations of α-TL conjugates may provide a useful biomarker of oxidative stress in diabetes and possibly in other clinical conditions in which oxidative stress has been implicated., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The clinical, neuropathological and electrophysiological evidence that vitamin E (alpha-tocopherol) is essential for normal neurological function will be reviewed. The possible reasons why neural tissues should be particularly affected by a deficiency of this fat-soluble vitamin and the mechanism(s) involved will be considered.

Objectives: To assess whether supplementation with antioxidants, folinic acid, or both improves the psychomotor and language development of children with Down's syndrome., Design: Randomised controlled trial with two by two factorial design., Setting: Children living in the Midlands, Greater London, and the south west of England., Participants: 156 infants aged under 7 months with trisomy 21., Intervention: Daily oral supplementation with antioxidants (selenium 10 mug, zinc 5 mg, vitamin A 0.9 mg, vitamin E 100 mg, and vitamin C 50 mg), folinic acid (0.1 mg), antioxidants and folinic acid combined, or placebo., Main Outcome Measures: Griffiths developmental quotient and an adapted MacArthur communicative development inventory 18 months after starting supplementation; biochemical markers in blood and urine at age 12 months., Results: Children randomised to antioxidant supplements attained similar developmental outcomes to those without antioxidants (mean Griffiths developmental quotient 57.3 v 56.1; adjusted mean difference 1.2 points, 95% confidence interval -2.2 to 4.6). Comparison of children randomised to folinic acid supplements or no folinic acid also showed no significant differences in Griffiths developmental quotient (mean 57.6 v 55.9; adjusted mean difference 1.7, -1.7 to 5.1). No between group differences were seen in the mean numbers of words said or signed: for antioxidants versus none the ratio of means was 0.85 (95% confidence interval 0.6 to 1.2), and for folinic acid versus none it was 1.24 (0.87 to 1.77). No significant differences were found between any of the groups in the biochemical outcomes measured. Adjustment for potential confounders did not appreciably change the results., Conclusions: This study provides no evidence to support the use of antioxidant or folinic acid supplements in children with Down's syndrome., Trial Registration: Clinical trials NCT00378456.

A severe and chronic deficiency of vitamin E (alpha-tocopherol) is associated with a characteristic neurological syndrome with typical "clinical," neuropathological, and electrophysiological abnormalities in both humans and experimental animals. Repletion of vitamin E-deficient human subjects with alpha-tocopherol typically halts the progression of the neural signs and symptoms, and in some cases, can result in objective improvement. Electrophysiological parameters provide an objective measure of neural and visual function and improvement of some of these measures has been reported after repletion with vitamin E in humans. In this longitudinal study, the effects of repleting rats with a diet containing 36 mg/kg all-rac-alpha-tocopheryl acetate for 20 wk after they had been receiving a vitamin E-deficient diet for 38 wk was studied. We report significant improvements in growth and a number of electrophysiological parameters of both neural and visual function after repletion. These results confirm the validity of the vitamin E-deficient rat as a model of vitamin E deficiency in humans.

A rat model of vitamin E (alpha-tocopherol) deficiency with similar "clinical," electrophysiological, and neuropathological abnormalities to those seen in man was used to investigate the effects of various amounts and forms of alpha-tocopheryl acetate (alphaTA) on neural and visual function. Electrophysiological techniques provide an objective, non-invasive measure of neural and visual function. These techniques were used in the animal model to determine the minimum dietary requirement of vitamin E necessary to prevent neural and visual abnormalities. They were also used to compare the biological activities of the natural (RRR-) and synthetic (all-rac-) forms of alpha-tocopherol in neural tissues. The results were as follows: (1) Significant differences in neural and visual function were observed between deficient and control rats after approximately 8 months. (2) An intake of 1.0 mg/kg all-rac- or 0.75 mg/kg RRR-alphaTA was observed to marginally protect nerves from vitamin E deficiency. (3) The biological activity of all-rac-alpha-tocopherol in neural tissues was approximately 75% of RRR-alpha-tocopherol. (4) The concentration of free malondialdehyde (an indicator of lipid peroxidation) was significantly increased in tissues from the deficient compared to the control animals. These results are consistent with a deficiency of alpha-tocopherol causing increased lipid peroxidation leading to abnormal neural electrophysiology. They could also be explained by more specific but as yet undefined function(s) of alpha-tocopherol in neural tissues.

The UK Food Standards Agency convened a group of expert scientists to review current research investigating the effect of dietary lipids on vascular function. The workshop highlighted the need for intervention studies to be sufficiently powered for these measures and that they should be corroborated with other, more validated, risk factors for CVD. Work presented at the workshop suggested a beneficial effect of long-chain n-3 PUFA and a detrimental effect of trans fatty acids. The workshop also considered the importance of the choice of study population in dietary intervention studies and that "at risk" subgroups within the general population may be more appropriate than subjects that are unrepresentatively healthy.

Objective: A rat model of vitamin E (alpha-tocopherol) deficiency with similar "clinical", electrophysiological and neuropathological abnormalities to that seen in man was used to investigate the effects of various dietary intakes of synthetic (all-rac-) and natural (RRR-) alpha-tocopheryl acetate (alphaTA) on visual function., Methods: Longitudinal measurements of the electroretinogram (ERG) and visual evoked potentials (VEPs) were made monthly for 14 months in 9 groups of rats (n=12/group) receiving different amounts and types of alphaTA. The animals were then killed for biochemical analyses., Results: (1) The first significant abnormalities of both the ERG and VEP were found after 8 months of deficiency. (2) A diet containing 1.25 mg/kg of alphaTA provided marginal protection. (3) The biological activity of all-rac- was approximately 75% of RRR-alphaTA. (4) The concentration of free malondialdehyde (a measure of lipid peroxidation) was significantly increased in all tissues, including the eye, from deficient compared to control rats., Conclusions: These results are consistent with alpha-tocopherol deficiency causing increased lipid peroxidation leading to abnormal visual function but could also be explained by more specific but undefined function(s) of alpha-tocopherol in the eye.

Background: Epidemiological studies have reported an inverse relationship between vitamin E status and coronary heart disease. This relationship has not, however, been confirmed by the majority of intervention studies, which have been carried out relatively late in the disease process. The protective effects of vitamin E may be more important earlier in life, before vascular changes have become established. This study investigated whether dietary vitamin E could prevent preclinical arterial changes in young adults relevant to the development of cardiovascular disease., Materials and Methods: Measures of vascular function (arterial distensibility and endothelial-dependent and -independent vascular responses) were assessed by noninvasive high resolution ultrasound and related to plasma vitamin E and total antioxidant concentrations in 326 adults, aged 20-28 years., Results: Neither vitamin E (alone or adjusted for lipids) nor total antioxidant status were significantly related to vascular endothelial function or arterial distensibility in either sex. There was no threshold level of vitamin E above which vascular function improved and neither vitamin E nor total antioxidant status interacted with any risk factor, such as smoking or increased low-density lipoprotein concentrations., Conclusions: Neither plasma vitamin E concentrations nor total antioxidant status achieved by dietary intake during young adulthood were related to vascular endothelial function or arterial distensibility.

Glucuronide and sulphate conjugates of 2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC), the major metabolite of alpha-tocopherol (vitamin E), have been synthesized and used for the first direct analysis of conjugated urinary vitamin E metabolites. The metabolites of vitamin E (alpha-tocopherol) could be useful as markers of the function(s) of vitamin E in vivo. A number of methods have been described for the analysis of urinary vitamin E metabolites but these have relied on either acid or enzymatic deconjugation of the metabolites prior to analysis by high performance liquid chromatography or gas chromatography/mass spectrometry. These methods have provided useful information about the amount and types of metabolites excreted in the urine but suffer from a number of disadvantages. Deconjugation has been shown to produce artifacts as a result of the conversion of alpha-CEHC to alpha-tocopheronolactone and the efficiency of deconjugation is also difficult to assess. Methods that allow the direct measurement of the conjugated metabolites would overcome these problems and would also substantially reduce the preparation and analysis time. Here we describe the use of conjugated standards to characterize alpha-CEHC conjugates in human urine by tandem mass spectrometry (MS-MS). The future use of MS-MS to measure urinary vitamin E metabolites is also discussed., (Copyright 2002 Elsevier Science Inc.)

An endothelial nitric oxide synthase (eNOS) gene polymorphism (Glu298Asp) has been associated with cardiovascular disease. We investigated whether carriage of the polymorphism was associated with functional changes in the endothelium, and how genotype altered the harmful and beneficial impact of environmental influences on the endothelium. Endothelium-dependent, flow-mediated brachial artery dilatation (FMD) and endothelium-independent dilatation response to glyceryl trinitrate were measured using high-resolution ultrasound in 248 subjects (131 female, 117 male, aged 20 to 28) genotyped for the Glu298Asp polymorphism. Vascular function was compared between genotype groups and interactions with the proatherogenic risk factor, smoking, and the antiatherogenic influence of n-3 fatty acids (n-3FA) were investigated. Vascular function was not related to genotype in the group as a whole or within sexes. However, among males, smoking was associated with lower FMD in Asp298 carriers (nonsmokers 0.125+/-0.085 mm versus smokers 0.070+/-0.060 mm, P=0.006) but not in Glu298 homozygotes (nonsmokers 0.103+/-0.090 mm versus smokers 0.124+/-0.106, P=0.5). In the whole group, n-3FA levels were positively related to FMD in Asp298 carriers (reg coeff=0.023 mm/%, P=0.04, r=0.20) but not in Glu298 homozygotes (reg coeff=-0.019 mm/%, P=0.1). These differences between genotype groups were significant in interaction models. The Glu298Asp polymorphism is associated with differences in endothelial responses to both smoking and n-3 FA in healthy young subjects. These findings raise the possibility of genotype-specific prevention strategies in cardiovascular disease.

Aims: Fish consumption is inversely associated with cardiovascular mortality, presumably because of n-3 fatty acids in fish. Whether the protection of n-3 fatty acids extends beyond clinical coronary disease to influence the early vascular biology of atherosclerosis remains unclear. This study determined whether circulating levels of n-3 fatty acids are associated with vascular endothelial function in early adulthood., Methods and Results: Three hundred and twenty-six adults (157 males, 169 females, aged 20 to 28 years) had high-resolution ultrasound measurements of flow-mediated brachial artery dilatation (FMD) (endothelium-dependent) and arterial response to glyceryl trinitrate (endothelium-independent). Levels of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid in plasma and erythrocyte membranes of subjects were measured. n-3 Fatty acid levels were not related to vascular function in the whole group. In smokers, however, n-3 fatty acids were positively related to flow-mediated dilatation (plasma DHA vs. FMD: 0.045 mm. %(-1), 95% CI 0.011 to 0.079, P=0.01). Flow-mediated dilatation was also associated with n-3 fatty acid levels in subjects in the top third of the insulin, glucose and triglyceride distributions., Conclusion: In young smokers and those with higher fasting insulin, glucose or triglyceride concentrations (factors associated with endothelial dysfunction), n-3 fatty acid levels were positively associated with flow-mediated dilatation. This raises the possibility that physiological levels of circulating n-3 fatty acids may protect the endothelium from early adulthood., (Copyright 2001 The European Society of Cardiology.)

Adult Refsum disease is an inherited disorder in which phytanic acid accumulates in tissues and serum. Two hypotheses have been proposed to explain the pathogenesis of this condition. The molecular distortion hypothesis suggests that phytanic acid may alter membrane composition and structure, thereby affecting membrane function(s). The anti-metabolite hypothesis suggests that an accumulation of phytanic acid in membranes may interfere with vitamin E function. These two hypotheses were investigated by studying the effects of modulating phytanic acid and alpha-tocopherol concentrations on the fatty acid composition and certain physical parameters of cultured retinal cells. Results showed that (a) the phospholipid fraction of retinal cells readily incorporated phytanic acid, (b) the incorporation of phytanic acid increased membrane fluidity, (c) there was no competition for uptake between phytanic acid and alpha-tocopherol, and (d) the incorporation of phytanic acid did not increase the susceptibility of membranes to lipid peroxidation in vitro. These results obtained with cultured retinal cells suggest that the molecular distortion hypothesis, but not the anti-metabolite hypothesis, could explain the pathogenesis of adult Refsum disease. In vitro tissue culture models can, however, only approximate to the much more complex situation that occurs in vivo.

There is currently interest in the metabolism of the various compounds which make up the vitamin E family, especially with regards to the possible use of vitamin E metabolites as markers of oxidative stress and adequate vitamin E supply. A number of vitamin E metabolites have been described to date and we have recently developed a method to extract and quantitate a range of vitamin E metabolites in human urine. During the development of this method a new metabolite of alpha-tocopherol was identified, which we tentatively characterised as 5-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)-2-methyl-pentanoic acid (alpha-CMBHC).(1) Here we describe the synthesis of alpha-CMBHC as a standard and confirm that it is a metabolite of alpha-tocopherol.

There is currently interest in measuring urinary metabolites of vitamin E. It has been suggested that alpha-to-copheronolactone (alphaTL), with an oxidized chroman ring, may be an indicator of in vivo oxidative stress and 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC), with a shortened side chain but intact hydroxychroman ring, may provide a measure of adequate or excess vitamin E status. To date, methods in the literature have tended to concentrate on the estimation of single metabolites. We describe the establishment and validation of a relatively simple and reproducible method to extract and quantitate a range of vitamin E metabolites using 0.5 ml of human urine. The vitamin E metabolites were extracted from urine using solid phase extraction cartridges, deconjugated enzymatically, and analyzed using gas chromatography-mass spectrometry. Using this method we have identified alphaTL and the CEHC metabolites derived from alpha-, delta-, and gamma-tocopherol. In addition we have tentatively identified a novel group of vitamin E metabolites, which are related to the CEHCs but have three extra carbons in the side chain. The possibility of the artifactual oxidation of alpha-CEHC to alphaTL during the assay procedure is also discussed.

Background: Total parenteral nutrition offers the chance of survival to children who have had extensive gut resections or gut failure. However, in infants it is often associated with serious complications including cholestatic liver disease. The causes of these complications remain unclear, although it has been suggested that the lipid emulsions used in total parenteral nutrition may be responsible., Methods: An in vitro system was developed to study the effect of lipid emulsions on hepatic cholesterol metabolism using cultured hepatocytes., Results: Incubations of Hep G2 cells with medium containing Intralipid (Pharmacia and Upjohn, Milton Keynes, UK) demonstrated that the fat emulsion mediated a powerful dose-dependent but reversible inhibition of cholesterol uptake. In addition Intralipid was shown to stimulate the efflux of cholesterol from Hep G2 cells. The component or components of the Intralipid responsible for these effects and the mechanism by which they act remain to be established., Conclusions: Intravenous lipid emulsions may interfere with hepatic cholesterol metabolism in vivo. This may have implications for the development of total parenteral nutrition-associated cholestasis in neonates.

Electrophysiological techniques provide an objective and non-invasive measure of neurological function. In order to undertake detailed evoked potential studies in rats on repeated occasions, it is necessary to find an appropriate anaesthetic agent which has minimal and reproducible effects on the parameters to be studied and also has a minimal effect on the general welfare of the animals. In this study we compared the effects of four common anaesthetic agents (ketamine-xylazine, medetomidine, isoflurane and fentanyl/fluanisone-midazolam) on somatosensory evoked potentials (SEPs) in rats following electrical stimulation of the fore- and hind-paw. Fentanyl/fluanisone-midazolam was found to be well tolerated by the animals and to have, in general, the least deleterious effect on SEPs. For example, the response recorded at the level of the somatosensory cortex (P1), following forelimb stimulation, appeared on average 1.80 ms earlier with fentanyl/fluanisone-midazolam than with the other agents and the peak-to-peak amplitude (CI to CII) of the response recorded at the cervical (C3) level was on average 5.86 microV greater with fentanyl/fluanisone-midazolam. Fentanyl/fluanisone-midazolam is, therefore, recommended as the anaesthetic of choice for longitudinal studies of SEPs in the rat.

Background/purpose: An increase in free radical activity has been observed in patients suffering from a variety of illnesses and has been correlated with disease severity. Free radical production is increased by the administration of total parenteral nutrition (TPN) and may be linked to its adverse effects. Some of the complications of TPN can be ameliorated by partial enteral feeding. The aim of this study was to investigate free radical activity during critical illness and during the administration of parenteral nutrition., Methods: Three groups of surgical infants were studied: (1) control infants (n = 8) before minor surgery, (2) stable infants on the ward recovering from a major operation (n = 24), (3) critically ill infants in the neonatal intensive care unit (NICU, n = 28). Fourteen patients in the ward and 17 patients in NICU were receiving parenteral nutrition. Of the 31 patients on TPN, 9 were also receiving minimal enteral feeding (3% to 24% of total calorie intake). Plasma malondialdehyde (MDA), an index of free radical activity, was measured in all 60 infants. The Paediatric Risk of Mortality (PRISM) score was obtained on NICU patients. The cytokines tumor necrosis factor (TNF-alpha) and interleukin 6 (IL-6) were measured in 25 patients., Results: Plasma MDA was significantly higher in (1) the stable patients on the ward compared with control patients (P < .001) and (2) patients in NICU compared with stable patients in the ward (P < .001). Parenteral nutrition was associated with higher levels of plasma MDA both in stable patients in the ward and critically ill infants in NICU. There was no correlation between the PRISM score and MDA. In patients not receiving TPN there is a correlation between MDA and TNF-alpha (r = 0.54, P = .02) and between MDA and IL-6 (r = 0.74, P = .001). The level of free radical activity in patients on TPN is not changed by partial enteral feeding., Conclusions: Critical illness causes a rise in free radical production. Parenteral nutrition causes a significant elevation in free radical activity in both stable infants in the ward and critically ill infants in NICU. The addition of minimal enteral feeding to parenteral nutrition does not reduce free radical activity. We hypothesize that the parenteral nutrition solution directly initiates free radical production.

Background/purpose: Increased oxygen-derived free radical activity has been reported during total parenteral nutrition (TPN) in infants and has been specifically linked to the fat infusion. The aim of this study was to test the hypothesis that during TPN, oxygen-derived free radical production can be reduced by increasing the utilisation of fat., Methods: In experiment A (17 patients) the fat infusion was kept constant (3 g/kg/d) and the carbohydrate infusion was changed from 18 g/kg/d on day 1 to 10 g/kg/d on day 2. In experiment B (six patients) the carbohydrate infusion remained constant and the fat infusion was changed from 3 g/kg/d on day 1 to 0 g/kg/d on day 2. Fat utilisation was measured by indirect calorimetry. Plasma malondialdehyde, an index of lipid peroxidation resulting from increased oxygen-derived free radical activity, was measured by a colorimetric assay., Results: In both experiments there was no significant change between the two study phases in oxygen consumption, carbon dioxide production, and resting energy expenditure demonstrating that the patients were metabolically stable. In experiment A there was a significant (P = .0005) increase in fat utilisation and a significant (P = .009) decrease in malondialdehyde (MDA) concentration between the two phases. In experiment B there was also a significant (P = .007) decrease in MDA concentration. The decrease in MDA concentration was similar between the two experiments., Conclusions: It is not necessary to stop the infusion of fat to reduce free radical production. Promoting fat utilisation by reducing the carbohydrate-fat ratio of the TPN reduces free radical activity to a similar extent as fat exclusion. These findings have important implications for the composition of TPN.

Physiological and biochemical studies have been carried out longitudinally over a period of 12 months in vitamin E deficient and control rats to gain an understanding of the mechanism whereby vitamin E conserves normal retinal function. Electroretinographic studies indicated that the primary effect of vitamin E deficiency was on the photoreceptors. Ultrastructural studies, however, did not show any morphological changes to the photoreceptors which could explain receptor dysfunction. A 30-40% loss of vitamin A (retinol) was found to be associated with vitamin E deficiency. This could be corrected by repletion with vitamin E, but there was no associated improvement in visual function. An irreversible loss of the long-chain polyunsaturated fatty acids from the retina, increased lipid peroxidation and alterations in membrane fluidity were also detected during vitamin E deficiency. We suggest that a deficiency of vitamin E leads to changes in the membrane microenvironment, which could affect photo transduction by either impairing the ability of rhodopsin to undergo conformational changes to the active form, or by disrupting the hyperpolarising and depolarising processes of the photoreceptors.

The aim of this study was to identify mutations in the lipoprotein lipase (LPL) gene in 20 unrelated patients with familial lipoprotein deficiency (FLLD) and to investigate the genotype/phenotype relationship. The previously reported G188E mutation (Monsalve et al., J Clin Invest 86:728-734, 1990) was screened for and found to be present in seven individuals (12/40 alleles). In addition, three patients were heterozygous for the 2.0 kb insertion (Langlois et al., Proc Nalt Acad Sci US 86:948-952, 1989). Two approaches were taken for new mutation detection; single-strand conformation polymorphism and sequencing to identify micro-mutations in the proximal promoter and exons 1-9 of the LPL gene and Southern blotting to identify gross mutations. Ten different point mutations were found (W86G, A158T, H183Q, G188E, S193R, P207L, L252X, N291S, M301T, L303P). Additionally, a two nucleotide deletion in exon 6 (delta1006-1007), a six nucleotide deletion in exon 8 (delta1441-1447), and a silent substitution in the wobble position of codon E118 were identified. In vitro mutagenesis and expression in COS-B cells suggested that the A158T and S193R substitutions virtually abolished enzyme activity. In analysing the genotype/phenotype relationship, there was no strong association between age at diagnosis, severity of symptoms, lipid levels, and the nature/position of the mutation. Triglyceride levels, however, were higher in compound heterozygotes compared to true homozygotes, possibly reflecting increased instability of heterodimers. Overall, 29 of 40 (72.5%) mutant alleles were identified. Failure to identify the mutation in 11 alleles might reflect the inadequacy of the method or the possibility that mutations lie within regions of the gene not screened in the study because of lack of availability of sequence.

The purpose of this study was to investigate the hypothesis that the gene for Friedreich's ataxia (FA) may be involved in the metabolism of α-tocopherol (vitamin E) or in other antioxidant systems. Concentrations of α-tocopherol, parameters of endogenous lipid peroxidation and susceptibility to in vitro oxidative stress were measured in neural tissues from four patients with FA and four controls. In general there were no significant differences in any of the parameters studied, although the brainstem whole homogenate from the FA patients was significantly (p < 0.02) less susceptible to in vitro oxidative stress than control material. These results, therefore, do not support the suggestion that abnormal metabolism of α-tocopherol or increased oxidative stress is involved in the aetiology of FA.

Rats were fed a control or vitamin E (all-rac-alpha-tocopheryl acetate)-deficient diet for 3 or 12 weeks. Serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan, and alpha-tocopherol concentrations were determined in the frontal cortex using HPLC, alpha-Tocopherol concentrations fell significantly to 27% of control values at 12 weeks. Tissue 5-HT, 5-HIAA, and tryptophan concentrations were not significantly altered by the vitamin E-deficient diet at either time point. In vivo microdialysis revealed normal basal and K(+)-stimulated concentrations of 5-HT and 5-HIAA, but extracellular concentrations of tryptophan were significantly decreased after 3 weeks on the vitamin E-deficient diet, which resulted in an increase in the tissue/extracellular ratio and suggested a change in compartmentation. However, after 12 weeks on the deficient diet these values had returned to normal. Results in general indicate that a prolonged and substantial depletion of brain vitamin E can occur without major disturbance of serotonergic function.

A severe and chronic deficiency of vitamin E results in a characteristic neurological syndrome in both man and experimental animals. This is presumed to result from increased oxidative stress arising from a reduction in antioxidant capacity. In this study we have examined parameters of endogenous lipid peroxidation and susceptibility to in vitro oxidative stress of neural tissues and fractions, and some non-neural tissues from 1-year-old vitamin E-deficient and control rats. We have shown: (1) an increase in endogenous lipid peroxidation (thiobarbituric acid reactive substances and malondialdehyde) in neural tissues from vitamin E-deficient animals compared to controls. (2) The following order of susceptibility of neural tissues to in vitro oxidative stress in both vitamin E-deficient and control animals: brain >> muscle > cord > nerve. (3) The susceptibility of different brain regions to in vitro oxidative stress varied in a consistent manner with the cortex, striatum, and cerebellum showing the greatest and brainstem and hypothalamus the least susceptibility. (4) Fractions isolated from myelinated nerves of brainstem showed the following order of susceptibility to in vitro oxidative stress: axoplasmic membranes and organelles > axolemma enriched fraction > whole homogenate > = myelin. These results would fit with the characteristic neuropathology associated with severe and chronic vitamin E deficiency.

A boy with a total plasma cholesterol concentration of 20.9 mmol/l which fell significantly with a low fat diet, cholestyramine and simvastatin, was shown to have two different mutations in the low density lipoprotein receptor gene, demonstrating that some patients with homozygous familial hypercholesterolaemia show a good lipid lowering response to treatment.

For many years the role of vitamin E (α-tocopherol) in human nutrition was uncertain, but it is now recognised that this fat soluble vitamin is necessary for normal neurological structure and function. The evidence came initially from patients with abetalipoproteinaemia, then from patients with other chronic and severe fat malabsorptive states, from patients with an isolated deficiency of vitamin E without generalised fat malabsorption, and from comparative neuropathological studies in vitamin E deficient man, monkey and rat. Severe and chronic vitamin E deficiency in the different patient groups resulted in a characteristic neurological disorder which progressed to crippling and blindness. Early and appropriate supplementation with vitamin E can prevent the development of all the neurological signs and symptoms, and treatment of patients with established lesions invariably halts and in some cases can reverse the neuropathy. These clinical and pathological findings raise a number of basic questions regarding the function of vitamin E in neural tissues which are currently being addressed in an animal model.

1. Recent initiatives which advocate an increase in dietary polyunsaturated fat intake have led to the study of the effects of this upon gastrointestinal function. 2. Weanling rats were for 21 weeks fed diets containing 10% fat that were either high or low in polyunsaturated fats. Jejunal function was studied in vitro in an Ussing chamber. 3. Basal intestinal short-circuit was similar in both groups. 4. A decreased EC50 for the non-neural electrogenic secretory responses to acetylcholine, bethanecol and isobutylmethylxanthine was apparent in the jejuna of rats fed a diet high in polyunsaturated fatty acids. 5. Submaximal electrogenic galactose absorption was increased in the rats fed a diet high in polyunsaturated fatty acids. 6. Changing the composition of dietary lipid resulted in a change in the fatty composition of the apical enterocyte membrane. 7. Diets high in polyunsaturated fatty acids may be both prosecretory and proabsorptive in the small intestine.

alpha-Tocopherol concentrations in brain were reduced to 3% of control levels in rats fed a vitamin E deficient diet for 52 weeks. Vitamin E deficiency resulted in a 19-33% loss of tyrosine hydroxylase (TH) immunopositive neurones in the substantia nigra, but not in the adjacent ventral tegmental area, compared with controls. Vitamin E deficiency, however, did not reduce striatal dopamine concentrations or turnover. When antioxidant defence mechanisms are defective, as in chronic vitamin E deficiency, the nigrostriatal pathway may be affected by oxidative damage and this may have implications for Parkinson's disease.

Four patients with vitamin E deficiency and sensory ataxia were studied using [18F]dopa positron emission tomography. The 2 most disabled patients, who had severe and prolonged vitamin E deficiency due to abetalipoproteinemia, showed reduced [18F]dopa uptake in both putamen and caudate. Putaminal uptake was in a similar range to that seen in Parkinson's disease. Studies of [3H]mazindol binding in the striatum of vitamin E--deficient rats indicated a reduced number of dopamine terminals, which was most severe in ventrolateral striatum. These observations suggest that severe and prolonged vitamin E deficiency results in loss of nigrostriatal nerve terminals, and support the hypothesis that oxidative stress may contribute to the etiology of Parkinson's disease.

Increased concentrations of reactive oxygen species in children with depleted antioxidant defences have been implicated in a cycle of malnutrition, malabsorption, and infection leading to protracted diarrhoea. A rat model of chronic vitamin E deficiency has been used to study the effects of antioxidant depletion on jejunal structure and function in vitro. Basal intestinal short circuit current (Isc), a measure of net electrogenic ion movement across the intestinal epithelium, was greater in chronically vitamin E deficient jejuna than controls, as was the electrogenic secretory response to aminophylline and Escherichia coli STa but not to bethanechol. The galactose stimulated current was also greater in vitamin E deficient jejuna. Indices of lipid peroxidation (concentrations of thiobarbituric acid reactive substances and malondialdehyde) were increased in the vitamin E deficient small bowel. Small intestinal brush border membranes from vitamin E deficient animals displayed changes in both static and dynamic components of membrane fluidity measured by steady state fluorescence polarography. The results of these studies support the hypothesis that oxidative stress in subjects with compromised antioxidant defences results in small intestinal hypersecretion, which could predispose to or perpetuate protracted diarrhoea.

Vitamin E deficiency in rats gives rise to a neuromuscular syndrome that includes a peripheral neuropathy as well as generalised muscle wasting and weakness. This is probably related to damage by oxygen-derived free radicals. In the present study, histological examination of lower limb muscles showed widespread myopathic changes which included the presence of amorphous electron-dense inclusions and tubular aggregates in muscle fibres and muscle fibre necrosis. Histochemical observations suggested a reduction in the activity of oxidative enzymes. The mitochondria showed nonspecific degenerative changes on electron microscopy; no paracrystalline inclusions were observed. Polarographic analysis of isolated muscle mitochondria revealed statistically significant decreases in oxygen utilisation rates with both NADH and FADH2-linked substrates. In confirmation of a generalised respiratory chain abnormality, enzymatic analyses revealed decreases in the activities of complexes I, II/III and IV, although only the decreases in complexes I and IV activities were statistically significant. Measurements of membrane fluidity showed that this is reduced in mitochondria from vitamin E deficient rats, indicating reduced stability of their membranes. The respiratory control ratio, derived from the polarographic results, was also reduced in mitochondria from vitamin E deficient animals, suggesting membrane damage. An altered lipid environment, possibly secondary to a higher level of lipid peroxidation, could result in the inhibition of complexes I and IV. This could also be caused by oxidative damage to the complexes or to mitochondrial DNA. The preservation of citrate synthase activity is against any generalised defect of mitochondrial function. The question as to whether these defects of mitochondrial respiratory chain function are responsible for the muscle fibre damage and necrosis requires further investigation.

1. A vicious cycle of malabsorption and malnutrition has been implicated in the pathogenesis of protracted diarrhoeal disease in infancy. Vitamin E deficiency is common in malnourished infants with protracted diarrhoea. We have studied the effects of chronic vitamin E deficiency on small-intestinal secretion and absorption in the rat. 2. Weanling rats were fed vitamin E-sufficient or -deficient diets for 21 weeks. Jejunal function was studied in vitro in an Ussing chamber after this period. 3. Steady-state isotopic flux experiments in unstimulated tissues demonstrated net Na+ and Cl- secretion in vitamin E-deficient jejuna but net Na+ and Cl- absorption in vitamin E-sufficient jejuna. 4. Basal intestinal short-circuit current was the same in both groups. 5. Cyclic nucleotide and maximal non-neuronal acetylcholine-mediated electrogenic secretion were increased in vitamin E-deficient jejuna. 6. Exogenous 5-hydroxytryptamine (serotonin) induced a smaller increment in electrogenic secretion in vitamin E-deficient jejuna. 7. Vitamin E-deficient jejuna were less responsive to exogenous noradrenaline, resulting in a smaller alpha 2-adrenergic-mediated decrease in intestinal short-circuit current. 8. Fasting for 72h produced a greater increment in intestinal short-circuit current in vitamin E-deficient jejuna. 9. Chronic vitamin E deficiency is prosecretory in the small intestine and may predispose to the perpetuation of protracted diarrhoeal diseases.

The mechanism(s) of uptake of vitamin E (alpha-tocopherol) by tissues is poorly understood. It has, however, been suggested from studies in vitro that the apolipoprotein B/E (apo B/E) receptor pathway for low-density lipoprotein (LDL) may be involved. To investigate the role of the apo B/E receptor pathway in vivo, we have studied the transport and uptake of alpha-tocopherol by tissues in Watanabe Heritable Hyperlipidaemic (WHHL) rabbits, which lack functional LDL (apo B/E) receptors, and controls. [3H]alpha-Tocopherol incorporated within LDL labelled with [14C]sucrose was used in these studies, as this enabled the uptake of both alpha-tocopherol and LDL to be studied independently. The principal findings were as follows. (1) Concentrations of the circulating lipids (including alpha-tocopherol) and LDL were increased and the plasma fractional disappearance rates of alpha-tocopherol and LDL decreased in the WHHL rabbits. (2) The WHHL rabbits clear more LDL and alpha-tocopherol from the circulation than controls do, because of their increased pool sizes of alpha-tocopherol and LDL. (3) The lipoprotein composition of the WHHL rabbits differed from that of the controls, and there was exchange of alpha-tocopherol between the lipoprotein fractions in vivo and in vitro. (4) High-affinity apo B/E receptors were not essential for the uptake of alpha-tocopherol by tissues. (5) Evidence from the plasma-clearance and tissue data suggest that alpha-tocopherol can be taken up by tissues in association with, and also independent of, LDL. We conclude that there are several different mechanisms for the uptake of alpha-tocopherol by tissues, which include receptor-dependent and receptor-independent pathways, independent transport and co-transport of alpha-tocopherol and LDL, and uptake from a number of different lipoproteins.

Vitamin E is a fat soluble antioxidant and as a result it is able to scavenge free radicals derived from oxygen. The premature infant and the retina are likely to be particularly vulnerable to the deleterious effects of these oxygen derived free radicals, and as a result prophylactic vitamin E has been suggested for the management of retinopathy of prematurity (ROP). However, despite numerous trials, prophylactic supplementation with vitamin E remains controversial. This paper will critically review the use of vitamin E in ROP and consider the risk/benefit relationship of such treatment in premature infants.

Flash electroretinograms, retinal oscillatory and cortical visual-evoked potentials were recorded in 10-month vitamin E deficient rats and in age-matched controls. A significant increase in the latency (P less than 0.0001) and decrease in amplitude (P less than 0.0001) of the electroretinogram a- and b-waves were observed in the vitamin E deficient rats compared with controls. The vitamin E deficient rats also showed a significant delay (P less than 0.002) in early oscillatory potentials. No significant group differences were obtained in the P1 latency or P1-N1 amplitude of the visual-evoked potential; however, the N1 peak was significantly delayed (P = 0.01) in the vitamin E deficient rats. This study shows, for the first time, that the electroretinogram and visual-evoked potential to flash stimulation provide a sensitive index for monitoring the visual effects of vitamin E deficiency in the rat.

Morphological and functional studies have been performed on experimental vitamin E deficient rats. The predominant morphological change was axonal dystrophy and degeneration in the rostral parts of the dorsal columns, particularly in the gracile fasciculi. The dystrophic changes comprised focal axonal swellings containing accumulations of normal and abnormal organelles which included tubulovesicular structures probably derived from the smooth endoplasmic reticulum, mitochondria, dense lamellar bodies, neurofilaments, multifascicular bodies and lysosomes. Similar but lesser changes were observed in distal peripheral nerves. The appearances suggested a disturbance of axonal transport with a defect of 'turnaround' in the distal axons. Studies on the axonal transport of endogenous acetylcholinesterase showed an impairment both of fast anterograde and retrograde transport. The changes were considered to be secondary to the lack of the antioxidant effect of vitamin E as the neurological deficits could be reduced by the concomitant dietary administration of the synthetic antioxidant ethoxyquin and were markedly aggravated by the administration of polyunsaturated fatty acids. It is suggested that the neurological syndrome produced by vitamin E deficiency could be the result of damage to the function of mitochondria and other intra-axonal membranous structures which would interfer both with fast anterograde transport and 'turnaround' and lead to a distal axonal degeneration.

A severe deficiency of vitamin E causes a characteristic neurological syndrome in man and experimental animals. In this study a number of electrophysiological modalities in vitamin E deficient and control rats have been investigated over a period of one year to define the time of onset and severity of the abnormalities associated with vitamin E deficiency in the rat. The mean velocities (n = 10) of the sensory evoked potentials were slower at all time points in the vitamin E deficient rats, with the central conduction velocities being more severely affected than the peripheral. Central conduction velocities, following both tibial and median nerve stimulation, were significantly delayed (P less than 0.005) after 8 months of deficiency. Differences in peripheral conduction following tibial stimulation became significantly delayed (P less than 0.005) after 11 months of deficiency. There were no significant differences in the brainstem auditory evoked potentials or peripheral sensory motor responses between the vitamin E deficient and control rats over the 1 year period. These results in the rat are essentially similar to those previously reported in vitamin E deficient man.

It is now recognized that vitamin E is essential for normal neurological structure and function in both man and experimental animals, with severe deficiency resulting in a characteristic neurological syndrome. The reasons why the neurological system should be particularly susceptible to a deficiency of this fat-soluble vitamin, and the mechanisms involved, are not known. In this review, the neurochemistry, neuropathology, and neurophysiology associated with vitamin E deficiency are described and correlated. A deficiency of vitamin E results in a "distal or dying back" axonal neuropathy which predominantly involves the centrally directed fibers of sensory neurons, with the large caliber myelinated fibers being particularly affected. Both the pathological and electrophysiological studies indicate that the primary abnormality is a degeneration of the axons which then results in a secondary demyelination. The mechanism(s) involved is assumed to involve lipid peroxidation of neuronal membranes as a consequence of a deficiency of the major lipid-soluble secondary (i.e., chain breaking) antioxidant in vivo.