Sarah Aldred

Plasma Amino Acid Levels in Children with Autism and Their Families.

Plasma amino acid levels were measured in autistic and Asperger syndrome patients, their siblings, and parents. The results were compared with values from age-matched controls. Patients with autism or Asperger syndrome and their siblings and parents all had raised glutamic acid, phenylalanine, asparagine, tyrosine, alanine, and lysine (p < .05) than controls, with reduced plasma glutamine. Other amino acids were at normal levels. These results show that children with autistic spectrum disorders come from a family background of dysregulated amino acid metabolism and provide further evidence for an underlying biochemical basis for the condition.

Oxidative stress in vascular dementia and Alzheimer's disease: a common pathology.

Alzheimers disease and vascular dementia are the two most common types of dementia with the former being the most predominant. It is evident that oxidative stress, an environment where pro-oxidant species overwhelm antioxidant species, is involved in the pathogenesis of both forms of dementia. An increased level of reactive oxygen species in the vasculature, reduced nitric oxide bioavailability, and endothelial dysfunction leading to vascular disease is associated with vascular dementia. In Alzheimers disease, an increased amount of amyloid-beta peptide induces elevated reactive oxygen species production thereby causing neuronal cell death and damage. The recent observation that increased atherosclerotic plaque formation is present in the main artery to the brain in Alzheimers disease, coupled with the association of vascular risk factors with this disease, suggests a link between these two dementias. This review will argue that Alzheimers disease and vascular dementia are two extremes of one disease, thus assuming a hypothesis where the clinical conditions referred to as dementia are part of a continuum. We propose that the majority of cases share a vascular pathology and that oxidative stress is central to this common pathology.

Plasma antioxidant status, immunoglobulin G oxidation and lipid peroxidation in demented patients: Relevance to Alzheimer disease and vascular dementia

A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. A vascular component might be critical in the pathophysiology of AD, but there is a substantial lack of data regarding the simultaneous behavior of peripheral antioxidants and biomarkers of oxidative stress in AD and vascular dementia (VaD). Sixty-three AD patients, 23 VaD patients and 55 controls were included in the study. We measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, β-cryptoxanthin, lycopene, α- and β-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation [malondialdehyde (MDA)] and of protein oxidation [immunoglobulin G (IgG) levels of protein carbonyls and dityrosine] in patients and controls. With the exception of β-carotene, all antioxidants were lower in demented patients as compared to controls. Furthermore, AD patients showed a significantly higher IgG dityrosine content as compared to controls. AD and VaD patients showed similar plasma levels of plasma antioxidants and MDA as well as a similar IgG content of protein carbonyls and dityrosine. We conclude that, independent of its nature – vascular or degenerative – dementia is associated with the depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. This might be relevant to the pathophysiology of dementing disorders, particularly in light of the recently suggested importance of the vascular component in AD development.

Latent Cytomegalovirus infection amplifies CD8 T-lymphocyte mobilisation and egress in response to exercise

Exercise induces mobilisation of CD8(+) T lymphocytes (CD8TL) into the peripheral blood. This response is largely confined to effector-memory CD8TLs: antigen experienced cells which have a strong tissue-homing and effector potential. This study investigated whether effector-memory cells also account for the CD8TL egress from peripheral blood following exercise. As latent Cytomegalovirus (CMV) infection is associated with a robust expansion in the number and proportion of effector-memory CD8TLs, we also investigated if CMV serostatus was a determinant of the CD8TL responses to exercise. Fourteen males (Mean age 35, SD ± 14 yrs), half of whom were CMV seropositive (CMV(+)), ran on a treadmill for 60 min at 80% VO(2) max. Blood was collected at baseline, during the final minute of exercise, and 15 min and 60 min thereafter. CD8TL memory subsets were characterised by flow cytometry, using the cell-surface markers CD45RA, CD27, and CD28. The results confirmed that CD8TLs with an effector-memory phenotype (CD27(-)CD28(-)CD45RA(+/-)) exhibited the largest increase during exercise (+200% to +250%), and also showed the largest egress from blood 60 min post-exercise (down to 40% of baseline values). Strikingly, the mobilisation and subsequent egress of total CD8TLs was nearly twice as large in CMV(+) individuals. This effect appeared specific to CD8TLs, and was not seen for CD4(+) T lymphocytes or total lymphocytes. This effect of CMV serostatus was largely driven by the higher numbers of exercise-responsive effector-memory CD8TLs in the CMV(+) participants. This is the first study to demonstrate that infection history is a determinant of immune system responses to exercise.

Low volume–high intensity interval exercise elicits antioxidant and anti-inflammatory effects in humans

Abstract The purpose of the present study was to compare acute changes in oxidative stress and inflammation in response to steady state and low volume, high intensity interval exercise (LV-HIIE). Untrained healthy males (n = 10, mean ± s: age 22 ± 3 years; VO2MAX 42.7 ± 5.0 ml · kg−1 · min−1) undertook three exercise bouts: a bout of LV-HIIE (10 × 1 min 90% VO2MAX intervals) and two energy-matched steady-state cycling bouts at a moderate (60% VO2MAX; 27 min, MOD) and high (80% VO2MAX; 20 min, HIGH) intensity on separate days. Markers of oxidative stress, inflammation and physiological stress were assessed before, at the end of exercise and 30 min post-exercise (post+30). At the end of all exercise bouts, significant changes in lipid hydroperoxides (LOOH) and protein carbonyls (PCs) (LOOH (nM): MOD +0.36; HIGH +3.09; LV-HIIE +5.51 and PC (nmol · mg−1 protein): MOD −0.24; HIGH −0.11; LV-HIIE −0.37) were observed. Total antioxidant capacity (TAC) increased post+30, relative to the end of all exercise bouts (TAC (µM): MOD +189; HIGH +135; LV-HIIE +102). Interleukin (IL)-6 and IL-10 increased post+30 in HIGH and LV-HIIE only (P < 0.05). HIGH caused the greatest lymphocytosis, adrenaline and cardiovascular response (P < 0.05). At a reduced energy cost and physiological stress, LV-HIIE elicited similar cytokine and oxidative stress responses to HIGH.

The interactions of oxidative stress and inflammation with vascular dysfunction in ageing: the vascular health triad

Oxidative stress and inflammation are increased with advancing age. Evidence suggests that oxidative stress and inflammation both lead to impaired vascular function. There is also evidence to suggest that inflammation may cause an increase in radical production leading to enhanced oxidative stress. In addition, oxidative stress may cause an increase in inflammation; however, the interactions between these factors are not fully understood. In this review, we propose the vascular health triad, which draws associations and interactions between oxidative stress and inflammation seen in ageing, and the consequences for vascular function. We review evidence suggesting that exercise may ameliorate the age-related decline in vascular function, through reductions in both oxidative stress and inflammation.

Localisation of dehydroepiandrosterone sulphotransferase in adult rat brain.

The presence and localisation of dehydroepiandrosterone sulphotransferase was assessed in adult rat brain. The activity of the enzyme was investigated and was found to be approximately four times less than that in rat liver. Rat brain dehydroepiandrosterone sulphotransferase activity was measured as 1.39+/-0.04 nm/microg/min. The protein expression of dehydroepiandrosterone sulphotransferase was evaluated using Western blotting. The presence of a band at 35 kDa signified the presence of this enzyme in adult rat brain. Finally, the localisation of this enzyme was investigated by immunohistochemistry and by assessing activity in nine regions of brain. Immunohistochemistry showed positive staining in the hippocampus and the dendate gyrus, and in the large neurons of the midbrain, indicating the presence of dehydroepiandrosterone sulphotransferase. Western blotting showed the presence of a band in all nine regions, and enzyme activity was highest in the hippocampus, frontal cortex, thalamus and basal ganglia. These results imply that dehydroepiandrosterone and dehydroepiandrosterone sulphate (DHEAS) have a defined role in brain function and are produced in situ independently of the peripheral endocrine system.

Decreased dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) concentrations in plasma of Alzheimer's disease (AD) patients

DHEA is secreted by the adrenal cortex and is also a neurosteroid. Its sulfate (DHEAS) is the most abundant steroid in circulation. The levels of both are seen to decline in concentration with age. Evidence is available for altered levels of DHEA and DHEAS in AD but is limited to relatively few studies assessing small cohorts. This study assessed plasma DHEA and DHEAS levels in AD sufferers (n=72) and compared them to age-matched controls (n=72). Plasma DHEA concentrations were significantly lower in AD patients compared to control (4.24+/-0.4 ng/ml for AD; 3.38+/-0.3 ng/ml for control, p=0.027, Mann-Whitney 1-tailed) and DHEA levels were significantly correlated to DHEAS levels in both control and AD conditions (Spearmans rho correlation coefficient=0.635 in controls and 0.467 in AD, p<or=0.01). This study highlighted a measurable difference in DHEA and DHEAS concentrations in plasma from a large cohort of patients suffering from AD when compared to age-matched controls.

The training stimulus experienced by the leg muscles during cycling in humans

Considerable variability exists between people in their health‐ and performance‐related adaptations to conventional endurance training. We hypothesized that some of this variability might be due to differences in the training stimulus received by the working muscles. In 71 young sedentary women we observed large variations in the ratio of one‐leg cycling muscle aerobic capacity to two‐leg cycling whole‐body maximal oxygen uptake ( ; Ratio1:2; range 0.58–0.96). The variability in Ratio1:2 was primarily due to differences between people in one‐leg (r= 0.71, P < 0.0005) and was not related to two‐leg (r= 0.15, P= 0.209). Magnetic resonance imaging (n= 30) and muscle biopsy sampling (n= 20) revealed that one‐leg was mainly determined by muscle volume (r= 0.73, P < 0.0005) rather than muscle fibre type or oxidative capacity. A high one‐leg was associated with favourable lipoprotein profiles (P= 0.033, n= 24) but this was not the case for two‐leg . Calculations based on these data suggest that conventional two‐leg exercise at 70% requires subjects with the lowest Ratio1:2 to work their legs at 60% of single‐leg , whilst those with the highest Ratio1:2 work their legs at only 36% of maximum. It was concluded that endurance training carried out according to current guidelines will result in highly variable training stimuli for the leg muscles and variable magnitudes of adaptation. These conclusions have implications for the prescription of exercise to improve health and for investigations into the genetic basis of muscle adaptations.

Prolonged depletion of antioxidant capacity after ultraendurance exercise.

PURPOSE The purpose of this study was to examine the short- and long-term (up to 1 month) effects of an ultraendurance running event on redox homeostasis. METHODS Markers of oxidative stress and antioxidant capacity in peripheral blood were assessed after a single-stage 233-km (143 miles) running event. Samples were collected from nine men (mean±SD: age=46.1±5.3 yr, body mass index=24.9±2.3 kg·m⁻², maximal oxygen uptake=56.3±3.3 mL·kg⁻¹·min⁻¹). Peripheral blood mononuclear cells were assayed for nonspecific DNA damage (frank strand breaks) and damage to DNA caused specifically by oxidative stress (formamidopyrimidine DNA glycosylase-dependent damage). Protein carbonylation and lipid peroxidation were assessed in plasma. Reduced glutathione (GSH) was measured in whole blood. RESULTS Peripheral blood mononuclear cell frank strand breaks were elevated above baseline at 24 h after the race (P<0.001). Formamidopyrimidine DNA glycosylase-dependent oxidative DNA damage was increased immediately after the race (P<0.05). Protein carbonylation remained elevated for 7 d after the race (P<0.04), whereas lipid peroxidation was increased for 24 h (P<0.05) and fell below baseline 28 d later (P<0.05). GSH, a measure of antioxidant capacity, also showed a biphasic response, increasing by one-third after the race (P<0.01) and falling to two-thirds of baseline levels 24 h later (P<0.001). GSH remained depleted to approximately one-third of prerace values 28 d after the race (P<0.01). CONCLUSIONS Ultraendurance exercise causes oxidative stress, which persists for one calendar month depending on the specific biomarker examined. These results suggest that ultraendurance events are associated with a prolonged period of reduced protection against oxidative stress.