Does a Facebook-enhanced Mindful Self-Compassion intervention improve body image? An evaluation study.

This study evaluates a brief intervention aimed at improving body image. The intervention comprised a Mindful Self-Compassion workshop complemented by a group discussion on Facebook. Young women (Mage = 18.31), screened for body concerns, were allocated by university campus to a 50-minute workshop intervention (n = 42) or a waitlist control (n = 34). Following the workshop, participants in the intervention group utilized self-compassion techniques when experiencing appearance distress and posted about their experiences on a private Facebook group three times per week for two weeks. Findings showed that, relative to control, the intervention group experienced lower upward appearance comparison, social appearance anxiety, body dissatisfaction, and drive for thinness, and higher body appreciation and self-compassion, at posttest and 1-month follow-up. All effects, except those for body dissatisfaction, were held at 3-month follow-up. Additionally, common humanity predicted gains in body appreciation from pretest to posttest. The Mindful Self-Compassion intervention involving a Facebook group may have resonated with young women as it allowed them to share moments of self-compassionate body image experiences in a private and supportive environment.

Mice lacking neuronal calcium sensor-1 show social and cognitive deficits.

Neuronal calcium sensor-1 or Frequenin is a calcium sensor widely expressed in the nervous system, with roles in neurotransmission, neurite outgrowth, synaptic plasticity, learning, and motivated behaviours. Neuronal calcium sensor-1 has been implicated in neuropsychiatric disorders including autism spectrum disorder, schizophrenia, and bipolar disorder. However, the role of neuronal calcium sensor-1 in behavioural phenotypes and brain changes relevant to autism spectrum disorder have not been evaluated. We show that neuronal calcium sensor-1 deletion in the mouse leads to a mild deficit in social approach and impaired displaced object recognition without affecting social interactions, behavioural flexibility, spatial reference memory, anxiety-like behaviour, or sensorimotor gating. Morphologically, neuronal calcium sensor-1 deletion leads to increased dendritic arbour complexity in the frontal cortex. At the level of hippocampal synaptic plasticity, neuronal calcium sensor-1 deletion leads to a reduction in long-term potentiation in the dentate gyrus, but not area Cornu Ammonis 1. Metabotropic glutamate receptor-induced long-term depression was unaffected in both dentate and Cornu Ammonis 1. These studies identify roles for neuronal calcium sensor-1 in specific subregions of the brain including a phenotype relevant to neuropsychiatric disorders.

Hypothalamic POMC or MC4R deficiency impairs counterregulatory responses to hypoglycemia in mice.

OBJECTIVE: Life-threatening hypoglycemia is a major limiting factor in the management of diabetes. While it is known that counterregulatory responses to hypoglycemia are impaired in diabetes, molecular mechanisms underlying the reduced responses remain unclear. Given the established roles of the hypothalamic proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit in regulating sympathetic nervous system (SNS) activity and the SNS in stimulating counterregulatory responses to hypoglycemia, we hypothesized that hypothalamic POMC as well as MC4R, a receptor for POMC derived melanocyte stimulating hormones, is required for normal hypoglycemia counterregulation. METHODS: To test the hypothesis, we induced hypoglycemia or glucopenia in separate cohorts of mice deficient in either POMC or MC4R in the arcuate nucleus (ARC) or the paraventricular nucleus of the hypothalamus (PVH), respectively, and measured their circulating counterregulatory hormones. In addition, we performed a hyperinsulinemic-hypoglycemic clamp study to further validate the function of MC4R in hypoglycemia counterregulation. We also measured Pomc and Mc4r mRNA levels in the ARC and PVH, respectively, in the streptozotocin-induced type 1 diabetes mouse model and non-obese diabetic (NOD) mice to delineate molecular mechanisms by which diabetes deteriorates the defense systems against hypoglycemia. Finally, we treated diabetic mice with the MC4R agonist MTII, administered stereotaxically into the PVH, to determine its potential for restoring the counterregulatory response to hypoglycemia in diabetes. RESULTS: Stimulation of epinephrine and glucagon release in response to hypoglycemia or glucopenia was diminished in both POMC- and MC4R-deficient mice, relative to their littermate controls. Similarly, the counterregulatory response was impaired in association with decreased hypothalamic Pomc and Mc4r expression in the diabetic mice, a phenotype that was not reversed by insulin treatment which normalized glycemia. In contrast, infusion of an MC4R agonist in the PVH restored the counterregulatory response in diabetic mice. CONCLUSION: In conclusion, hypothalamic Pomc as well as Mc4r, both of which are reduced in type 1 diabetic mice, are required for normal counterregulatory responses to hypoglycemia. Therefore, enhancing MC4R function may improve hypoglycemia counterregulation in diabetes.

Design and Application of a DNA-Encoded Macrocyclic Peptide Library.

A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed.

The Iridoid Myodesert-1-ene and Elemol/Eudesmol are found in Distinct Chemotypes of the Australian Aboriginal Medicinal Plant Eremophila dalyana (Scrophulariaceae).

The strongly aromatic Australian desert species Eremophila dalyana is an Aboriginal medicinal plant that continues to be used today in Central Australia in the treatment of respiratory complaints and Sarcoptes scabiei infestation. Using hydrodistillation of aerial parts of the plant, the new natural product myodesert-l- ene was isolated in two disjunct populations at up to 98% of the volatiles present in the hydrodistilled oils. Weak antimicrobial activities were observed for whole oils and myodesert-l-ene. Activities in the hydrodistilled oil were attributed to the antimicrobial sesquiterpenes elemol and eudesmol which showed good activity when isolated and were relatively abundant in the chemotype used medicinally. The biogenesis of myodesert-l-ene from iridodial is proposed.

Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC.

Neurons in the anterior cingulate cortex (ACC) are assumed to play important roles in the perception of nociceptive signals and the associated emotional responses. However, the neuronal types within the ACC that mediate these functions are poorly understood. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC and to assess their ability to modulate peripheral mechanical hypersensitivity in freely moving mice. We found that selective activation of pyramidal neurons rapidly and acutely reduced nociceptive thresholds and that this effect was occluded in animals made hypersensitive using Freund's Complete Adjuvant (CFA). Conversely, inhibition of ACC pyramidal neurons rapidly and acutely reduced hypersensitivity induced by CFA treatment. A similar analgesic effect was induced by activation of parvalbumin (PV) expressing interneurons, whereas activation of somatostatin (SOM) expressing interneurons had no effect on pain thresholds. Our results provide direct evidence of the pivotal role of ACC excitatory neurons, and their regulation by PV expressing interneurons, in nociception.

Chemogeography and antimicrobial activity of essential oils from Geijera parviflora and Geijera salicifolia (Rutaceae): two traditional Australian medicinal plants.

Essential oils were hydrodistilled from 27 specimens of Geijera parviflora Lindl., (Rutaceae) and nine specimens of Geijera salicifolia Schott, collected over a wide geographic range in New South Wales, Queensland and South Australia. Essential oils were produced by traditional hydrodistillation and characterised using GC-MS. From one specimen a serendipitous discovery was made of bioactive coumarins dissolved in the hydrosol, which were the coumarins isopsoralen, xanthyletine and osthole. These coumarins were not present in the essential oil from that specimen. Using essential oil composition from all specimens, principal component analysis (PCA) demonstrated nine clusters for G. parviflora and three for G. salicifolia. Some clusters are representative of previously described chemotypes and some are reflective of possible chemotypes requiring more comprehensive sampling for confirmation. Thus, another three or four possible chemotypes of G. parviflora and one of G. salicifolia have been tentatively identified. Using micro-titre plate broth dilution assays, antibacterial and antifungal activity of all chemotypes was investigated. In this regard, the 'green oil' chemotype, restricted to G. parviflora, with major components linalool, geijerene/pregeijerene, 1,8-cineol and bicyclogermacrene, demonstrated the highest antimicrobial and free radical scavenging activity. Thus, in the light of traditional use reports of local analgaesia and bioactivity demonstrated in the current study, oils from select chemotypes of G. parviflora may be useful in suitably compounded lotions and creams designed for topical antimicrobial applications and local pain relief. In addition, because major components are known for insecticidal activities, such lotions may also be useful as topically applied insect repellents.

Composition and antimicrobial activity of the essential oils from the Phebalium squamulosum species complex (Rutaceae) in New South Wales, Australia.

Essential oils have been hydrodistilled and characterized from 21 populations of taxa currently assigned to the endemic Australian species Phebalium squamulosum (Rutaceae: Boronieae) using GC-MS, NMR and quantified using GC-FID. Essential oils were further examined using principle component analysis to distinguish chemotypes, then screened for antimicrobial activity using broth dilution and TLC-bioautography. Collections of subspecies of P. squamulosum, namely subsp. coriaceum, subsp. gracile, subsp. lineare, subsp. squamulosum, subsp. ozothamnoides and subsp. verrucosum, were made from the wild and one from a cultivated plant of known provenance within New South Wales. Results demonstrated considerable intra- and interspecific essential oil component variation, suggesting the existence of distinct chemotypes and supporting previously observed segregate species based on morphological evidence. Antimicrobial testing revealed moderate to high activity for all essential oils dominated by sesquiterpene alcohols; elemol and eudesmol isomers. Conversely, very low antimicrobial activity was observed from essential oils dominated by monoterpenes. This study constitutes the most exhaustive investigation of essential oils from P. squamulosum subspecies to date and provides the first report of antimicrobial activity.

Leptin-derived peptides that stimulate food intake and increase body weight following peripheral administration.

We previously showed that peptides containing leptin sequences 1-33 or 61-90 are taken up by the rat brain. We now report the effects of these peptides on food intake and body weight in mature rats. Peptides were infused intravenously for 4weeks, using Alzet minipumps. Dosages were 20µg/kg/day in experiment I, and 60µg/kg/day in experiment 2. In experiment 1, female rats receiving peptides 1-33 and 61-90 each underwent an approximate doubling of the weight gain of control rats. These peptides also increased food intake in female rats. Peptide 15-32, which has a lesser degree of brain uptake, gave a smaller weight gain. Peptide 83-108, which is not taken up by the brain, had no effect on weight gain or food intake. Similar results were obtained in experiment 2. In male rats, however, none of the peptides caused significant changes in food intake or body weight. This was at least partly due to the fact that all male rats underwent vigorous weight increases. We conclude that peptides 1-33 and 61-90 acted as leptin antagonists, stimulating food intake and body weight increases, at least in female rats. These peptides may lead to clinical applications in conditions such as anorexia and cachexia.

Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety.

Generalized anxiety is thought to result, in part, from impairments in contingency awareness during conditioning to cues that predict aversive or fearful outcomes. Dopamine neurons of the ventral midbrain exhibit heterogeneous responses to aversive stimuli that are thought to provide a critical modulatory signal to facilitate orientation to environmental changes and assignment of motivational value to unexpected events. Here we describe a mouse model in which activation of dopamine neurons in response to an aversive stimulus is attenuated by conditional genetic inactivation of functional NMDA receptors on dopamine neurons. We discovered that altering the magnitude of excitatory responses by dopamine neurons in response to an aversive stimulus was associated with impaired conditioning to a cue that predicts an aversive outcome. Impaired conditioning by these mice was associated with the development of a persistent, generalized anxiety-like phenotype. These data are consistent with a role for dopamine in facilitating contingency awareness that is critical for the prevention of generalized anxiety.

Lack of interactions between fire ant control products and white grubs (Coleoptera: Scarabaeidae) in turfgrass.

Insecticides are widely used to manage turfgrass pest such as white grubs (Coleoptera: Scarabaeidae). Red imported fire ants, Solenopsis invicta (Buren) are important predators and pests in managed turfgrass. We tested the susceptibility of white grub life stages (adults, egg, and larvae) to predation by S. invicta and determined if insecticides applied for control of S. invicta would result in locally greater white grub populations. Field trials over 2 yr evaluated bifenthrin, fipronil, and hydramethylnon applied to large and small scale turfgrass plots for impacts on fire ant foraging and white grub populations. Coincident with these trials, adults, larvae, and eggs of common scarab species were evaluated for susceptibility to predation by S. invicta under field conditions. Field trials with insecticides failed to show a significant increase in white grub populations resulting from treatment of turfgrass for fire ants. This, in part, may be because of a lack of predation of S. invicta on adult and larval scarabs. Egg predation was greatest at 70% but < 20% of adults and larvae were attacked in a 24 h test. Contrary to other studies, results presented here suggest that fire ants and fire ant control products applied to turfgrass have a minimal impact on white grub populations.

BoTULS: a multicentre randomised controlled trial to evaluate the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A.

OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A plus an upper limb therapy programme with the upper limb therapy programme alone. DESIGN: A multicentre open-label parallel-group randomised controlled trial and economic evaluation. SETTING: Twelve stroke services in the north of England, UK. PARTICIPANTS: Three hundred and thirty-three adults with upper limb spasticity at the shoulder, elbow, wrist or hand and reduced upper limb function due to stroke more than 1 month previously. INTERVENTIONS: The intervention group received botulinum toxin type A injection(s) plus a 4-week programme of upper limb therapy. The control group received the upper limb therapy programme alone. Participants were clinically reassessed at 3, 6 and 9 months to determine the need for repeat botulinum toxin type A injection(s) and/or therapy. MAIN OUTCOME MEASURES: The primary outcome was upper limb function 1 month after study entry measured by the Action Research Arm Test (ARAT). A successful outcome was defined as: (1) a change of three or more points on the ARAT scale for a participant whose baseline ARAT score was between 0 and 3, (2) a change of six or more points on the ARAT scale for a participant whose baseline ARAT score was between 4 and 51, or (3) a final ARAT score of 57 for a participant whose baseline ARAT score was 52-56. Outcome assessments were undertaken at 1, 3 and 12 months by an assessor who was blinded to the study group allocation. Upper limb impairment and activity limitation were assessed by: Modified Ashworth Scale; Motricity Index; grip strength; ARAT; Nine-Hole Peg Test; upper limb basic functional activity questions and the Barthel Activities of Daily Living (ADL) Index. Stroke-related quality of life/participation restriction was measured using the Stroke Impact Scale, European Quality of Life-5 Dimensions (EQ-5D) and the Oxford Handicap Scale. Upper limb pain was assessed using numerical rating scales. Participant-selected upper limb goal achievement (1 month only) was measured using the Canadian Occupational Performance Measure. Adverse events were compared. Health-care and social services resource use was compared during the first 3 months postrandomisation. EQ-5D data were used to calculate the quality-adjusted life-years (QALYs) associated with intervention and control treatments, and the incremental cost per QALY gained of botulinum toxin type A plus therapy compared with therapy alone was estimated. The sensitivity of the base-case results to alternative assumptions was investigated, and cost-effectiveness acceptability curves, which summarise the evidence of botulinum toxin type A plus therapy being cost-effective for a range of societal willingness to pay for a QALY values, are presented. RESULTS: Randomisation groups were well matched at baseline. There was no significant difference between the groups for the primary outcome of improved arm function at 1 month. This was achieved by 30/154 (19.5%) in the control group and 42/167 (25.1%) in the intervention group (p = 0.232). The relative risk of having a 'successful treatment' in the intervention group compared with the control group was 1.3 [95% confidence interval (CI) 0.9 to 2.0]. No significant differences in improved arm function were seen at 3 or 12 months. In terms of secondary outcomes, muscle tone/spasticity at the elbow was decreased in the intervention group compared with the control group at 1 month. The median change in the Modified Ashworth Scale was - 1 in the intervention group compared with zero in the control group (p < 0.001). No difference in spasticity was seen at 3 or 12 months. Participants treated with botulinum toxin type A showed improvement in upper limb muscle strength at 3 months. The mean change in strength from baseline (upper limb component of the Motricity Index) was 3.5 (95% CI 0.1 to 6.8) points greater in the intervention group compared with the control group. No differences were seen at 1 or 12 months. Participants in the intervention group were more likely to be able to undertake specific basic functional activities, e.g. dress a sleeve, clean the palm and open the hand for cutting fingernails. At 1 month, 109/144 (75.7%) of the intervention group and 79/125 (63.2%) of the control group had improved by at least one point on a five-point Likert scale for at least one of these tasks (p = 0.033). At 3 months the corresponding proportions were 102/142 (71.8%) of the intervention group and 71/122 (58.2%) of the control group (p = 0.027). Improvement was sustained at 12 months for opening the hand for cleaning the palm and opening the hand for cutting the nails but not for other activities. Pain rating improved by two points on a 10-point severity rating scale in the intervention group compared with zero points in the control group (p = 0.004) at 12 months, but no significant differences were seen at 1 or 3 months. There were a number of occasions when there were statistically significant differences in favour of the intervention group; however, these differences were small and of uncertain clinical relevance. These differences were: 3 months - upper limb function (change in ARAT score from baseline), pain (EQ-5D) and participation restriction (Oxford Handicap Scale); 12 months - anxiety/depression (EQ-5D) and participation restriction (Oxford Handicap Scale). No differences in grip strength, dexterity or the Barthel ADL Index were found at any time point. There were no differences between the groups for achievement of patient-selected goals. There was a higher incidence of general malaise/flu-like/cold symptoms in participants treated with botulinum toxin type A with a relative risk of 7.6 (95% CI 1.8 to 32.3). Only one serious adverse event (dysphagia) was potentially related to botulinum toxin type A. Time since stroke and severity of initial upper limb function were preplanned subgroup analyses. There was no significant difference in either subgroup for achievement of ARAT 'success' following treatment with botulinum toxin type A. The base-case incremental cost-effectiveness ratio was 93,500 pounds per QALY gained and estimation of the cost-effectiveness acceptability curve for botulinum toxin type A plus the upper limb therapy programme indicated that there was only a 0.36 probability of it being cost-effective at a threshold ceiling ratio of 20,000 pounds per QALY. CONCLUSIONS: The addition of botulinum toxin type A to an upper limb therapy programme to treat spasticity due to stroke did not enhance improvement in upper limb function when assessed by the prespecified primary outcome measure at 1 month. However, improvements were seen in muscle tone at 1 month, upper limb strength at 3 months, upper limb functional activities related to undertaking specific basic functional tasks at 1, 3 and 12 months, and upper limb pain at 12 months. Botulinum toxin was well tolerated and side effects were minor. The addition of botulinum toxin type A to an upper limb therapy programme for the treatment of upper limb spasticity due to stroke was not estimated to be cost-effective at levels of willingness to pay for a QALY set by NHS decision-makers. TRIAL REGISTRATION: ISRCTN78533119; EudraCT 2004-002427-40; CTA 17136/0230/001.

After the honeymoon comes divorce: long-term use of the antegrade continence enema procedure.

BACKGROUND: Having reported that 18% of children discontinue use of the antegrade continence enema (ACE) after 5 years, we aimed to determine long-term use after an ACE procedure. METHODS: A postal/telephone questionnaire was conducted. Subjects were consecutive children undergoing an ACE between 1993 and 1999. Outcome measures were use of ACE, reasons for nonuse, complications, and overall satisfaction. RESULTS: Of 84 eligible subjects, data were available on 61 (73%) aged 22.4 years (15.5-35.1 years). Underlying diagnoses included spina bifida (n = 27), anorectal malformations (n = 18), constipation (n = 11), Hirschsprung's disease (n = 1), sacral agenesis (n = 2), and trauma/tumor (n = 2). Follow-up was 11.02 years (8.34-14.39 years). Thirty-six (59%) of 61 patients were still using their ACE. Reasons for nonuse were lack of effectiveness (n = 14), complications (n = 5), psychologic issues (n = 2), and poor compliance (n = 2). There was no association between diagnosis and nonuse (chi(2), P = .63). In those still using ACE, the overall satisfaction score was 4.1 (1-5). Several individuals reported feeling abandoned on becoming adults and losing the support they had in childhood. CONCLUSION: There is a late "failure" rate for the ACE procedure. However, satisfaction was high among those still using the ACE. This study further emphasizes the need for robust transitional care arrangements.

Effects of estrogen on basal forebrain cholinergic neurons and spatial learning.

Estrogen receptors are expressed in several areas of the brain associated with cognition, including the basal forebrain cholinergic nuclei, and numerous reports have described improvements in memory in response to estrogen supplementation. The relationship between estrogen's effects on the basal cholinergic system and improvements in cognitive function, however, are obscure. We therefore undertook a study to determine the effects of estrogen on several parameters of the cholinergic system in ovariectomized rats and measured the concomitant effects on performance in the Barnes maze, a test of spatial memory. Six weeks of estradiol treatment caused an increase in choline acetyltransferase activity throughout the projection fields of the basal forebrain, including the hippocampal formation (14%), olfactory bulb (30%), and cerebral cortex (35%). Estrogen treatment also caused an increase in cell soma size of cholinergic neurons in the horizontal diagonal limb of the band of Broca and in the basal nucleus of Meynert. There was no change in the number of neurons positive for p75(NTR), nor in the level of p75(NTR) expression per neuron. Barnes maze performance was markedly improved after estradiol treatment, reinforcing the view that estrogen has beneficial cognitive effects, particularly on spatial memory. The beneficial cognitive effect was likely mediated in part by stimulation of the basal forebrain cholinergic system, especially in its neocortical projection, but was not associated with changes in the level of p75(NTR) expression.

Mindfulness-based cognitive therapy for recurring depression in older people: a qualitative study.

Mindfulness-based Cognitive Therapy (MBCT) is a meditation-based intervention designed to reduce recurrence in people with histories of relapsing unipolar major depression. MBCT is an eight-session course delivered to groups of participants who are currently not (or only mildly) depressed. We sought to determine whether MBCT is suitable for older people, and what modifications they may require. We recruited 38 participants aged over 65, of whom 30 completed an MBCT course. Their responses at assessment, post-course and one-year follow-up interviews, plus comments at three-monthly 'reunion' meetings, provided data for thematic analysis. Main themes emerging for participants as a group are considered, as are individuals' understandings and uses of MBCT, and how these developed during and following the course. We found MBCT promising as a cost-effective addition to clinicians' repertoire for addressing depression in old age, and identified issues for further research. Participants' comments indicated that they considered MBCT a helpful intervention for older sufferers from recurring depression.

Effects of three biodiesels and a low sulfur diesel in male rats--a pilot 4-week oral study.

Because of the accessible and renewable nature of feedstock and the potential for the reduction of harmful combustion emissions and greenhouse gases, biodiesels have received increasing interest as an alternate fuel. Oral exposure to biodiesels is a concern because of contact during refuelling, accidental ingestion and exposure through ground water contamination. Although biodiesels from various feedstock are in use commercially and experimentally, very little is known about their potential adverse effects and no data is available on their potential for ground water contamination. A study was performed on male rats following oral treatment with experimental biodiesels (dissolved in corn oil) derived from canola oil (Bio-C), soy oil (Bio-S) and fish oil (Bio-F), at 500 mg/kg body weight/day, 5 days per week, for 4 weeks. Separate groups of animals were treated with low sulfur diesel (LSD) for comparison purpose, and with corn oil alone to serve as control. The potential for ground water contamination by biodiesels was investigated by the preparation of water-accommodated fractions (WAF) followed by gas chromatographic analysis. WAF from Bio-F and Bio-S was found to have the highest level of dichloromethane extractable materials. Gas chromatographic analysis indicated that the extractable materials from biodiesels contained much higher proportion of C15-C30 materials than LSD. Increased liver weight was observed in animal treated with Bio-C, Bio-S and LSD and decreased thymus weight was found in those treated with Bio-S. Histopathological changes typical of male-rat specific hyaline-droplet nephropathy were detected in kidney tubules of animals treated with LSD, Bio-S and Bio-C. Mild adaptive changes were observed in thyroids of animals treated with LSD, Bio-S and Bio-F. Clinical chemical and biochemical changes were confined to Bio-S and LSD treated rats and included elevation in some hepatic phase-I and phase-II drug metabolizing enzymes and hepatic palmitoyl Co-A oxidase, and elevated urinary concentrations of ascorbic acid and albumin. At the given dose level of 500 mg/kg bw/day, the overall treatment-related effects of biodiesels and LSD are mild, and the severity of the treatment effects may be ranked as: LSD>Bio-S>Bio-C>Bio-F. Considered together with the presence of a higher level of water extractable materials, Bio-S may be more of a concern for potential human health than Bio-C and Bio-F in an oral exposure scenario. Further studies are needed to identify and characterize the constituents contributing to the treatment-related effects specific to these experimental biodiesels.

Structure-activity relationship studies on N3-substituted willardiine derivatives acting as AMPA or kainate receptor antagonists.

N3-substitution of the uracil ring of willardiine with a variety of carboxyalkyl or carboxybenzyl substituents produces AMPA and kainate receptor antagonists. In an attempt to improve the potency and selectivity of these AMPA and kainate receptor antagonists a series of analogues with different terminal acidic groups and interacidic group spacers was synthesized and pharmacologically characterized. (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLU(K5)-containing kainate receptors (K(D) 0.105 +/- 0.007 microM vs kainate on native GLU(K5); K(D) 71.4 +/- 8.3 microM vs (S)-5-fluorowillardiine on native AMPA receptors). On recombinant human GLU(K5), GLU(K5)/GLU(K6), and GLU(K5)/GLU(K2), K(B) values of 0.12 +/- 0.03, 0.12 +/- 0.01, and 0.18 +/- 0.02 microM, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLU(K6) or GLU(K7) kainate receptors or homomeric GLU(A1-4) AMPA receptors (IC(50) values > 100 microM). Thus, 43 is a potent and selective GLU(K5) receptor antagonist.

Biomarkers of oxidative stress study II: are oxidation products of lipids, proteins, and DNA markers of CCl4 poisoning?

Oxidation products of lipids, proteins, and DNA in the blood, plasma, and urine of rats were measured as part of a comprehensive, multilaboratory validation study searching for noninvasive biomarkers of oxidative stress. This article is the second report of the nationwide Biomarkers of Oxidative Stress Study using acute CCl4 poisoning as a rodent model for oxidative stress. The time-dependent (2, 7, and 16 h) and dose-dependent (120 and 1200 mg/kg i.p.) effects of CCl4 on concentrations of lipid hydroperoxides, TBARS, malondialdehyde (MDA), isoprostanes, protein carbonyls, methionine sulfoxidation, tyrosine products, 8-hydroxy-2'-deoxyguanosine (8-OHdG), leukocyte DNA-MDA adducts, and DNA-strand breaks were investigated to determine whether the oxidative effects of CCl4 would result in increased generation of these oxidation products. Plasma concentrations of MDA and isoprostanes (both measured by GC-MS) and urinary concentrations of isoprostanes (measured with an immunoassay or LC/MS/MS) were increased in both low-dose and high-dose CCl4-treated rats at more than one time point. The other urinary markers (MDA and 8-OHdG) showed significant elevations with treatment under three of the four conditions tested. It is concluded that measurements of MDA and isoprostanes in plasma and urine as well as 8-OHdG in urine are potential candidates for general biomarkers of oxidative stress. All other products were not changed by CCl4 or showed fewer significant effects.

Moderate alcohol consumption and levels of antioxidant vitamins and isoprostanes in postmenopausal women.

BACKGROUND: Although alcohol intake has been positively associated with breast cancer risk in epidemiologic studies, the mechanisms mediating this association are speculative. OBJECTIVE: The Postmenopausal Women's Alcohol Study was designed to explore the effects of moderate alcohol consumption on potential risk factors for breast cancer. In the present analysis, we evaluated the relationship of alcohol consumption with antioxidant nutrients and a biomarker of oxidative stress. DESIGN: Participants (n=53) consumed a controlled diet plus each of three treatments (15 or 30 g alcohol/day or a no-alcohol placebo beverage), during three 8-week periods in random order. We measured the antioxidants, vitamin E (alpha (alpha)- and gamma (gamma)-tocopherols), selenium, and vitamin C in fasting blood samples which were collected at the end of diet periods, treated and frozen for assay at the end of the study. We also measured 15-F(2t)-IsoP isoprostane, produced by lipid peroxidation, which serves as an indicator of oxidative stress and may serve as a biomarker for conditions favorable to carcinogenesis. RESULTS: After adjusting for BMI (all models) and total serum cholesterol (tocopherol and isoprostane models) we observed a significant 4.6% decrease (P=0.02) in alpha-tocopherol and a marginally significant 4.9% increase (P=0.07) in isoprostane levels when women consumed 30 g alcohol/day (P=0.06 and 0.05 for overall effect of alcohol on alpha-tocopherol and isoprostanes, respectively). The other antioxidants were not significantly modified by the alcohol treatment. CONCLUSIONS: These results suggest that moderate alcohol consumption increases some biomarkers of oxidative stress in postmenopausal women.