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OBJECTIVES/GOALS: We have designed an analogue of the Vitamin E tocotrienols called tocoflexol, which improves their pharmacokinetic limitations to make it an effective radiation medical countermeasure. Our goal is to demonstrate that tocoflexol is an effective radiomitigator in vivo when administered after exposure to lethal doses of total body irradiation. METHODS/STUDY POPULATION: Tocoflexol was designed using computational techniques to improve binding to ATTP, the key transporter that reduces the rate of elimination of tocols. In vitro studies compared the antioxidant and cell uptake properties to conventional tocotrienols. Next, we used a mouse model of lethal total body irradiation to evaluate its radioprotection efficacy (treating before radiation). To determine the optimal administration route for radiomitigation (treating after radiation), we will test oral and subcutaneous dosing. Mouse survival will be monitored for 30 days after irradiation. Sample tissues will be taken to evaluate the ability of tocoflexol to protect key organs from acute radiation syndrome. The bioavailability of tocoflexol will be evaluated in a rodent model. RESULTS/ANTICIPATED RESULTS: Known Results: Results show that tocoflexol has potent antioxidant properties and high cell uptake. When tocoflexol was administered 24 hours before exposure to lethal doses of radiation, tocoflexol-treated mice showed 100% survival. Anticipated Results: Because of its improved bioavailability and pharmacokinetic properties, we expect that tocoflexol will show radiomitigation efficacy when administered 24 hours after radiation, improving survival and protecting key organ systems from acute radiation syndrome. DISCUSSION/SIGNIFICANCE: There is an unmet need for safe and effective radiomitigators that can offer multi-organ protection and be rapidly administered in the event of nuclear emergencies. Demonstration of radiomitigation efficacy will position tocoflexol as a prime candidate to be developed into a nuclear medical countermeasure and stockpiled for emergencies.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Diets varying in SFA and MUFA content can impact glycaemic control; however, whether underlying differences in genetic make-up can influence blood glucose responses to these dietary fatty acids is unknown. We examined the impact of dietary oils varying in SFA/MUFA content on changes in blood glucose levels (primary outcome) and whether these changes were modified by variants in the stearoyl-CoA desaturase (SCD) gene (secondary outcome). Obese men and women participating in the randomised, crossover, isoenergetic, controlled-feeding Canola Oil Multicenter Intervention Trial II consumed three dietary oils for 6 weeks, with washout periods of ˜6 weeks between each treatment. Diets studied included a high SFA/low MUFA Control oil (36·6 % SFA/28·2 % MUFA), a conventional canola oil (6·2 % SFA/63·1 % MUFA) and a high-oleic acid canola oil (5·8 % SFA/74·7 % MUFA). No differences in fasting blood glucose were observed following the consumption of the dietary oils. However, when stratified by SCD genotypes, significant SNP-by-treatment interactions on blood glucose response were found with additive models for rs1502593 (P = 0·01), rs3071 (P = 0·02) and rs522951 (P = 0·03). The interaction for rs3071 remained significant (P = 0·005) when analysed with a recessive model, where individuals carrying the CC genotype showed an increase (0·14 (sem 0·09) mmol/l) in blood glucose levels with the Control oil diet, but reductions in blood glucose with both MUFA oil diets. Individuals carrying the AA and AC genotypes experienced reductions in blood glucose in response to all three oils. These findings identify a potential new target for personalised nutrition approaches aimed at improving glycaemic control.
Rapid diagnosis of dementia is essential to ensure optimum patient care. This study used real-world data to quantify the dementia diagnostic pathway in Australia.
A real-world, cross-sectional survey of physicians and patients.
Primary care or specialist physicians managing patients with cognitive impairment (CI).
Descriptive analyses focused on key events in the diagnostic pathway. Regression modeling compared the duration between first consultation and formal diagnosis with various factors.
Data for 600 patients were provided by 60 physicians. Mean time from initial symptoms to first consultation was 6.1 ± 4.4 months; 20% of patients had moderate or severe CI at first consultation. Mean time from first consultation to formal diagnosis was 4.0 ± 7.4 months (1.2 ± 3.6 months if not referred to a secondary physician, and 5.3 ± 8.3 months if referred). Time from first consultation to diagnosis was significantly associated with CI severity at first consultation; time was shorter with more severe CI. There was no association of disease severity and referral to a secondary physician; 69.5% of patients were referred, the majority (57.1%) to a geriatrician. The highest proportion of patients were diagnosed by geriatricians (47.4%). Some form of test or scale was used to aid diagnosis in 98.8% of patients.
A substantial number of Australians experience cognitive decline and behavioral changes some time before consulting a physician or being diagnosed with dementia. Increasing public awareness of the importance of early diagnosis is essential to improve the proportion of patients receiving comprehensive support prior to disease progression.
C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.
To explore CRP in MDD and its phenotypic associations.
We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes.
Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood.
CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.
Declaration of interest
S.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.
Vitamin D insufficiency and deficiency have been associated with an increased risk of adverse pregnancy outcomes. Controversy remains as findings have been inconsistent between disparate populations. The aim of this study was to investigate the relationship between vitamin D status and pregnancy outcomes in a large, prospective pregnancy cohort. 25-Hydroxyvitamin D concentration was analysed in serum samples collected at 15 weeks of gestation from 1710 New Zealand women participating in a large, observational study. Associations between vitamin D status and pre-eclampsia, preterm birth, small for gestational age (SGA) and gestational diabetes were investigated. The mean 25-hydroxyvitamin D concentration was 72·9 nmol/l. In all, 23 % had 25-hydroxyvitamin D concentrations <50 nmol/l, and 5 % of participants had concentrations <25 nmol/l. Women with 25-hydroxyvitamin D concentrations <75 nmol/l at 15 weeks of gestation were more likely to develop gestational diabetes mellitus than those with concentrations >75 nmol/l (OR 2·3; 95 % CI 1·1, 5·1). However, this effect was not significant when adjustments were made for BMI and ethnicity (OR 1·8; 95 % CI 0·8, 4·2). 25-Hydroxyvitamin D concentration at 15 weeks was not associated with development of pre-eclampsia, spontaneous preterm birth or SGA infants. Pregnancy complications were low in this largely vitamin D-replete population.
Fatty acid ethanolamides (FAE), a group of lipid mediators derived from long-chain fatty acids (FA), mediate biological activities including activation of cannabinoid receptors, stimulation of fat oxidation and regulation of satiety. However, how circulating FAE levels are influenced by FA intake in humans remains unclear. The objective of the present study was to investigate the response of six major circulating FAE to various dietary oil treatments in a five-period, cross-over, randomised, double-blind, clinical study in volunteers with abdominal obesity. The treatment oils (60 g/12 552 kJ per d (60 g/3000 kcal per d)) provided for 30 d were as follows: conventional canola oil, high oleic canola oil, high oleic canola oil enriched with DHA, flax/safflower oil blend and corn/safflower oil blend. Two SNP associated with FAE degradation and synthesis were studied. Post-treatment results showed overall that plasma FAE levels were modulated by dietary FA and were positively correlated with corresponding plasma FA levels; minor allele (A) carriers of SNP rs324420 in gene fatty acid amide hydrolase produced higher circulating oleoylethanolamide (OEA) (P=0·0209) and docosahexaenoylethanolamide (DHEA) levels (P=0·0002). In addition, elevated plasma DHEA levels in response to DHA intake tended to be associated with lower plasma OEA levels and an increased gynoid fat mass. In summary, data suggest that the metabolic and physiological responses to dietary FA may be influenced via circulating FAE. Genetic analysis of rs324420 might help identify a sub-population that appears to benefit from increased consumption of DHA and oleic acid.
Combining state-of-the-art research with a strong pedagogic approach, this text provides a detailed and complete guide to the theory, practice and applications of optical tweezers. In-depth derivation of the theory of optical trapping and numerical modelling of optical forces are supported by a complete step-by-step design and construction guide for building optical tweezers, with detailed tutorials on collecting and analysing data. Also included are comprehensive reviews of optical tweezers research in fields ranging from cell biology to quantum physics. Featuring numerous exercises and problems throughout, this is an ideal self-contained learning package for advanced lecture and laboratory courses, and an invaluable guide to practitioners wanting to enter the field of optical manipulation. The text is supplemented by www.opticaltweezers.org, a forum for discussion and a source of additional material including free-to-download, customisable research-grade software (OTS) for calculation of optical forces, digital video microscopy, optical tweezers calibration and holographic optical tweezers.
However, this bottle was not marked ‘poison’, so Alice ventured to taste it, and finding it very nice (it had, in fact, a sort of mixed flavour of cherry-tart, custard, pine-apple, roast turkey, toffee, and hot buttered toast), she very soon finished it off.
‘What a curious feeling!’ said Alice. ‘I must be shutting up like a telescope.’