Flavonoid supplement improves leg health and reduces fluid retention in pre-menopausal women in a double-blind, placebo-controlled study

Flavonoid extracts derived from plant foods have been shown to benefit certain types of fluid retention. However, no studies have investigated these compounds for use in premenstrual fluid retention, a complaint common among women with otherwise normal menstrual cycles. Therefore, we conducted a double-blind, placebo-controlled, pilot study into the effect of a daily flavonoid extract (Colladeen(R), 320 mg oligomeric procyanidins) on premenstrual fluid retention. Fluid retention was assessed at baseline and throughout 4 menstrual cycles of the intervention using validated questionnaires. Leg girth was also measured at baseline and at the end of the study. Thirty subjects completed the study (n = 18 active treatment; n = 12 placebo). Although no significant changes in leg girth measurements were noted, there was a significant improvement in subjective "leg health" scores after flavonoid treatment compared to placebo (p = 0.013). Furthermore, this was accompanied by an improvement in reported premenstrual fluid retention nearing significance (p = 0.066). We conclude that flavonoids supplements may provide a new therapeutic direction to counter premenstrual fluid retention and improve leg health. A larger study is now warranted.

The measurement of maternal plasma corticotropin-releasing factor (CRF) and CRF-binding protein improves the early prediction of preeclampsia

In the present study we measured maternal plasma concentrations of two placental neurohormones, corticotropin-releasing factor (CRF) and CRF-binding protein (CRF-BP), in 58 at-risk pregnant women consecutively enrolled between 28 and 29 wk of pregnancy to evaluate whether their evaluation may predict third trimester-onset preeclampsia ( PE). The statistical significance was assessed by t test. The cut-off points for defining altered CRF and CRF-BP levels for prediction of PE were chosen by receiving operator characteristics curve analysis, and the probability of developing PE was calculated for several combinations of hormone testing results. CRF and CRF-BP levels were significantly ( both P < 0.0001) higher and lower, respectively, in the patients (n = 20) who later developed PE than in those who did not present PE at follow-up. CRF at the cut-off 425.95 pmol/liter achieved a sensitivity of 94.8% and a specificity of 96.9%, whereas CRF-BP at the cut-off 125.8 nmol/liter combined a sensitivity of 92.5% and a specificity of 82.5% as single markers for prediction of PE. The probability of PE was 34.5% in the whole study population, 93.75% when both CRF and CRF-BP levels were changed, and 0% if both hormone markers were unaltered. The measurement of CRF and CRF-BP levels may add significant prognostic information for predicting PE in at-risk pregnant women.

Flavonoid supplement improves leg health and reduces fluid retention in pre-menopausal women in a double-blind, placebo-controlled study

Flavonoid extracts derived from plant foods have been shown to benefit certain types of fluid retention. However, no studies have investigated these compounds for use in premenstrual fluid retention, a complaint common among women with otherwise normal menstrual cycles. Therefore, we conducted a double-blind, placebo-controlled, pilot study into the effect of a daily flavonoid extract (Colladeen(R), 320 mg oligomeric procyanidins) on premenstrual fluid retention. Fluid retention was assessed at baseline and throughout 4 menstrual cycles of the intervention using validated questionnaires. Leg girth was also measured at baseline and at the end of the study. Thirty subjects completed the study (n = 18 active treatment; n = 12 placebo). Although no significant changes in leg girth measurements were noted, there was a significant improvement in subjective "leg health" scores after flavonoid treatment compared to placebo (p = 0.013). Furthermore, this was accompanied by an improvement in reported premenstrual fluid retention nearing significance (p = 0.066). We conclude that flavonoids supplements may provide a new therapeutic direction to counter premenstrual fluid retention and improve leg health. A larger study is now warranted.

Artichoke leaf extract reduces symptoms of irritable bowel syndrome and improves quality of life in otherwise healthy volunteers suffering from concomitant dyspepsia: a subset analysis

Objectives: Does artichoke leaf extract (ALE) ameliorate symptoms of Irritable bowel syndrome (IBS) in otherwise healthy volunteers suffering concomitant dyspepsia? Methods: A subset analysis of a previous dose-ranging, open, postal study, in adults suffering dyspepsia. Two hundred and eight (208) adults were identified post hoc as suffering with IBS. IBS incidence, self-reported usual bowel pattern, and the Nepean Dyspepsia Index (NDI) were compared before and after a 2-month intervention period. Results: There was a significant fall in IBS incidence of 26.4% (p<0.001) after treatment. A significant shift in self-reported usual bowel pattern away from "alternating constipation/diarrhea" toward "normal" (p<0.001) was observed. NDI total symptom score significantly decreased by 41% (p<0.001) after treatment. Similarly, there was a significant 20% improvement in the NDI total quality-of-life (QOL) score in the subset after treatment. Conclusion: This report supports previous findings that ALE ameliorates symptoms of IBS, plus improves health-related QOL.

Evidence that indirect inhibition of saccade initiation improves saccade accuracy

Saccadic eye-movements to a visual target are less accurate if there are distracters close to its location (local distracters). The addition of more distracters, remote from the target location (remote distracters), invokes an involuntary increase in the response latency of the saccade and attenuates the effect of local distracters on accuracy. This may be due to the target and distracters directly competing (direct route) or to the remote distracters acting to impair the ability to disengage from fixation (indirect route). To distinguish between these we examined the development of saccade competition by recording saccade latency and accuracy responses made to a target and local distracter compared with those made with an addition of a remote distracter. The direct route would predict that the remote distracter impacts on the developing competition between target and local distracter, while the indirect route would predict no change as the accuracy benefit here derives from accessing the same competitive process but at a later stage. We found that the presence of the remote distracter did not change the pattern of accuracy improvement. This suggests that the remote distracter was acting along an indirect route that inhibits disengagement from fixation, slows saccade initiation, and enables more accurate saccades to be made.

Modification of cell wall properties in lettuce improves shelf life

It is proposed that post-harvest longevity and appearance of salad crops is closely linked to pre-harvest leaf morphology (cell and leaf size) and biophysical structure (leaf strength). Transgenic lettuce plants (Lactuca sativa cv. Valeria) were produced in which the production of the cell wall-modifying enzyme xyloglucan endotransglucosylase/hydrolase (XTH) was down-regulated by antisense inhibition. Independently transformed lines were shown to have multiple members of the LsXTH gene family down-regulated in mature leaves of 6-week-old plants and during the course of shelf life. Consequently, xyloglucan endotransglucosylase (XET) enzyme activity and action were down-regulated in the cell walls of these leaves and it was established that leaf area and fresh weight were decreased while leaf strength was increased in the transgenic lines. Membrane permeability was reduced towards the end of shelf life in the transgenic lines relative to the controls and bacteria were evident inside the leaves of control plants only. Most importantly, an extended shelf-life of transgenic lines was observed relative to the non-transgenic control plants. These data illustrate the potential for engineering cell wall traits for improving quality and longevity of salad crops using either genetic modification directly, or by using markers associated with XTH genes to inform a commercial breeding programme.

Semi-dwarfing (Rht-B1b) improves nitrogen-use efficiency in wheat, but not at economically optimal levels of nitrogen availability

A UK field experiment compared a complete factorial combination of three backgrounds (cvs Mercia, Maris Huntsman and Maris Widgeon), three alleles at the Rht-B1 locus as Near Isogenic Lines (NILs: rht-B1a (tall), Rht-B1b (semi-dwarf), Rht-B1c (severe dwarf)) and four nitrogen (N) fertilizer application rates (0, 100, 200 and 350 kg N/ha). Linear+exponential functions were fitted to grain yield (GY) and nitrogen-use efficiency (NUE; GY/available N) responses to N rate. Averaged over N rate and background Rht-B1b conferred significantly (P<0.05) greater GY, NUE, N uptake efficiency (NUpE; N in above ground crop / available N) and N utilization efficiency (NUtEg; GY / N in above ground crop) compared with rht-B1a and Rht-B1c. However the economically optimal N rate (Nopt) for N:grain price ratios of 3.5:1 to 10:1 were also greater for Rht-B1b, and because NUE, NUpE and NUtE all declined with N rate, Rht-Blb failed to increase NUE or its components at Nopt. The adoption of semi-dwarf lines in temperate and humid regions, and the greater N rates that such adoption justifies economically, greatly increases land-use efficiency, but not necessarily, NUE.

Codon and mRNA sequence optimization of microdystrophin transgenes improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer

Duchenne muscular dystrophy is a fatal muscle-wasting disorder. Lack of dystrophin compromises the integrity of the sarcolemma and results in myofibers that are highly prone to contraction-induced injury. Recombinant adenoassociated virus (rAAV)-mediated dystrophin gene transfer strategies to muscle for the treatment of Duchenne muscular dystrophy (DMD) have been limited by the small cloning capacity of rAAV vectors and high titers necessary to achieve efficient systemic gene transfer. In this study, we assess the impact of codon optimization on microdystrophin (ΔAB/R3-R18/ΔCT) expression and function in the mdx mouse and compare the function of two different configurations of codon-optimized microdystrophin genes (ΔAB/R3-R18/ΔCT and ΔR4-R23/ΔCT) under the control of a muscle-restrictive promoter (Spc5-12). Codon optimization of microdystrophin significantly increases levels of microdystrophin mRNA and protein after intramuscular and systemic administration of plasmid DNA or rAAV2/8. Physiological assessment demonstrates that codon optimization of ΔAB/R3-R18/ΔCT results in significant improvement in specific force, but does not improve resistance to eccentric contractions compared with noncodon-optimized ΔAB/ R3-R18/ΔCT. However, codon-optimized microdystrophin ΔR4-R23/ΔCT completely restored specific force generation and provided substantial protection from contraction-induced injury. These results demonstrate that codon optimization of microdystrophin under the control of a muscle-specific promoter can significantly improve expression levels such that reduced titers of rAAV vectors will be required for efficient systemic administration.

Delivery of AAV2/9-microdystrophin genes incorporating helix 1 of the coiled-coil motif in the C-terminal domain of dystrophin improves muscle pathology and restores the level of α1-syntrophin and α-dystrobrevin in skeletal muscles of mdx mice. Level of α1-Syntrophin and α-Dystrobrevin in Skeletal Muscles of mdx Mice

Duchenne muscular dystrophy is a severe X-linked inherited muscle wasting disorder caused by mutations in the dystrophin gene. Adeno-associated virus (AAV) vectors have been extensively used to deliver genes efficiently for dystrophin expression in skeletal muscles. To overcome limited packaging capacity of AAV vectors (<5 kb), truncated recombinant microdystrophin genes with deletions of most of rod and carboxyl-terminal (CT) domains of dystrophin have been developed. We have previously shown the efficiency of mRNA sequence–optimized microdystrophin (ΔR4-23/ΔCT, called MD1) with deletion of spectrin-like repeat domain 4 to 23 and CT domain in ameliorating the pathology of dystrophic mdx mice. However, the CT domain of dystrophin is thought to recruit part of the dystrophin-associated protein complex, which acts as a mediator of signalling between extracellular matrix and cytoskeleton in muscle fibers. In this study, we extended the ΔR4-23/ΔCT microdystrophin by incorporating helix 1 of the coiled-coil motif in the CT domain of dystrophin (MD2), which contains the α1-syntrophin and α-dystrobrevin binding sites. Intramuscular injection of AAV2/9 expressing CT domain–extended microdystrophin showed efficient dystrophin expression in tibialis anterior muscles of mdx mice. The presence of the CT domain of dystrophin in MD2 increased the recruitment of α1-syntrophin and α-dystrobrevin at the sarcolemma and significantly improved the muscle resistance to lengthening contraction–induced muscle damage in the mdx mice compared with MD1. These results suggest that the incorporation of helix 1 of the coiled-coil motif in the CT domain of dystrophin to the microdystrophins will substantially improve their efficiency in restoring muscle function in patients with Duchenne muscular dystrophy.

Phenolic acid intake, delivered via moderate champagne wine consumption, improves spatial working memory via the modulation of hippocampal and cortical protein expression/activation.

Aims: While much data exist for the effects of flavonoid-rich foods on spatial memory in rodents, there are no such data for foods/beverages predominantly containing hydroxycinnamates and phenolic acids. To address this, we investigated the effects of moderate Champagne wine intake, which is rich in these components, on spatial memory and related mechanisms relative to the alcohol- and energy-matched controls. Results: In contrast to the isocaloric and alcohol-matched controls, supplementation with Champagne wine (1.78 ml/kg BW, alcohol 12.5% vol.) for 6 weeks led to an improvement in spatial working memory in aged rodents. Targeted protein arrays indicated that these behavioral effects were paralleled by the differential expression of a number of hippocampal and cortical proteins (relative to the isocaloric control group), including those involved in signal transduction, neuroplasticity, apoptosis, and cell cycle regulation. Western immunoblotting confirmed the differential modulation of brain-derived neurotrophic factor, cAMP response-element-binding protein (CREB), p38, dystrophin, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, mammalian target of rapamycin (mTOR), and Bcl-xL in response to Champagne supplementation compared to the control drink, and the modulation of mTOR, Bcl-xL, and CREB in response to alcohol supplementation. Innovation: Our data suggest that smaller phenolics such as gallic acid, protocatechuic acid, tyrosol, caftaric acid, and caffeic acid, in addition to flavonoids, are capable of exerting improvements in spatial memory via the modulation in hippocampal signaling and protein expression. Conclusion: Changes in spatial working memory induced by the Champagne supplementation are linked to the effects of absorbed phenolics on cytoskeletal proteins, neurotrophin expression, and the effects of alcohol on the regulation of apoptotic events in the hippocampus and cortex. Antioxid. Redox Signal. 00, 000-000.

Intrastriatal transplantation of adult human neural crest-derived stem cells improves functional outcome in parkinsonian rats

Parkinson's disease (PD) is considered the second most frequent and one of the most severe neurodegenerative diseases, with dysfunctions of the motor system and with nonmotor symptoms such as depression and dementia. Compensation for the progressive loss of dopaminergic (DA) neurons during PD using current pharmacological treatment strategies is limited and remains challenging. Pluripotent stem cell-based regenerative medicine may offer a promising therapeutic alternative, although the medical application of human embryonic tissue and pluripotent stem cells is still a matter of ethical and practical debate. Addressing these challenges, the present study investigated the potential of adult human neural crest-derived stem cells derived from the inferior turbinate (ITSCs) transplanted into a parkinsonian rat model. Emphasizing their capability to give rise to nervous tissue, ITSCs isolated from the adult human nose efficiently differentiated into functional mature neurons in vitro. Additional successful dopaminergic differentiation of ITSCs was subsequently followed by their transplantation into a unilaterally lesioned 6-hydroxydopamine rat PD model. Transplantation of predifferentiated or undifferentiated ITSCs led to robust restoration of rotational behavior, accompanied by significant recovery of DA neurons within the substantia nigra. ITSCs were further shown to migrate extensively in loose streams primarily toward the posterior direction as far as to the midbrain region, at which point they were able to differentiate into DA neurons within the locus ceruleus. We demonstrate, for the first time, that adult human ITSCs are capable of functionally recovering a PD rat model.

Commensalism in an agroecosystem: hydraulic redistribution by deep-rooted legumes improves survival of a droughted shallow-rooted legume companion

We investigated commensalism of water use among annual shallow-rooted and perennial deep-rooted pasture legumes by examining the effect of hydraulic lift by Cullen pallidum (N.T.Burb.) J.W.Grimes and Medicago sativa on growth, survival and nutrient uptake of Trifolium subterraneum L. A vertically split-root design allowed separate control of soil water in top and bottom soil. Thirty-five days after watering ceased in the top tube, but soil remained at field capacity in the bottom tube, an increase in shallow soil water content by hydraulic lift was 5.6 and 5.9 g kg−1 soil overnight for C. pallidum and M. sativa, respectively. Trifolium subterraneum in this treatment maintained higher leaf water potentials (with M. sativa) or exhibited a slower decline (with C. pallidum) than without companion perennial plants; and shoot biomass of T. subterraneum was 56% (with C. pallidum) and 67% (with M. sativa) of that when both top and bottom tubes were at field capacity. Uptake of rubidium (a potassium analog) and phosphorus by T. subterraneum was not facilitated by hydraulic lift. Interestingly, phosphorus content was threefold greater, and shoot biomass 1.5–3.3-fold greater when T. subterraneum was interplanted with C. pallidum compared with M. sativa, although dry weight of C. pallidum was much greater than that of M. sativa. This study showed that interplanting with deep-rooted perennial legumes has benefited the survival of T. subterraneum.

Training on the use of a bespoke continuing professional development framework improves the quality of CPD records

BACKGROUND: Using continuing professional development (CPD) as part of the revalidation of pharmacy professionals has been proposed in the UK but not implemented. We developed a CPD Outcomes Framework (‘the framework’) for scoring CPD records, where the score range was -100 to +150 based on demonstrable relevance and impact of the CPD on practice. OBJECTIVE: This exploratory study aimed to test the outcome of training people to use the framework, through distance-learning material (active intervention), by comparing CPD scores before and after training. SETTING: Pharmacy professionals were recruited in the UK in Reading, Banbury, Southampton, Kingston-upon-Thames and Guildford in 2009. METHOD: We conducted a randomised, double-blinded, parallel-group, before and after study. The control group simply received information on new CPD requirements through the post; the active intervention group also received the framework and associated training. Altogether 48 participants (25 control, 23 active) completed the study. All participants submitted CPD records to the research team before and after receiving the posted resources. The records (n=226) were scored blindly by the researchers using the framework. A subgroup of CPD records (n=96) submitted first (before-stage) and rewritten (after-stage) were analysed separately. MAIN OUTCOME MEASURE: Scores for CPD records received before and after distributing group-dependent material through the post. RESULTS: Using a linear-regression model both analyses found an increase in CPD scores in favour of the active intervention group. For the complete set of records, the effect was a mean difference of 9.9 (95% CI = 0.4 to 19.3), p-value = 0.04. For the subgroup of rewritten records, the effect was a mean difference of 17.3 (95% CI = 5.6 to 28.9), p-value = 0.0048. CONCLUSION: The intervention improved participants’ CPD behaviour. Training pharmacy professionals to use the framework resulted in better CPD activities and CPD records, potentially helpful for revalidation of pharmacy professionals. IMPACT: • Using a bespoke Continuing Professional Development outcomes framework improves the value of pharmacy professionals’ CPD activities and CPD records, with the potential to improve patient care. • The CPD outcomes framework could be helpful to pharmacy professionals internationally who want to improve the quality of their CPD activities and CPD records. • Regulators and officials across Europe and beyond can assess the suitability of the CPD outcomes framework for use in pharmacy CPD and revalidation in their own setting.

Cocoa flavanol intake improves endothelial function and Framingham Risk Score in healthy men and women: a randomised, controlled, double-masked trial: the Flaviola Health Study

Cocoa flavanol (CF) intake improves endothelial function in patients with cardiovascular risk factors and disease. We investigated the effects of CF on surrogate markers of cardiovascular health in low risk, healthy, middle-aged individuals without history, signs or symptoms of CVD. In a 1-month, open-label, one-armed pilot study, bi-daily ingestion of 450 mg of CF led to a time-dependent increase in endothelial function (measured as flow-mediated vasodilation (FMD)) that plateaued after 2 weeks. Subsequently, in a randomised, controlled, double-masked, parallel-group dietary intervention trial (Clinicaltrials.gov: NCT01799005), 100 healthy, middle-aged (35–60 years) men and women consumed either the CF-containing drink (450 mg) or a nutrient-matched CF-free control bi-daily for 1 month. The primary end point was FMD. Secondary end points included plasma lipids and blood pressure, thus enabling the calculation of Framingham Risk Scores and pulse wave velocity. At 1 month, CF increased FMD over control by 1·2 % (95 % CI 1·0, 1·4 %). CF decreased systolic and diastolic blood pressure by 4·4 mmHg (95 % CI 7·9, 0·9 mmHg) and 3·9 mmHg (95 % CI 6·7, 0·9 mmHg), pulse wave velocity by 0·4 m/s (95 % CI 0·8, 0·04 m/s), total cholesterol by 0·20 mmol/l (95 % CI 0·39, 0·01 mmol/l) and LDL-cholesterol by 0·17 mmol/l (95 % CI 0·32, 0·02 mmol/l), whereas HDL-cholesterol increased by 0·10 mmol/l (95 % CI 0·04, 0·17 mmol/l). By applying the Framingham Risk Score, CF predicted a significant lowering of 10-year risk for CHD, myocardial infarction, CVD, death from CHD and CVD. In healthy individuals, regular CF intake improved accredited cardiovascular surrogates of cardiovascular risk, demonstrating that dietary flavanols have the potential to maintain cardiovascular health even in low-risk subjects.

Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study

Background: The beneficial cardiovascular effects of vegetables may be underpinned by their high inorganic nitrate content. Objective: We sought to examine the effects of a 6-wk once-daily intake of dietary nitrate (nitrate-rich beetroot juice) compared with placebo intake (nitrate-depleted beetroot juice) on vascular and platelet function in untreated hypercholesterolemics. Design: A total of 69 subjects were recruited in this randomized, double-blind, placebo-controlled parallel study. The primary endpoint was the change in vascular function determined with the use of ultrasound flow-mediated dilatation (FMD). Results: Baseline characteristics were similar between the groups, with primary outcome data available for 67 patients. Dietary nitrate resulted in an absolute increase in the FMD response of 1.1% (an ∼24% improvement from baseline) with a worsening of 0.3% in the placebo group (P < 0.001). A small improvement in the aortic pulse wave velocity (i.e., a decrease of 0.22 m/s; 95% CI: −0.4, −0.3 m/s) was evident in the nitrate group, showing a trend (P = 0.06) to improvement in comparison with the placebo group. Dietary nitrate also caused a small but significant reduction (7.6%) in platelet-monocyte aggregates compared with an increase of 10.1% in the placebo group (P = 0.004), with statistically significant reductions in stimulated (ex vivo) P-selectin expression compared with the placebo group (P < 0.05) but no significant changes in unstimulated expression. No adverse effects of dietary nitrate were detected. The composition of the salivary microbiome was altered after the nitrate treatment but not after the placebo treatment (P < 0.01). The proportions of 78 bacterial taxa were different after the nitrate treatment; of those taxa present, 2 taxa were responsible for >1% of this change, with the proportions of Rothia mucilaginosa trending to increase and Neisseria flavescens (P < 0.01) increased after nitrate treatment relative to after placebo treatment. Conclusions: Sustained dietary nitrate ingestion improves vascular function in hypercholesterolemic patients. These changes are associated with alterations in the oral microbiome and, in particular, nitrate-reducing genera. Our findings provide additional support for the assessment of the potential of dietary nitrate as a preventative strategy against atherogenesis in larger cohorts. This trial was registered at clinicaltrials.gov as NCT01493752.