Elevated plasma ceramide levels in post-menopausal women: a cross-sectional study.

Circulating ceramide levels are abnormally elevated in age-dependent pathologies such as cardiovascular diseases, obesity and Alzheimer's disease. Nevertheless, the potential impact of age on plasma ceramide levels has not yet been systematically examined. In the present study, we quantified a focused panel of plasma ceramides and dihydroceramides in a cohort of 164 subjects (84 women) 19 to 80 years of age. After adjusting for potential confounders, multivariable linear regression analysis revealed a positive association between age and ceramide (d18:1/24:0) (β (SE) = 5.67 (2.38); p = .0198) and ceramide (d18:1/24:1) (β (SE) = 2.88 (.61); p < .0001) in women, and between age and ceramide (d18:1/24:1) in men (β (SE) = 1.86 (.77); p = .0179). In women of all ages, but not men, plasma ceramide (d18:1/24:1) was negatively correlated with plasma estradiol (r = -0.294; p = .007). Finally, in vitro experiments in human cancer cells expressing estrogen receptors showed that incubation with estradiol (10 nM, 24 h) significantly decreased ceramide accumulation. Together, the results suggest that aging is associated with an increase in circulating ceramide levels, which in post-menopausal women is at least partially associated with lower estradiol levels

Changes in cardiovascular risk factors for diabetes among young versus older English adult populations

Background: To examine the prevalence of cardiovascular disease (CVD) risk factors among young, middle-aged and older adults with and without diabetes. Method: Among 23,501 participants of pooled nationally representative Health Survey for England years 2003, 2006, 2011 and 2017 (new sample was interviewed each year), CVD risk-factors associated with diabetes versus non-diabetes among young (18-54y), middle (55-74y) and older (≥ 75y) adults were assessed. Models were adjusted for age, sex, locality, ethnicity, qualification, survey year, cardiovascular disease, raised blood pressure, dyslipidaemia, combined obesity, current smoking, and excessive drinking. Results: 11.9% of adults had diabetes: prevalence was 5.3% in aged 18-54y, 18.1% in aged 55-74y, and 29.1% in older adults. Diabetes prevalence was higher in 2017 than 2003 in each age-group. After adjustments for confounding variables, significant predictors of diabetes among young were CVD history, raised BP, dyslipidaemia, combined obesity, and survey year 2006. Effect of dyslipidaemia in young adults on the risk of diabetes was stronger in more recent years 2006 (Odds Ratio =3.87), 2011 (3.04) and 2017 (3.42) as compared with 2003. Among middle age, CVD history, raised BP, dyslipidaemia, combined obesity and survey years 2006 and 2011 were significant predictors of diabetes whereas in older populations only dyslipidaemia, combined obesity and survey year 2011 showed strong association with risk of diabetes. Irrespective of age, smoking and excessive drinking were not significantly associated with diabetes. Conclusion: Young adults with diabetes have higher odds of having cardiovascular risk factors, with dyslipidaemia being the strongest risk factor. Early and specific intervention among young adults would delay CVD outcomes

'You were quiet - I did all the marching': Research processes involved in hearing the voices of South Asian girls

This article is available open access through the publisher’s website at the link below. Copyright @ 2011 A B Academic Publishers.This article provides insights into the outcomes of reflection following two interview approaches used to explore narratives of the lived, individual experiences of South-Asian girls living in West London. In attempting to illuminate and re-present the cultural experiences as told by these girls, the choice of interview approach became critical in allowing the voices to be effectively heard (Rogers, 2005). This article therefore considers how a semi-structured interview approach offered valuable insights into the girls' experiences but became constraining for both researcher and participant in unveiling the complexity and depth of their lives. These constraints emerged through reflection by both participants and researcher. As a result of reflexivity during the research process, the researcher moved towards the use of research conversations during the second phase of the study. Ultimately the study revealed how the girls felt empowered by the opportunity to narrate their individual experiences and tell of their lives. In narrating their reflections on being part of the research, there was a clear recognition that the process facilitated the articulation of new voices and ‘multi-voicedness’ (Moen, 2006

An animal's sex influences the effects of the excipient PEG 400 on the intestinal P-gp protein and mRNA levels, which has implications for oral drug absorption

There is a growing body of evidence which suggests that formerly regarded "inert" pharmaceutical excipients have the potential to influence oral drug bioavailability. The solubilizing agent polyethylene glycol 400 (PEG 400), for instance, has a sex-specific effect on P-glycoprotein (P-gp)-mediated drug bioavailability. We hypothesized that such an effect could be via PEG-induced alteration of P-gp activity and/or expression to different extents in males and females. To test this hypothesis in vivo, we investigated the influence of orally administered PEG 400 on the protein content and mRNA expression of P-gp in different regions of the gastrointestinal tract in male and female rats. Fasted rats received an oral dose of PEG 400 and at different time intervals, rats were sacrificed and their intestines were collected. The P-gp protein and mRNA expression in different intestinal segments (duodenum, jejunum, ileum and colon) were measured by Western blotting and PCR, respectively. It was found that P-gp protein and mRNA levels increased along the gastrointestinal tract in control animals (i.e. without PEG administration), and was higher in males compared to the female rats. The oral administration of PEG 400 decreased the P-gp expression in the jejunum, ileum and colon of males but not in the corresponding segments in females. This sex-dependent influence of PEG 400 on P-gp levels reflects and explains the sex-related effect of PEG 400 on oral absorption of certain drugs. The data further adds to the growing literature on the importance of taking into consideration an individual's sex for optimal drug administration

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry

P-glycoprotein expression in the gastrointestinal tract of male and female rats is influenced differently by food

The aim of this study was to explore the influence of food on P-glycoprotein (P-gp) relative expression in both male and female rats, and its effect on intestinal permeation of P-gp substrates (ranitidine and ganciclovir) and a P-gp non-substrate (metformin). The intestine of 12 male and 12 female Wistar rats were excised and segmented into the duodenum, jejunum, ileum and colon. P-gp extracted from each segment was then determined via Western-blotting. In male rats, the relative P-gp expression decreased significantly after food intake in all segments of the intestine except in the duodenum. The most notable change was demonstrated in the colon where relative expression decreased from 1.75 ± 0.36 in the fasted-state to 0.31 ± 0.15 in the fed-state. In female rats, a fundamentally different result was observed. Food ingestion resulted in a significant increase in relative P-gp expression in all regions of the intestine except in the colon. The largest difference was observed in the jejunum of the fed-state female rat intestine where P-gp expression was 1.76 ± 0.95 which was a six-fold increase from the fasted state at 0.34 ± 0.13. Intestinal permeation studies in an Ussing chamber showed that both ganciclovir and ranitidine exhibited a sex difference in intestinal permeability in the fasted-state. No sex differences and food effects were observed on metformin small intestine permeability. The permeability results of the three drugs highly supported that there was a sex-related food effect on P-gp function in the small intestine. In summary, the current study reports stark differences between male and female rats at a physiological level relating to P-gp expression and the influence of food

ICAM-1-expressing neutrophils exhibit enhanced effector functions in murine models of endotoxemia

This work was supported by funds from the Wellcome Trust (098291/Z/12/Z and 101604/Z/13/Z) (S.N.) and the British Heart Foundation (FS/11/19/28761) (A.W.)

End-to-End Waveform and Beamforming Optimization for RF Wireless Power Transfer

Abstract Radio frequency (RF) wireless power transfer (WPT) is a key technology for future low-power wireless systems. However, the inherently low end-to-end power transfer efficiency (PTE) is challenging for practical applications. The main factors contributing to it are the channel losses, transceivers’ power consumption, and losses related, e.g., to the digital-to-analog converter (DAC), high-power amplifier, and rectenna. Optimizing PTE requires careful consideration of these factors, motivating the current work. Herein, we consider an analog multi-antenna power transmitter that aims to charge a single energy harvester. We first provide a mathematical framework to calculate the harvested power from multi-tone signal transmissions and the system power consumption. Then, we formulate the joint waveform and analog beamforming design problem to minimize power consumption and meet the charging requirements. Finally, we propose an optimization approach relying on swarm intelligence to solve the specified problem. Simulation results quantify the power consumption reduction as the DAC, phase shifters resolution, and antenna length are increased, while it is seen that increasing system frequency results in higher power consumption.Abstract Radio frequency (RF) wireless power transfer (WPT) is a key technology for future low-power wireless systems. However, the inherently low end-to-end power transfer efficiency (PTE) is challenging for practical applications. The main factors contributing to it are the channel losses, transceivers’ power consumption, and losses related, e.g., to the digital-to-analog converter (DAC), high-power amplifier, and rectenna. Optimizing PTE requires careful consideration of these factors, motivating the current work. Herein, we consider an analog multi-antenna power transmitter that aims to charge a single energy harvester. We first provide a mathematical framework to calculate the harvested power from multi-tone signal transmissions and the system power consumption. Then, we formulate the joint waveform and analog beamforming design problem to minimize power consumption and meet the charging requirements. Finally, we propose an optimization approach relying on swarm intelligence to solve the specified problem. Simulation results quantify the power consumption reduction as the DAC, phase shifters resolution, and antenna length are increased, while it is seen that increasing system frequency results in higher power consumption

Stereolithography (SLA) 3D printing of a bladder device for intravesical drug delivery

Intravesical instillation therapy is an alternative approach to oral medications for the treatment of severe bladder diseases, offering high drug concentrations at the site of action while minimising systemic side effects. However, therapeutic efficacy is often limited because of the short residence time of the drug in the bladder and the need for repeated instillations. This study reports, for the first time, the use of stereolithography (SLA) 3D printing to manufacture novel indwelling bladder devices using an elastic polymer to achieve extended and localised delivery of lidocaine hydrochloride. The devices were designed to be inserted into and retrieved from the bladder using a urethral catheter. Two types of bladder devices (hollow and solid) were prepared with a resilient material (Elastic Resin) incorporating three drug loads of lidocaine hydrochloride (10% w/w, 30% w/w and 50% w/w); a drug frequently used to treat interstitial cystitis and bladder pain. All of the devices showed acceptable blood compatibility, good resistance to compressive and stretching forces and were able to recover their original shape immediately once external forces were removed. In vitro drug release studies showed that a complete release of lidocaine was achieved within 4 days from the hollow devices, whereas the solid devices enabled sustained drug release for up to 14 days. SLA 3D printing therefore provides a new manufacturing route to produce bladder-retentive drug delivery devices using elastic polymers, and offers a revolutionary and personalised approach for clinical intravesical drug delivery