Mitochondrial - Endoplasmic reticulum interactions in the trophoblast: Stress and senescence.

Placental stress has been implicated in the pathophysiology of complications of pregnancy, including growth restriction and pre-eclampsia. Initially, attention focused on oxidative stress, but recently mitochondrial and endoplasmic reticulum stress have been identified. Complex molecular interactions exist among these different forms of stress, making it unlikely that any occurs in isolation. In part, this is due to close physiological connections between the two organelles principally involved, mitochondria and the endoplasmic reticulum (ER), mediated through Ca2+ signalling. Here, we review the involvement of the mitochondria-ER unit in the generation of stress within the trophoblast, and consider consequences for obstetric outcome. Mild stress may induce adaptive responses, including upregulation of antioxidant defences and autophagy, while moderate levels may affect stem cell behaviour and reduce cell proliferation, contributing to the growth-restricted phenotype. High levels of stress can stimulate release of pro-inflammatory cytokines and anti-angiogenic factors, increasing the risk of pre-eclampsia. In addition, chronic stress may promote senescence of the trophoblast, which in other cell types leads to a pro-inflammatory senescence-associated secretory phenotype. Evidence from rodents suggests that a degree of trophoblastic stress develops with increasing gestational age in normal pregnancies. The increase in maternal concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1) and reduction in placental growth factor (PlGF) suggest the same may occur in the human, starting around 30 weeks of pregnancy. Placental malperfusion, or co-existing maternal conditions, such as diabetes, will exacerbate that stress. Amelioration of trophoblastic stress should remain a research priority, but will be difficult due to the complexity of the molecular pathways involved.The authors thank all their colleagues and collaborators who have contributed to their studies cited here. GJB gratefully acknowledges the support of the Wellcome Trust (069027/Z/02/Z and 084804/2/08/Z), the MRC and Tommy’s; AJM thanks the Research Councils UK, Action Medical Research (SP4545) and the WYNG Foundation of Hong Kong.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.placenta.2016.04.00

Endoscopic versus percutaneous drainage of symptomatic pancreatic fluid collections: a 14-year experience from a tertiary hepatobiliary centre

INTRODUCTION: Endoscopic transmural drainage (ED) or percutaneous drainage (PD) has mostly replaced surgery for the initial management of patients with symptomatic pancreatic fluid collections (PFCs). This study aimed to compare outcomes for patients undergoing ED or PD of symptomatic PFCs. METHODS: Between January 2000 and December 2013, all patients who required PD or ED of a PFC were included. Rates of treatment success, length of hospital stay, adverse events, re-interventions and length of follow-up were recorded retrospectively in all cases. RESULTS: In total, 164 patients were included in the study; 109 patients underwent ED; and 55 had PD alone. During the 14-year study period, the incidence of ED increased and PD fell. In the 109 patients who were managed by ED, treatment success was considerably higher than in those managed by PD (70 vs. 31 %). Rates of procedural adverse events were higher in the ED cohort compared to the PD group (10 vs. 1 %), but patients managed by ED required fewer interventions (median of 1.8 vs. 3.3) had lower rates of residual collections (21 vs. 67 %) and need for surgical intervention (4 vs. 11 %). In the ED group, treatment success was similar for walled-off pancreatic necrosis (WOPN) and pseudocysts (67 vs. 72 %, P = 0.77). There were no procedure-related deaths. CONCLUSION: Compared with PD, ED of symptomatic PFCs was associated with higher rates of treatment success, lower rates of re-intervention, including surgery and shorter lengths of hospital stay. Outcomes in WOPN were comparable to those in patients with pseudocysts

Sexually dimorphic role for vasopressin in the development of social play

Despite the well-established role of vasopressin (AVP) in adult social behavior, its role in social development is relatively unexplored. In this paper, we focus on the most prominent social behavior of juvenile rats, social play. Previous pharmacological experiments in our laboratory suggested that AVP regulates play in a sex- and brain region-specific manner in juvenile rats. Here we investigate the role of specific AVP systems in the emergence of social play. We first characterize the development of play in male and female Wistar rats and then ask whether the development of AVP mRNA expression correlates with the emergence of play. Unexpectedly, play emerged more rapidly in weanling-aged females than in males, resulting in a sex difference opposite of that typically reported for older, juvenile rats. AVP mRNA and play were correlated in males only, with a negative correlation in the bed nucleus of the stria terminalis and a positive correlation in the paraventricular nucleus of the hypothalamus. These findings support the hypothesis that AVP acts differentially on multiple systems in a sex-specific manner to regulate social play and suggest a role for PVN and BNST AVP systems in the development of play. Differential neuropeptide regulation of male and female social development may underlie well-documented sex differences in incidence, progression, and symptom severity of behavioral disorders during development

Operating the renewed school estate - an empirical insight into cost and PFI

The use of the Private Finance Initiative (PFI) as a procurement method for capital schools projects over the past decade has been considerable, and a controversial issue. The relevance of procurement method for the operational performance of projects and facilities is an area cited as needing more research by amongst others the National Audit Office. Recently, the relative benefits of rebuilding versus refurbishment have also become an issue, especially in the context of cancelation of the Building Schools for the Future programme, and the James Review of how to get better value from a likely decreasing total capital expenditure on schools. In attempting to fill this knowledge gap, this study presents comparative samples of normalised expenditures post-renewal on facility service costs in renewed English comprehensive secondary schools. Data is presented in elapsed time relative to year of school renewal, sampled to produce early facility life cost profiles up to a maximum of 9 elapsed years, by both procurement method (PFI and non-PFI) and type of capital works (refurbishment and rebuild). The results include that total facility services costs are higher (though not significantly) in PFI schools in six of the nine elapsed years. Total facility services costs are broadly similar over the nine elapsed years following renewal in rebuilt and refurbished schools. The influence of procurement method on expenditure on certain facility services, coupled with high correlations between procurement method and type of capital works, prevents clear conclusions on the independent impact of type of capital works on operational expenditure. [Winner of the RICS Research Best Paper Award in Construction: COBRA 2011 Conference

Influence of speed of sample processing on placental energetics and signalling pathways: implications for tissue collection.

INTRODUCTION: The placenta is metabolically highly active due to extensive endocrine and active transport functions. Hence, placental tissues soon become ischaemic after separation from the maternal blood supply. Ischaemia rapidly depletes intracellular ATP, and leads to activation of stress-response pathways aimed at reducing metabolic demands and conserving energy resources for vital functions. Therefore, this study aimed to elucidate the effects of ischaemia ex vivo as may occur during tissue collection on phosphorylation of placental proteins and kinases involved in growth and cell survival, and on mitochondrial complexes. METHODS: Eight term placentas obtained from normotensive non-laboured elective caesarean sections were kept at room-temperature and sampled at 10, 20, 30 and 45 min after delivery. Samples were analyzed by Western blotting. RESULTS: Between 10 and 45 min the survival signalling pathway intermediates, P-AKT, P-GSK3α and β, P-4E-BP1 and P-p70S6K were reduced by 30-65%. Stress signalling intermediates, P-eIF2α increased almost 3 fold after 45 min. However, other endoplasmic reticulum stress markers and the Heat Shock Proteins, HSP27, HSP70 and HSP90, did not change. Phosphorylation of AMPK, an energy sensor, was elevated 2 fold after 45 min. Contemporaneously, there was an ∼25% reduction in mitochondrial complex IV subunit I. DISCUSSION AND CONCLUSIONS: These results suggest that for placental signalling studies, samples should be taken and processed within 10 min of caesarean delivery to minimize the impact of ischaemia on protein phosphorylation

Higher premorbid serum testosterone predicts COVID-19-related mortality risk in men.

Objective: Men are at greater risk from COVID-19 than women. Older, overweight men, and those with type 2 diabetes, have lower testosterone concentrations and poorer COVID-19-related outcomes. We analysed the associations of premorbid serum testosterone concentrations, not confounded by the effects of acute SARS-CoV-2 infection, with COVID-19-related mortality risk in men. Design: This study is a United Kingdom Biobank prospective cohort study of community-dwelling men aged 40-69 years. Methods: Serum total testosterone and sex hormone-binding globulin (SHBG) were measured at baseline (2006-2010). Free testosterone values were calculated (cFT). the incidence of SARS-CoV-2 infections and deaths related to COVID-19 were ascertained from 16 March 2020 to 31 January 2021 and modelled using time-stratified Cox regression. Results: In 159 964 men, there were 5558 SARS-CoV-2 infections and 438 COVID-19 deaths. Younger age, higher BMI, non-White ethnicity, lower educational attainment, and socioeconomic deprivation were associated with incidence of SARS-CoV-2 infections but total testosterone, SHBG, and cFT were not. Adjusting for potential confounders, higher total testosterone was associated with COVID-19-related mortality risk (overall trend P = 0.008; hazard ratios (95% CIs) quintile 1, Q1 vs Q5 (reference), 0.84 (0.65-1.12) Q2:Q5, 0.82 (0.63-1.10); Q3:Q5, 0.80 (0.66-1.00); Q4:Q5, 0.82 (0.75-0.93)). Higher SHBG was also associated with COVID-19 mortality risk (P = 0.008), but cFT was not (P = 0.248). Conclusions: Middle-aged to older men with the highest premorbid serum total testosterone and SHBG concentrations are at greater risk of COVID-19-related mortality. Men could be advised that having relatively high serum testosterone concentrations does not protect against future COVID-19-related mortality. Further investigation of causality and potential underlying mechanisms is warranted

The role of chaotic resonances in the solar system

Our understanding of the Solar System has been revolutionized over the past decade by the finding that the orbits of the planets are inherently chaotic. In extreme cases, chaotic motions can change the relative positions of the planets around stars, and even eject a planet from a system. Moreover, the spin axis of a planet-Earth's spin axis regulates our seasons-may evolve chaotically, with adverse effects on the climates of otherwise biologically interesting planets. Some of the recently discovered extrasolar planetary systems contain multiple planets, and it is likely that some of these are chaotic as well.Comment: 28 pages, 9 figure

The role of multidisciplinary meetings for benign pancreatobiliary diseases: a tertiary centre experience

Multidisciplinary meetings are central to the management of chronic and complex diseases and they have become widely established across the modern healthcare. Patients with pancreatobiliary diseases can often present with complex clinical dilemmas, which fall out with the scope of current guidelines. Therefore, these patients require a personalised management approach discussed in a multidisciplinary meeting

A mathematical modelling study of an athlete's sprint time when towing a weighted sled

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s12283-013-0114-2.This study used a mathematical model to examine the effects of the sled, the running surface, and the athlete on sprint time when towing a weighted sled. Simulations showed that ratio scaling is an appropriate method of normalising the weight of the sled for athletes of different body size. The relationship between sprint time and the weight of the sled was almost linear, as long as the sled was not excessively heavy. The athlete’s sprint time and rate of increase in sprint time were greater on running surfaces with a greater coefficient of friction, and on any given running surface an athlete with a greater power-to-weight ratio had a lower rate of increase in sprint time. The angle of the tow cord did not have a substantial effect on an athlete’s sprint time. This greater understanding should help coaches set the training intensity experienced by an athlete when performing a sled-towing exercise

Biochemical and cytological characterization of wheat/Aegilops ventricosa addition and transfer lines carrying chromosome 4MV

The gene encoding a variant of alcohol dehydrogenase, Adh-, has been found to be associated with the chromosome of the Mv genome which is present in type 9 wheat/Aegilops ventricosa addition line, to which the genes for protein CM-4 and for a phosphatase variant, Aph-v, had been previously assigned. Transfer line H-93-33, which has 42 chromosomes and has been derived from the cross (Triticum turgidum x Ae. ventricosa) x T. aestivum, carries genes encoding all three biochemical markers. Linkage between these genes has been demonstrated by analysis of individual kernels of the F2 (H-93-33 x T. aestivum cv. Almatense H-10-15). A study of the hybrids of line H-93-33 with T. aestivum H-10-15 and with the 4DS ditelosomic line has confirmed that, as suspected, the linkage group corresponds to chromosome 4Mv from Ae. ventricosa. Additionally, it has been found that the previously reported resistance of line H-93-33 to powdery mildew (Erysiphe graminis) is also linked to the biochemical markers; this indicates that either the gene responsible for it is different from that in lines H-93-8 and H-93-35, or that a translocation between two different Mv chromosomes has occurred in line H-93-33