Cardiovascular Stress Reactivity and Health: Recent Questions and Future Directions

OBJECTIVE: High cardiovascular reactions to psychological stress are associated with the development of hypertension, systemic atherosclerosis, and cardiovascular disease. However, it has become apparent that low biological stress reactivity also may have serious consequences for health, although less is known about the mechanisms of this. The objective of this narrative review and opinion paper is to summarise and consider where we are now in terms of the usefulness of the reactivity hypothesis and reactivity research, given that both ends of the reactivity spectrum appear to be associated with poor health, and to address some of the key criticisms and future challenges for the research area. METHODS: This review is authored by the members of a panel discussion held at the American Psychosomatic Society meeting 2019 which included questions such as: How do we measure high and low reactivity? Can high reactivity ever indicate better health? Does low or blunted reactivity simply reflect less effort on task challenges? Where does low reactivity originate from, and what is a low reactor? RESULTS: Cardiovascular (and cortisol) stress reactivity are used as a model to: demonstrate an increased understanding of the different individual pathways from stress responses to health/disease and show the challenges of how to understand and best use the reconstruction of a long-standing reactivity hypothesis given recent data. CONCLUSIONS: This discussion elucidates the gaps in knowledge and key research issues that still remain to be addressed in this field, and that systematic reviews and meta-analyses continue to be required

Profiling unauthorized natural resource users for better targeting of conservation interventions

Unauthorized use of natural resources is a key threat to many protected areas. Approaches to reducing this threat include law enforcement and integrated conservation and development (ICD) projects, but for such ICDs to be targeted effectively, it is important to understand who is illegally using which natural resources and why. The nature of unauthorized behavior makes it difficult to ascertain this information through direct questioning. Bwindi Impenetrable National Park, Uganda, has many ICD projects, including authorizing some local people to use certain nontimber forest resources from the park. However, despite over 25 years of ICD, unauthorized resource use continues. We used household surveys, indirect questioning (unmatched count technique), and focus group discussions to generate profiles of authorized and unauthorized resource users and to explore motivations for unauthorized activity. Overall, unauthorized resource use was most common among people from poor households who lived closest to the park boundary and farthest from roads and trading centers. Other motivations for unauthorized resource use included crop raiding by wild animals, inequity of revenue sharing, and lack of employment, factors that created resentment among the poorest communities. In some communities, benefits obtained from ICD were reported to be the greatest deterrents against unauthorized activity, although law enforcement ranked highest overall. Despite the sensitive nature of exploring unauthorized resource use, management‐relevant insights into the profiles and motivations of unauthorized resource users can be gained from a combination of survey techniques, as adopted here. To reduce unauthorized activity at Bwindi, we suggest ICD benefit the poorest people living in remote areas and near the park boundary by providing affordable alternative sources of forest products and addressing crop raiding. To prevent resentment from driving further unauthorized activity, ICDs should be managed transparently and equitably

Impaired 17,20-lyase activity in male mice lacking cytochrome b5 in Leydig cells

Androgen and estrogen biosynthesis in mammals requires the 17,20-lyase activity of cytochrome P450 17A1 (steroid 17-hydroxylase/17,20-lyase). Maximal 17,20-lyase activity in vitro requires the presence of cytochrome b5 (b5), and rare cases of b5 deficiency in human beings causes isolated 17,20-lyase deficiency. To study the consequences of conditional b5 removal from testicular Leydig cells in an animal model, we generated Cyb5(flox/flox):Sf1-Cre (LeyKO) mice. The LeyKO male mice had normal body weights, testis and sex organ weights, and fertility compared with littermates. Basal serum and urine steroid profiles of LeyKO males were not significantly different than littermates. In contrast, marked 17-hydroxyprogesterone accumulation (100-fold basal) and reduced testosterone synthesis (27% of littermates) were observed after human chorionic gonadotropin stimulation in LeyKO animals. Testis homogenates from LeyKO mice showed reduced 17,20-lyase activity and a 3-fold increased 17-hydroxylase to 17,20-lyase activity ratio, which were restored to normal upon addition of recombinant b5. We conclude that Leydig cell b5 is required for maximal androgen synthesis and to prevent 17-hydroxyprogesterone accumulation in the mouse testis; however, the b5-independent 17,20-lyase activity of mouse steroid 17-hydroxylase/17,20-lyase is sufficient for normal male genital development and fertility. LeyKO male mice are a good model for the biochemistry but not the physiology of isolated 17,20-lyase deficiency in human beings

Evaluating estuarine nursery use and life history patterns of Pomatomus saltatrix in eastern Australia

Estuaries provide important nursery habitats for juvenile fish, but many species move between estuarine and coastal habitats throughout their life. We used otolith chemistry to evaluate the use of estuaries and the coastal marine environment by juvenile Pomatomus saltatrix in eastern Australia. Otolith chemical signatures of juveniles from 12 estuaries, spanning 10° of latitude, were characterised using laser ablation-inductively coupled plasma-mass spectrometry. Based upon multivariate otolith elemental signatures, fish collected from most estuaries could not be successfully discriminated from one another. This was attributed to the varying influence of marine water on otolith elemental composition in fish from all estuaries. Using a reduced number of estuarine groups, the multivariate juvenile otolith elemental signatures and univariate Sr:Ca ratio suggest that between 24 and 52% of adult P. saltatrix had a juvenile period influenced by the marine environment. Elemental profiles across adult (age-1) otoliths highlighted a variety of life history patterns, not all consistent with a juvenile estuarine phase. Furthermore, the presence of age-0 juveniles in coastal waters was confirmed from historical length-frequency data from coastal trawls. Combining multiple lines of evidence suggests considerable plasticity in juvenile life history for P. saltatrix in eastern Australia through their utilisation of both estuarine and coastal nurseries. Knowledge of juvenile life history is important for the management of coastal species of commercial and recreational importance such as P. saltatrix.info:eu-repo/semantics/publishedVersio

Improving the management of pain from advanced cancer in the community: study protocol for a pragmatic multi-centre randomised controlled trial

Introduction: For patients with advanced cancer, research shows that pain is frequent, burdensome and undertreated. Evidence-based approaches to support cancer pain management have been developed but have not been implemented within the context of the UK National Health Service. This protocol is for a pragmatic multi-centre randomised controlled trial to assess feasibility, acceptability, effectiveness and cost effectiveness for a multi-component intervention for pain management in patients with advanced cancer. Methods and Analysis: This trial will assess the feasibility of implementation and uptake of evidence based interventions, developed and piloted as part of the IMPACCT Programme grant, into routine clinical practice and determine whether there are potential differences with respect to patient rated pain, patient pain knowledge and experience, healthcare use, quality of life, and cost effectiveness. 160 patients will receive either the intervention (usual care plus supported self-management) delivered within the oncology clinic and palliative care services by locally assigned community palliative care nurses, consisting of a self-management educational intervention and eHealth intervention for routine pain assessment and monitoring; or usual care. The primary outcomes are to assess implementation and uptake of the interventions, and differences in terms of pain severity. Secondary outcomes include pain interference, participant pain knowledge and experience, and cost effectiveness. Outcome assessment will be blinded and patient reported outcome measures collected via post at 6 and 12 weeks following randomisation. Ethics and Dissemination: This RCT has the potential to significantly influence NHS service delivery to community based patients with pain from advanced cancer. We aim to provide definitive evidence of whether two simple interventions delivered by community palliative care nurse in palliative care that support-self-management are clinically and cost effective additions to standard community palliative care

Long-term result of Memokath urethral sphincter stent in spinal cord injury patients

BACKGROUND: Memokath urethral sphincter stents are used to facilitate bladder emptying in patients with spinal cord injury, but long term follow-up has not been reported. METHODS: Case series of ten men with spinal cord injury who underwent insertion of Memokath stents and were followed for up to nine years. RESULTS: Within four years, the stent had to be removed in nine out of ten patients because of: extensive mucosal proliferation causing obstruction to the lumen of the stent; stone around the proximal end of the stent, incomplete bladder emptying, and recurrent urinary infections; migration of the stent into the bladder related to digital evacuation of bowels; large residual urine; concretions within the stent causing obstruction to flow of urine, and partial blockage of the stent causing frequent episodes of autonomic dysreflexia. In one patient the stent continued to function satisfactorily after nine years. CONCLUSIONS: The Memokath stent has a role as a temporary measure for treatment of detrusor-sphincter dyssynergia in selected SCI patients who do not get recurrent urinary infection and do not require manual evacuation of bowels

Definition of the σW regulon of Bacillus subtilis in the absence of stress

Bacteria employ extracytoplasmic function (ECF) sigma factors for their responses to environmental stresses. Despite intensive research, the molecular dissection of ECF sigma factor regulons has remained a major challenge due to overlaps in the ECF sigma factor-regulated genes and the stimuli that activate the different ECF sigma factors. Here we have employed tiling arrays to single out the ECF σW regulon of the Gram-positive bacterium Bacillus subtilis from the overlapping ECF σX, σY, and σM regulons. For this purpose, we profiled the transcriptome of a B. subtilis sigW mutant under non-stress conditions to select candidate genes that are strictly σW-regulated. Under these conditions, σW exhibits a basal level of activity. Subsequently, we verified the σW-dependency of candidate genes by comparing their transcript profiles to transcriptome data obtained with the parental B. subtilis strain 168 grown under 104 different conditions, including relevant stress conditions, such as salt shock. In addition, we investigated the transcriptomes of rasP or prsW mutant strains that lack the proteases involved in the degradation of the σW anti-sigma factor RsiW and subsequent activation of the σW-regulon. Taken together, our studies identify 89 genes as being strictly σW-regulated, including several genes for non-coding RNAs. The effects of rasP or prsW mutations on the expression of σW-dependent genes were relatively mild, which implies that σW-dependent transcription under non-stress conditions is not strictly related to RasP and PrsW. Lastly, we show that the pleiotropic phenotype of rasP mutant cells, which have defects in competence development, protein secretion and membrane protein production, is not mirrored in the transcript profile of these cells. This implies that RasP is not only important for transcriptional regulation via σW, but that this membrane protease also exerts other important post-transcriptional regulatory functions

Assessing whether genetic scores explain extra variation in birthweight, when added to clinical and anthropometric measures

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials The datasets analysed during the current study (EFSOCH) can be requested for access by writing in the first instance to the EFSOCH data team via the Exeter Clinical Research Facility [email protected]. The GWAS summary statistics for birthweight that were used to generate the genetic scores are publicly available can be downloaded from http://egg-consortium.org/BACKGROUND: Human birthweight is a complex, multifactorial trait. Maternal characteristics contribute to birthweight variation by influencing the intrauterine environment. Variation explained by genetic effects is also important, but their contributions have not been assessed alongside other key determinants. We aimed to investigate variance in birthweight explained by genetic scores in addition to easily-measurable clinical and anthropometric variables. METHODS: We analysed 549 European-ancestry parent-offspring trios from a UK community-based birth cohort. We investigated variance explained in birthweight (adjusted for sex and gestational age) in multivariable linear regression models including genetic scores, routinely-measured maternal characteristics, and parental anthropometric variables. We used R-Squared (R2) to estimate variance explained, adjusted R-squared (Adj-R2) to assess improvement in model fit from added predictors, and F-tests to compare nested models. RESULTS: Maternal and fetal genetic scores together explained 6.0% variance in birthweight. A model containing maternal age, weight, smoking, parity and 28-week fasting glucose explained 21.7% variance. Maternal genetic score explained additional variance when added to maternal characteristics (Adj-R2 = 0.233 vs Adj-R2 = 0.210, p < 0.001). Fetal genetic score improved variance explained (Adj-R2 = 0.264 vs 0.248, p < 0.001) when added to maternal characteristics and parental heights. CONCLUSIONS: Genetic scores account for variance explained in birthweight in addition to easily measurable clinical variables. Parental heights partially capture fetal genotype and its contribution to birthweight, but genetic scores explain additional variance. While the genetic contribution is modest, it is comparable to that of individual clinical characteristics such as parity, which suggests that genetics could be included in tools aiming to predict risk of high or low birthweights.Diabetes UKWellcome TrustNational Institute for Health and Care Research (NIHR

Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths