Bridging the age gap in breast cancer: cluster randomized trial of two decision support interventions for older women with operable breast cancer on quality of life, survival, decision quality, and treatment choices.

BACKGROUND: Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice. METHODS: A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice. RESULTS: A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference -0.20, 95 per cent confidence interval (C.I.) -2.69 to 2.29; P = 0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P = 0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P = 0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference -4.5 (C.I. -8.0 to 0) per cent; P = 0.013). Survival was similar in both arms. CONCLUSION: The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection. Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com).

A systematic review and meta-analysis of nutrition interventions for chronic noncancer pain.

BACKGROUND: This systematic review aimed to evaluate the impact of nutrition interventions on participant reported pain severity and intensity in populations with chronic pain. METHODS: Eight databases were systematically searched for studies that included adult populations with a chronic pain condition, a nutrition intervention and a measure of pain. Where possible, data were pooled using meta-analysis. Seventy-one studies were included, with 23 being eligible for meta-analysis. RESULTS: Studies were categorised into four groups: (i) altered overall diet with 12 of 16 studies finding a significant reduction in participant reported pain; (ii) altered specific nutrients with two of five studies reporting a significant reduction in participant reported pain; (iii) supplement-based interventions with 11 of 46 studies showing a significant reduction in pain; and (iv) fasting therapy with one of four studies reporting a significant reduction in pain. The meta-analysis found that, overall, nutrition interventions had a significant effect on pain reduction with studies testing an altered overall diet or just one nutrient having the greatest effect. CONCLUSIONS: This review highlights the importance and effectiveness of nutrition interventions for people who experience chronic pain.

Chronic oligodendrogenesis and remyelination after spinal cord injury in mice and rats.

Adult progenitor cells proliferate in the acutely injured spinal cord and their progeny differentiate into new oligodendrocytes (OLs) that remyelinate spared axons. Whether this endogenous repair continues beyond the first week postinjury (wpi), however, is unknown. Identifying the duration of this response is essential for guiding therapies targeting improved recovery from spinal cord injury (SCI) by enhancing OL survival and/or remyelination. Here, we used two PDGFRα-reporter mouse lines and rats injected with a GFP-retrovirus to assess progenitor fate through 80 d after injury. Surprisingly, new OLs were generated as late as 3 months after injury and their processes ensheathed axons near and distal to the lesion, colocalized with MBP, and abutted Caspr+ profiles, suggesting newly formed myelin. Semithin sections confirmed stereotypical thin OL remyelination and few bare axons at 10 wpi, indicating that demyelination is relatively rare. Astrocytes in chronic tissue expressed the pro-OL differentiation and survival factors CNTF and FGF-2. In addition, pSTAT3+ NG2 cells were present through at least 5 wpi, revealing active signaling of the Jak/STAT pathway in these cells. The progenitor cell fate genes Sox11, Hes5, Id2, Id4, BMP2, and BMP4 were dynamically regulated for at least 4 wpi. Collectively, these data verify that the chronically injured spinal cord is highly dynamic. Endogenous repair, including oligodendrogenesis and remyelination, continues for several months after SCI, potentially in response to growth factors and/or transcription factor changes. Identifying and understanding spontaneous repair processes such as these is important so that beneficial plasticity is not inadvertently interrupted and effort is not exerted to needlessly duplicate ongoing spontaneous repair.

Fetal in vivo continuous cardiovascular function during chronic hypoxia.

Although the fetal cardiovascular defence to acute hypoxia and the physiology underlying it have been established for decades, how the fetal cardiovascular system responds to chronic hypoxia has been comparatively understudied. We designed and created isobaric hypoxic chambers able to maintain pregnant sheep for prolonged periods of gestation under controlled significant (10% O2) hypoxia, yielding fetal mean P(aO2) levels (11.5 ± 0.6 mmHg) similar to those measured in human fetuses of hypoxic pregnancy. We also created a wireless data acquisition system able to record fetal blood flow signals in addition to fetal blood pressure and heart rate from free moving ewes as the hypoxic pregnancy is developing. We determined in vivo longitudinal changes in fetal cardiovascular function including parallel measurement of fetal carotid and femoral blood flow and oxygen and glucose delivery during the last third of gestation. The ratio of oxygen (from 2.7 ± 0.2 to 3.8 ± 0.8; P < 0.05) and of glucose (from 2.3 ± 0.1 to 3.3 ± 0.6; P < 0.05) delivery to the fetal carotid, relative to the fetal femoral circulation, increased during and shortly after the period of chronic hypoxia. In contrast, oxygen and glucose delivery remained unchanged from baseline in normoxic fetuses. Fetal plasma urate concentration increased significantly during chronic hypoxia but not during normoxia (Δ: 4.8 ± 1.6 vs. 0.5 ± 1.4 µmol l(-1), P<0.05). The data support the hypotheses tested and show persisting redistribution of substrate delivery away from peripheral and towards essential circulations in the chronically hypoxic fetus, associated with increases in xanthine oxidase-derived reactive oxygen species.

UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.

BACKGROUND: Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. METHODS: The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. RESULTS: 247 354 individuals aged 50-75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm(3) or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm(3) at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569). CONCLUSIONS: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective-this needs to be confirmed using data on observed lung cancer mortality reduction. TRIAL REGISTRATION: ISRCTN 78513845.

A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse.

Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by α-motor neuron loss in the spinal cord anterior horn. SMA results from deletion or mutation of the Survival Motor Neuron 1 gene (SMN1) and retention of SMN2. A single nucleotide difference between SMN1 and SMN2 results in exclusion of exon 7 from the majority of SMN2 transcripts, leading to decreased SMN protein levels and development of SMA. A series of splice enhancers and silencers regulate incorporation of SMN2 exon 7; these splice motifs can be blocked with antisense oligomers (ASOs) to alter SMN2 transcript splicing. We have evaluated a morpholino (MO) oligomer against ISS-N1 [HSMN2Ex7D(-10,-29)], and delivered this MO to postnatal day 0 (P0) SMA pups (Smn-/-, SMN2+/+, SMNΔ7+/+) by intracerebroventricular (ICV) injection. Survival was increased markedly from 15 days to >100 days. Delayed CNS MO injection has moderate efficacy, and delayed peripheral injection has mild survival advantage, suggesting that early CNS ASO administration is essential for SMA therapy consideration. ICV treatment increased full-length SMN2 transcript as well as SMN protein in neural tissue, but only minimally in peripheral tissue. Interval analysis shows a decrease in alternative splice modification over time. We suggest that CNS increases of SMN will have a major impact on SMA, and an early increase of the SMN level results in correction of motor phenotypes. Finally, the early introduction by intrathecal delivery of MO oligomers is a potential treatment for SMA patients.

Recognition of cancer warning signs and anticipated delay in help-seeking in a population sample of adults in the UK.

BACKGROUND: Not recognising a symptom as suspicious is a common reason given by cancer patients for delayed help-seeking; but inevitably this is retrospective. We therefore investigated associations between recognition of warning signs for breast, colorectal and lung cancer and anticipated time to help-seeking for symptoms of each cancer. METHODS: Computer-assisted telephone interviews were conducted with a population-representative sample (N=6965) of UK adults age ≥ 50 years, using the Awareness and Beliefs about Cancer scale. Anticipated time to help-seeking for persistent cough, rectal bleeding and breast changes was categorised as >2 vs ≤ 2 weeks. Recognition of persistent cough, unexplained bleeding and unexplained lump as cancer warning signs was assessed (yes/no). Associations between recognition and help-seeking were examined for each symptom controlling for demographics and perceived ease of health-care access. RESULTS: For each symptom, the odds of waiting for >2 weeks were significantly increased in those who did not recognise the related warning sign: breast changes: OR=2.45, 95% CI 1.47-4.08; rectal bleeding: OR=1.77, 1.36-2.30; persistent cough: OR=1.30, 1.17-1.46, independent of demographics and health-care access. CONCLUSION: Recognition of warning signs was associated with anticipating faster help-seeking for potential symptoms of cancer. Strategies to improve recognition are likely to facilitate earlier diagnosis.

Differences in cancer awareness and beliefs between Australia, Canada, Denmark, Norway, Sweden and the UK (the International Cancer Benchmarking Partnership): do they contribute to differences in cancer survival?

BACKGROUND: There are wide international differences in 1-year cancer survival. The UK and Denmark perform poorly compared with other high-income countries with similar health care systems: Australia, Canada and Sweden have good cancer survival rates, Norway intermediate survival rates. The objective of this study was to examine the pattern of differences in cancer awareness and beliefs across these countries to identify where these might contribute to the pattern of survival. METHODS: We carried out a population-based telephone interview survey of 19079 men and women aged ≥ 50 years in Australia, Canada, Denmark, Norway, Sweden and the UK using the Awareness and Beliefs about Cancer measure. RESULTS: Awareness that the risk of cancer increased with age was lower in the UK (14%), Canada (13%) and Australia (16%) but was higher in Denmark (25%), Norway (29%) and Sweden (38%). Symptom awareness was no lower in the UK and Denmark than other countries. Perceived barriers to symptomatic presentation were highest in the UK, in particular being worried about wasting the doctor's time (UK 34%; Canada 21%; Australia 14%; Denmark 12%; Norway 11%; Sweden 9%). CONCLUSION: The UK had low awareness of age-related risk and the highest perceived barriers to symptomatic presentation, but symptom awareness in the UK did not differ from other countries. Denmark had higher awareness of age-related risk and few perceived barriers to symptomatic presentation. This suggests that other factors must be involved in explaining Denmark's poor survival rates. In the UK, interventions that address barriers to prompt presentation in primary care should be developed and evaluated.

Concerns and coping during cancer genetic risk assessment.

OBJECTIVE: To gain an 'in-depth' understanding of patients' concerns and their related coping strategies during the genetic risk assessment process. METHODS: Participants were the 'usual care' arm of a trial of a coping intervention targeted at men and women undergoing assessment of genetic risk for familial cancer. Participants completed questionnaires measuring the degree to which they experienced up to 11 concerns and which of 8 coping strategies they used to respond to each of them at entry into the programme and 1 month subsequently (before they received their risk information). FINDINGS: A majority of participants were at least 'quite worried' about all the identified concerns, although the levels of concern fell over the waiting period. Participants used several strategies in response to their varying concerns - although a primary coping strategy for each concern was identifiable. The emotion-focused strategies of acceptance and positive appraisal were generally used in response to concerns they could not change, and seeking social support was used primarily to gain information, but not emotional support from their family. Cluster analysis identified three unique clusters of coping responses. CONCLUSIONS: Genetic risk assessment comprises a number of different stressors each of which is coped with using different strategies.

Content variability of active drug substance in compounded oral 3,4-diaminopyridine products.

WHAT IS KNOWN AND OBJECTIVE: 3,4-diaminopyridine (3,4-DAP; amifampridine) is used for symptomatic treatment of Lambert-Eaton myasthenic syndrome. Until recently, it was only available as a compounded product, which raises safety concerns because of possible high variability in active drug substance content. The objective of this study was to evaluate the variability in dosage form weight, active content variability and impurity of compounded oral 3,4-DAP drug products. METHODS: Ten samples each of 9 oral 3,4-DAP compounded products were weighed, extracted with water and the 3,4-DAP content determined by ultra high-performance liquid chromatography. RESULTS AND DISCUSSION: Variability in dosage form weight ranged from 0·81% relative standard deviation (RSD) to 4·82% RSD. In the 90 samples tested, 3,4-DAP content ranged from 22·2% to 125·2% of declared label content. All 10 samples of one compounded product had active drug substance content well below the declared label content (35·0%, 51·7% RSD). No compounded product achieved the Good Manufacturing Practice (GMP) standard of 95-105% range limit of declared label content; one achieved 90-110%, and four others achieved 80-120% of declared content for all 10 samples. There was no evidence of a significant presence of degradation products or related substances in any compounded product. WHAT IS NEW AND CONCLUSION: Compounded 3,4-DAP products are subject to considerable variability in active drug substance content. This variability seems to be principally because of heterogeneous formulated material rather than variation in dosage form weight.

Safety and efficacy of therapeutic taping in primary dysmenorrhea: a systematic review and meta-analysis.

Primary dysmenorrhea (PD) is a common gynecological condition among adolescent and adult women. Several pharmacological and alternative therapies (e.g. therapeutic taping) have been used to treat PD, with varying effect. This systematic review and meta-analysis was performed to evaluate the safety and efficacy of therapeutic taping on clinical symptoms of PD, considering pain as the primary outcome. MEDLINE, Cochrane Library, Embase, PEDro, CINAHL and gray literature sources were searched from inception to February 2022 for randomized controlled trials (RCTs) that assessed the effect of therapeutic taping for PD. The language was restricted to English. A total of ten studies were included in the systematic review, involving 685 participants. Eight studies were included in quantitative analysis. The quality of the studies ranged from 4 to 7 with a median of 5 as assessed by PEDro scale. Meta-analyses indicated short-term improvements of pain compared to sham and no interventions. Elastic therapeutic taping (ETT) indicated short term improvements in anxiety associated with PD. Moderate to high quality of evidence suggested that ETT is an effective intervention in improving pain, anxiety, and quality of life of women with PD. A scarcity of evidence on the long-term effects of therapeutic taping in PD is observed.

In vitro human skin absorption of linalool: Effects of vehicle composition, evaporation and occlusion on permeation and distribution.

In vitro human skin permeation and distribution of the fragrance material linalool (3,7-dimethyl-1,6-octadien-3-ol, CAS No. 78-70-6) following application in a range of single and mixed vehicles was determined, under unoccluded and occluded conditions, using human epidermal membranes. Vehicles were (70/30 v/v) ethanol[EtOH]/water, dipropyleneglycol [DPG], diethyl phthalate [DEP], (25/75 v/v) EtOH/DEP, (25/75 v/v) EtOH/DPG and petrolatum. Worst case absorbed dose values (% applied dose) for linalool under unoccluded conditions varied from 1.84% (DPG) to 4.08% (EtOH/water) and under occluded conditions from 5.9% (DEP) to 14.7% (EtOH/water). Occlusion always increased absorption but the magnitude of the effect varied with the vehicle from 2 to 6-fold. This study demonstrated that in vitro human skin permeation of linalool varied quite widely between test vehicles and that the magnitude of the effect of occlusion was also vehicle dependent. This was particularly significant in view of the reported variations in biological responses using different vehicles (Lalko et al., 2004; Politano et al., 2006).

Targeting proliferative retinopathy: Arginase 1 limits vitreoretinal neovascularization and promotes angiogenic repair.

Current therapies for treatment of proliferative retinopathy focus on retinal neovascularization (RNV) during advanced disease and can trigger adverse side-effects. Here, we have tested a new strategy for limiting neurovascular injury and promoting repair during early-stage disease. We have recently shown that treatment with a stable, pegylated drug form of the ureohydrolase enzyme arginase 1 (A1) provides neuroprotection in acute models of ischemia/reperfusion injury, optic nerve crush, and ischemic stroke. Now, we have determined the effects of this treatment on RNV, vascular repair, and retinal function in the mouse oxygen-induced retinopathy (OIR) model of retinopathy of prematurity (ROP). Our studies in the OIR model show that treatment with pegylated A1 (PEG-A1), inhibits pathological RNV, promotes angiogenic repair, and improves retinal function by a mechanism involving decreased expression of TNF, iNOS, and VEGF and increased expression of FGF2 and A1. We further show that A1 is expressed in myeloid cells and areas of RNV in retinal sections from mice with OIR and human diabetic retinopathy (DR) patients and in blood samples from ROP patients. Moreover, studies using knockout mice with hemizygous deletion of A1 show worsened RNV and retinal injury, supporting the protective role of A1 in limiting the OIR-induced pathology. Collectively, A1 is critically involved in reparative angiogenesis and neuroprotection in OIR. Pegylated A1 may offer a novel therapy for limiting retinal injury and promoting repair during proliferative retinopathy.

The evolution of worry after breast cancer risk assessment: 6-year follow-up of the TRACE study cohort.

OBJECTIVES: There is little evidence regarding the long-term psychological implications of breast cancer risk assessment for women at moderate genetic risk. A follow-up study of a trial cohort was conducted to evaluate psychological outcomes and their predictors at 6-year follow-up. A further aim was to examine threshold scores for high cancer worry. METHODS: Questionnaires were sent to 384 women assessed as moderate risk during a UK trial of genetic assessment (TRACE). Measures included cancer worry, perceived risk, health behaviours, general anxiety, psychological morbidity, optimism, and background variables assessed during TRACE and at 6-year follow-up. RESULTS: Reductions from baseline cancer worry and breast self-examination (BrSE) frequency were maintained 6 years after risk assessment, with relatively consistent levels over short- and long-term follow-up. Provision of risk information led to short-term reductions in perceived risk. During the 6-year period, 43% of women reported having made lifestyle changes and 27% had requested a mammogram. Baseline and post-risk cancer worry were the only significant predictors of long-term cancer worry. Greater worry at baseline predicted more frequent BrSE and higher perceived risk, but not lifestyle change or mammogram requests, at 6 years. Eighteen percent of women reported cancer worry above a threshold of 12.5 at long-term follow-up, compared with 30% at baseline. CONCLUSIONS: Overall reductions in cancer worry following moderate risk assessment were maintained in the long term. However, women at risk of sustained high cancer worry should be identified at an early stage in the risk assessment process for more intensive psycho-educational intervention. Copyright © 2010 John Wiley & Sons, Ltd.

Ion channel modulators and urinary tract function.

The membrane potential fulfils an important role in initiating smooth muscle contraction, through its depolarization and the subsequent influx of Ca(2+) through voltage-gated Ca(2+) channels. Changes in membrane potential can also coordinate contraction across great distances, utilizing the speed of electrical current flow through gap junctions. Hence, regulating membrane potential can greatly influence smooth muscle function. In this chapter, we will consider the influence of ion channels, as dynamic gatekeepers of membrane permeability, on urogenital function. Through their ability to act as key regulators of both the resting membrane potential and its dynamic changes, they provide important pharmacological targets for influencing urogenital function.Urogenital smooth muscle and urothelia contain a diverse range of molecularly and functionally distinct K(+) channels, which are key to regulating the resting membrane and for re-establishing the normal membrane potential following both active and passive changes. The voltage-gated Ca(2+) channels are key to initiating contraction and causing rapid depolarization, supplemented in some smooth muscles by rapid Na(+) conductances. The Cl(-) channels, often assumed to be passive, can actively change the membrane potential, and hence, cellular function, because Cl(-) is not usually at its equilibrium potential. The useful ways in which these ion channels can be targeted therapeutically in the ureter, bladder and urethra are discussed, focussing particularly on treatments for ureteric obstruction and detrusor overactivity. Current treatments for many urinary tract disorders, particularly the overactive bladder, are complicated by side effects. While ion channels have traditionally been considered as poor therapeutic targets by the pharmaceutical industry, our increasing knowledge of the molecular diversity of K(+) and Cl(-) channels gives new hope for more narrowly focused drug targeting, while the exciting discoveries of active currents in interstitial cells give us a new set of cellular targets for drugs.

Impacts of pre-fire conifer density and wildfire severity on ecosystem structure and function at the forest-tundra ecotone.

Wildfire frequency and extent is increasing throughout the boreal forest-tundra ecotone as climate warms. Understanding the impacts of wildfire throughout this ecotone is required to make predictions of the rate and magnitude of changes in boreal-tundra landcover, its future flammability, and associated feedbacks to the global carbon (C) cycle and climate. We studied 48 sites spanning a gradient from tundra to low-density spruce stands that were burned in an extensive 2013 wildfire on the north slope of the Alaska Range in Denali National Park and Preserve, central Alaska. We assessed wildfire severity and C emissions, and determined the impacts of severity on understory vegetation composition, conifer tree recruitment, and active layer thickness (ALT). We also assessed conifer seed rain and used a seeding experiment to determine factors controlling post-fire tree regeneration. We found that an average of 2.18 ± 1.13 Kg C m-2 was emitted from this fire, almost 95% of which came from burning of the organic soil. On average, burn depth of the organic soil was 10.6 ± 4.5 cm and both burn depth and total C combusted increased with pre-fire conifer density. Sites with higher pre-fire conifer density were also located at warmer and drier landscape positions and associated with increased ALT post-fire, greater changes in pre- and post-fire understory vegetation communities, and higher post-fire boreal tree recruitment. Our seed rain observations and seeding experiment indicate that the recruitment potential of conifer trees is limited by seed availability in this forest-tundra ecotone. We conclude that the expected climate-induced forest infilling (i.e. increased density) at the forest-tundra ecotone could increase fire severity, but this infilling is unlikely to occur without increases in the availability of viable seed.

Long-term cohort study of women at intermediate risk of familial breast cancer: experiences of living at risk.

AIMS: To identify how women adjusted to living at intermediate risk of breast cancer six years following risk assessment, and what factors contributed to health service usage. METHOD: Two studies are reported. Both report data from a cohort of women found at intermediate risk of breast cancer six years previously. In the first, 30 women with a range of Cancer Worry Scale (Lerman et al. Health Psychol 1991;10:259-267) scores were interviewed about how they lived with their risk of cancer and their use of health resources. The generalisability of these findings was tested in a sample of 387 women from the same cohort using psychometrically appropriate measures. FINDINGS: In study 1, women scoring above the median baseline BCWS scale score were most likely to perceive their family history as a burden, exaggerate their susceptibility to breast cancer, not be reassured by genetic counselling, be focussed on the need for mammographic screening, and have a low reliance on breast self-examination. Key findings of the second study were that over a quarter of the cohort were experiencing at least moderate levels of intrusive worries. Worries were associated with perceptions of high personal vulnerability to and severity of cancer and breast cancer being highly salient. Women aged over 50 years with high levels of worry-related distress were most likely to request a mammogram. CONCLUSION: The high levels of distress in this cohort reinforce the need to provide appropriate interventions for vulnerable women following risk assessment.

The development of a cancer genetic-specific measure of coping: the GRACE.

OBJECTIVE: Generic measures of coping fail to capture the process of undergoing specific health processes such as cancer genetic risk assessment. The Genetic Risk Assessment Coping Evaluation (GRACE) has been developed to provide greater specificity of measurement. METHOD: Based upon previous research findings, the GRACE measures the degree of stress associated with 11 recognised sources of stress for individuals undergoing the early stages of cancer genetic risk assessment, and the use of up to eight coping strategies they may elicit. This paper reports preliminary data from the piloting of the GRACE within a randomised trial of a coping intervention. RESULTS: Of the 265 participants who completed and returned their baseline questionnaire (prior to being informed of their level of genetic risk), 257 completed the GRACE. The most highly endorsed sources of stress involved concerns relating to family members, endorsed by over 60% of respondents, and concerns about how the participants would cope if found to be at increased risk (59%). Participants made use of multiple coping strategies across different sources of stress. The most frequently reported coping strategies were emotion-focused, which may reflect the stage of the assessment process. CONCLUSION: The completion rates for the matrix and specificity of responses provided suggest that the GRACE may be an acceptable measurement tool. Further data collection and validation is ongoing.

Translatable mitochondria-targeted protection against programmed cardiovascular dysfunction.

The prenatal origins of heart disease in offspring have been established. However, research in species with developmental milestones comparable to humans is lacking, preventing translation of this knowledge to clinical contexts. Using sheep and chickens, two species with similar cardiovascular developmental milestones to humans, we combined in vivo experiments with in vitro studies at organ, cellular, mitochondrial, and molecular levels. We tested mitochondria-targeted antioxidant intervention with MitoQ against cardiovascular dysfunction programmed by developmental hypoxia, a common complication in human pregnancy. Experiments in sheep determined in vivo fetal and adult cardiovascular function through surgical techniques not possible in humans, while those in chicken embryos isolated effects independent of maternal or placental influences. We show that hypoxia generates mitochondria-derived oxidative stress during cardiovascular development, programming endothelial dysfunction and hypertension in adult offspring. MitoQ treatment during hypoxic development protects against this cardiovascular risk via enhanced nitric oxide signaling, offering a plausible intervention strategy.

Neuroeffector Ca2+ transients for the direct measurement of purine release and indirect measurement of cotransmitters in rodents.

Determining whether ATP and noradrenaline are released from the same vesicle at mature autonomic neuroeffector junctions is challenging because of the difficulty of simultaneously detecting the packeted release of these neurotransmitters. Contraction, overflow and electrophysiology experiments all show that both ATP and noradrenaline are released following field stimulation (although the ratio might vary) from autonomic nerves in tissues including the vas deferens, rat tail artery and mesenteric artery. The occurrence of purinergic neuroeffector Ca(2+) transients (NCTs) has been used to detect the packeted release of the neurotransmitter ATP acting on postjunctional P2X receptors to cause Ca(2+) influx. Neuroeffector Ca(2+) transients can also be used to detect the local effects of noradrenaline through its alpha(2)-adrenoceptor-mediated prejunctional autoinhibitory effects on nerve terminal Ca(2+) concentration and the probability of exocytosis (measured by counting NCTs). Evidence is presented that exocytosis from sympathetic varicosities does not occur in a manner independent of the history of that varicosity, but rather that the release of a packet of ATP transiently suppresses (or predicts the transient suppression of) subsequent release. This could arise by autoinhibition (by the prejunctional action of noradrenaline or purines) or due to a transient shortage of vesicles readily available for release. In summary, two high-resolution approaches are proposed to measure the intermittent release of packets of neurotransmitter: (1) local transient suppression of nerve terminal Ca(2+) transients; and (2) the local and transient inhibition of NCTs to infer local autoinhibition, hence transmitter release. Such approaches may allow the packeted corelease of ATP and noradrenaline to be investigated without the need to measure both neurotransmitters directly.