Effects and moderators of coping skills training on symptoms of depression and anxiety in patients with cancer: Aggregate data and individual patient data meta-analyses.

PURPOSE: This study evaluated the effects of coping skills training (CST) on symptoms of depression and anxiety in cancer patients, and investigated moderators of the effects. METHODS: Overall effects and intervention-related moderators were studied in meta-analyses of pooled aggregate data from 38 randomized controlled trials (RCTs). Patient-related moderators were examined using linear mixed-effect models with interaction tests on pooled individual patient data (n = 1953) from 15 of the RCTs. RESULTS: CST had a statistically significant but small effect on depression (g = -0.31,95% confidence interval (CI) = -0.40;-0.22) and anxiety (g = -0.32,95%CI = -0.41;-0.24) symptoms. Effects on depression symptoms were significantly larger for interventions delivered face-to-face (p = .003), led by a psychologist (p = .02) and targeted to patients with psychological distress (p = .002). Significantly larger reductions in anxiety symptoms were found in younger patients (pinteraction < 0.025), with the largest reductions in patients <50 years (ß = -0.31,95%CI = -0.44;-0.18) and no significant effects in patients ≥70 years. Effects of CST on depression (ß = -0.16,95%CI = -0.25;-0.07) and anxiety (ß = -0.24,95%CI = -0.33;-0.14) symptoms were significant in patients who received chemotherapy but not in patients who did not (pinteraction < 0.05). CONCLUSIONS: CST significantly reduced symptoms of depression and anxiety in cancer patients, and particularly when delivered face-to-face, provided by a psychologist, targeted to patients with psychological distress, and given to patients who were younger and received chemotherapy.

Rapid Electron Acceleration in Low-Density Regions of Saturn's Radiation Belt by Whistler Mode Chorus Waves.

Electron acceleration at Saturn due to whistler mode chorus waves has previously been assumed to be ineffective; new data closer to the planet show it can be very rapid (factor of 104 flux increase at 1 MeV in 10 days compared to factor of 2). A full survey of chorus waves at Saturn is combined with an improved plasma density model to show that where the plasma frequency falls below the gyrofrequency additional strong resonances are observed favoring electron acceleration. This results in strong chorus acceleration between approximately 2.5 R S and 5.5 R S outside which adiabatic transport may dominate. Strong pitch angle dependence results in butterfly pitch angle distributions that flatten over a few days at 100s keV, tens of days at MeV energies which may explain observations of butterfly distributions of MeV electrons near L=3. Including cross terms in the simulations increases the tendency toward butterfly distributions.

Protocol of a two arm randomised, multi-centre, 12-month controlled trial: evaluating the impact of a Cognitive Behavioural Therapy (CBT)-based intervention Supporting UPtake and Adherence to antiretrovirals (SUPA) in adults with HIV.

BACKGROUND: Delay to start antiretroviral therapy (ART) and nonadherence compromise the health and wellbeing of people living with HIV (PLWH), raise the cost of care and increase risk of transmission to sexual partners. To date, interventions to improve adherence to ART have had limited success, perhaps because they have failed to systematically elicit and address both perceptual and practical barriers to adherence. The primary aim of this study is to determine the efficacy of the Supporting UPtake and Adherence (SUPA) intervention. METHODS: This study comprises 2 phases. Phase 1 is an observational cohort study, in which PLWH who are ART naïve and recommended to take ART by their clinician complete a questionnaire assessing their beliefs about ART over 12 months. Phase 2 is a randomised controlled trial (RCT) nested within the observational cohort study to investigate the effectiveness of the SUPA intervention on adherence to ART. PLWH at risk of nonadherence (based on their beliefs about ART) will be recruited and randomised 1:1 to the intervention (SUPA intervention + usual care) and control (usual care) arms. The SUPA intervention involves 4 tailored treatment support sessions delivered by a Research Nurse utilising a collaborative Cognitive Behavioural Therapy (CBT) and Motivational Interviewing (MI) approach. Sessions are tailored to individual needs and preferences based on the individual patient's perceptions and practical barriers to ART. An animation series and intervention manual have been developed to communicate a rationale for the personal necessity for ART and illustrate concerns and potential solutions. The primary outcome is adherence to ART measured using Medication Event Monitoring System (MEMS). Three hundred seventy-two patients will be sufficient to detect a 15% difference in adherence with 80% power and an alpha of 0.05. Costs will be compared between intervention and control groups. Costs will be combined with the primary outcome in cost-effectiveness analyses. Quality adjusted life-years (QALYs) will also be estimated over the follow-up period and used in the analyses. DISCUSSION: The findings will enable patients, healthcare providers and policy makers to make informed decisions about the value of the SUPA intervention. TRIAL REGISTRATION: The trial was retrospectively registered 21/02/2014, ISRCTN35514212 .

Formation of electron radiation belts at Saturn by Z-mode wave acceleration.

At Saturn electrons are trapped in the planet's magnetic field and accelerated to relativistic energies to form the radiation belts, but how this dramatic increase in electron energy occurs is still unknown. Until now the mechanism of radial diffusion has been assumed but we show here that in-situ acceleration through wave particle interactions, which initial studies dismissed as ineffectual at Saturn, is in fact a vital part of the energetic particle dynamics there. We present evidence from numerical simulations based on Cassini spacecraft data that a particular plasma wave, known as Z-mode, accelerates electrons to MeV energies inside 4 RS (1 RS = 60,330 km) through a Doppler shifted cyclotron resonant interaction. Our results show that the Z-mode waves observed are not oblique as previously assumed and are much better accelerators than O-mode waves, resulting in an electron energy spectrum that closely approaches observed values without any transport effects included.

Effects and moderators of psychosocial interventions on quality of life, and emotional and social function in patients with cancer: An individual patient data meta-analysis of 22 RCTs.

OBJECTIVE: This individual patient data (IPD) meta-analysis aimed to evaluate the effects of psychosocial interventions (PSI) on quality of life (QoL), emotional function (EF), and social function (SF) in patients with cancer, and to study moderator effects of demographic, clinical, personal, and intervention-related characteristics. METHODS: Relevant studies were identified via literature searches in 4 databases. We pooled IPD from 22 (n = 4217) of 61 eligible randomized controlled trials. Linear mixed-effect model analyses were used to study intervention effects on the post-intervention values of QoL, EF, and SF (z-scores), adjusting for baseline values, age, and cancer type. We studied moderator effects by testing interactions with the intervention for demographic, clinical, personal, and intervention-related characteristics, and conducted subsequent stratified analyses for significant moderator variables. RESULTS: PSI significantly improved QoL (ß = 0.14,95%CI = 0.06;0.21), EF (ß = 0.13,95%CI = 0.05;0.20), and SF (ß = 0.10,95%CI = 0.03;0.18). Significant differences in effects of different types of PSI were found, with largest effects of psychotherapy. The effects of coping skills training were moderated by age, treatment type, and targeted interventions. Effects of psychotherapy on EF may be moderated by cancer type, but these analyses were based on 2 randomized controlled trials with small sample sizes of some cancer types. CONCLUSIONS: PSI significantly improved QoL, EF, and SF, with small overall effects. However, the effects differed by several demographic, clinical, personal, and intervention-related characteristics. Our study highlights the beneficial effects of coping skills training in patients treated with chemotherapy, the importance of targeted interventions, and the need of developing interventions tailored to the specific needs of elderly patients.

International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates.

Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug. INTRODUCTION: Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients. METHODS: The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis. RESULTS: Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and 3 months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%. CONCLUSIONS: If a significant decrease is observed, the treatment can continue, but if no decrease occurs, the clinician should reassess to identify problems with the treatment, mainly low adherence.

The 'molecularly unstratified' patient: a focus for moral, psycho-social and societal research.

The biomedical paradigm of personalised precision medicine - identification of specific molecular targets for treatment of an individual patient - offers great potential for treatment of many diseases including cancer. This article provides a critical analysis of the promise, the hype and the pitfalls attending this approach. In particular, we focus on 'molecularly unstratified' patients - those who, for various reasons, are not eligible for a targeted therapy. For these patients, hope-laden therapeutic options are closed down, leaving them left out, and left behind, bobbing untidily about in the wake of technological and scientific 'advance'. This process creates a distinction between groups of patients on the basis of biomarkers and challenges our ability to provide equitable access to care for all patients. In broadening our consideration of these patients to include the research ecosystem that shapes their experience, we hypothesise that the combination of immense promise with significant complexity creates particular individual and organisational challenges for researchers. The novelty and complexity of their research consumes high levels of resource, possibly in parallel with undervaluing other 'low hanging fruit', and may be challenging current regulatory thinking. We outline future research to consider the societal, psycho-social and moral issues relating to 'molecularly unstratified' patients, and the impact of the drive towards personalisation on the research, funding, and regulatory ecosystem.

Factors affecting uptake and adherence to breast cancer chemoprevention: a systematic review and meta-analysis.

BACKGROUND: Preventive therapy is a risk reduction option for women who have an increased risk of breast cancer. The effectiveness of preventive therapy to reduce breast cancer incidence depends on adequate levels of uptake and adherence to therapy. We aimed to systematically review articles reporting uptake and adherence to therapeutic agents to prevent breast cancer among women at increased risk, and identify the psychological, clinical and demographic factors affecting these outcomes. DESIGN: Searches were carried out in PubMed, CINAHL, EMBASE and PsychInfo, yielding 3851 unique articles. Title, abstract and full text screening left 53 articles, and a further 4 studies were identified from reference lists, giving a total of 57. This review was prospectively registered with PROSPERO (CRD42014014957). RESULTS: Twenty-four articles reporting 26 studies of uptake in 21 423 women were included in a meta-analysis. The pooled uptake estimate was 16.3% [95% confidence interval (CI) 13.6-19.0], with high heterogeneity (I(2) = 98.9%, P < 0.001). Uptake was unaffected by study location or agent, but was significantly higher in trials [25.2% (95% CI 18.3-32.2)] than in non-trial settings [8.7% (95% CI 6.8-10.9)] (P < 0.001). Factors associated with higher uptake included having an abnormal biopsy, a physician recommendation, higher objective risk, fewer side-effect or trial concerns, and older age. Adherence (day-to-day use or persistence) over the first year was adequate. However, only one study reported a persistence of ≥ 80% by 5 years. Factors associated with lower adherence included allocation to tamoxifen (versus placebo or raloxifene), depression, smoking and older age. Risk of breast cancer was discussed in all qualitative studies. CONCLUSION: Uptake of therapeutic agents for the prevention of breast cancer is low, and long-term persistence is often insufficient for women to experience the full preventive effect. Uptake is higher in trials, suggesting further work should focus on implementing preventive therapy within routine care.

Learning from the QUEST multicentre feasibility randomization trials in breast reconstruction after mastectomy.

BACKGROUND: Breast reconstruction aims to improve health-related quality of life after mastectomy. However, evidence guiding patients and surgeons in shared decision-making concerning the optimal type or timing of surgery is lacking. METHODS: QUEST comprised two parallel feasibility phase III randomized multicentre trials to assess the impact of the type and timing of latissimus dorsi breast reconstruction on health-related quality of life when postmastectomy radiotherapy is unlikely (QUEST A) or highly probable (QUEST B). The primary endpoint for the feasibility phase was the proportion of women who accepted randomization, and it would be considered feasible if patient acceptability rates exceeded 25 per cent of women approached. A companion QUEST Perspectives Study (QPS) of patients (both accepting and declining trial participation) and healthcare professionals assessed trial acceptability. RESULTS: The QUEST trials opened in 15 UK centres. After 18 months of recruitment, 17 patients were randomized to QUEST A and eight to QUEST B, with overall acceptance rates of 19 per cent (17 of 88) and 22 per cent (8 of 36) respectively. The QPS recruited 56 patients and 51 healthcare professionals. Patient preference was the predominant reason for declining trial entry, given by 47 (53 per cent) of the 88 patients approached for QUEST A and 22 (61 per cent) of the 36 approached for QUEST B. Both trials closed to recruitment in December 2012, acknowledging the challenges of achieving satisfactory patient accrual. CONCLUSION: Despite extensive efforts to overcome recruitment barriers, it was not feasible to reach timely recruitment targets within a feasibility study. Patient preferences for breast reconstruction types and timings were common, rendering patients unwilling to enter the trial.

Preference and satisfaction with a 6-month subcutaneous injection versus a weekly tablet for treatment of low bone mass.

UNLABELLED: The Preference and Satisfaction Questionnaire (PSQ) compares patient preference and satisfaction between a 6-month subcutaneous injection and weekly oral tablet for treatment of bone loss. Patients preferred and were more satisfied with a treatment that was administered less frequently, suggesting the acceptability of the 6-month injection for treatment of bone loss. INTRODUCTION: The PSQ compares patient preference and satisfaction between a 6-month subcutaneous injection and a weekly oral tablet for treatment of bone loss. METHODS: Postmenopausal women with low bone mass who enrolled in two separate randomized phase 3 double-blind, double-dummy studies received a 6-month subcutaneous denosumab injection (60 mg) plus a weekly oral placebo or a weekly alendronate tablet (70 mg) plus a 6-month subcutaneous placebo injection. After 12 months, patients completed the PSQ to rate their preference, satisfaction, and degree of bother with each regimen. RESULTS: Most enrolled patients (1,583 out of 1,693; 93.5%) answered >or=1 item of the PSQ. Significantly more patients preferred and were more satisfied with the 6-month injection versus the weekly tablet (P < 0.001). More patients reported no bother with the 6-month injection (90%) than the weekly tablet (62%). CONCLUSION: Patients preferred, were more satisfied, and less bothered with a 6-month injection regimen for osteoporosis.

Comparison of evoked arousability in breast and formula fed infants.

BACKGROUND: Currently, there is no consistent evidence that breast feeding reduces the risk for sudden infant death syndrome (SIDS). Arousal from sleep is believed to be an important survival mechanism that may be impaired in victims of SIDS. Previously it has been shown that arousability is impaired by the major risk factors for SIDS such as prone sleeping and maternal smoking. AIMS: To establish whether arousability was altered by method of feeding, and whether breast fed infants would have lower arousal thresholds. METHODS: Forty three healthy term infants were studied using daytime polysomnography on three occasions: 2-4 weeks post-term, 2-3 months post-term, and 5-6 months post-term. Multiple measurements of arousal threshold (cm H(2)O) in response to nasal air jet stimulation applied alternately to the nares were made in both active sleep (AS) and quiet sleep (QS) while infants slept supine. Arousal thresholds and sleep period lengths were compared between formula fed and breast fed infants at each age. RESULTS: Arousal thresholds were not different between breast fed and formula fed infants in QS. However, in AS breast fed infants were significantly more arousable than formula fed infants at 2-3 months of age. There was no difference between groups of infants when sleep period length was compared at any study. CONCLUSIONS: Breast fed infants are more easily aroused from AS at 2-3 months of age than formula fed infants. This age coincides with the peak incidence of SIDS.

Effects of maternal tobacco smoking, sleeping position, and sleep state on arousal in healthy term infants.

OBJECTIVES: To investigate whether a history of maternal tobacco smoking affected the maturation of arousal responses and whether sleeping position and infant age alters these relations. DESIGN: Healthy term infants (13 born to mothers who did not smoke and 11 to mothers who smoked during pregnancy) were studied using daytime polysomnography on three occasions: (a) two to three weeks after birth, (b) two to three months after birth, and (c) five to six months after birth. Multiple measurements of arousal threshold in response to air jet stimulation were made in both active sleep (AS) and quiet sleep (QS) when infants slept both prone and supine. RESULTS: Maternal smoking significantly elevated arousal threshold in QS when infants slept supine at 2-3 months of age (p<0.05). Infants of smoking mothers also had fewer spontaneous arousals from QS at 2-3 months in both prone (p<0.05) and supine (p<0.001) sleeping positions. In infants of non-smoking mothers, arousal thresholds were elevated in the prone position in AS at 2-3 months (p<0.01) and QS at 2-3 weeks (p<0.05) and 2-3 months (p<0.001). CONCLUSIONS: Maternal tobacco smoking significantly impairs both stimulus induced and spontaneous arousal from QS when infants sleep in the supine position, at the age when the incidence of sudden infant death syndrome is highest.

Patients' beliefs about prescribed medicines and their role in adherence to treatment in chronic physical illness.

The aim of this cross-sectional study was to quantify patients' personal beliefs about the necessity of their prescribed medication and their concerns about taking it and to assess relations between beliefs and reported adherence among 324 patients from four chronic illness groups (asthma, renal, cardiac, and oncology). The findings revealed considerable variation in reported adherence and beliefs about medicines within and between illness groups. Most patients (89%) believed that their prescribed medication was necessary for maintaining health. However, over a third had strong concerns about their medication based on beliefs about the dangers of dependence or long-term effects. Beliefs about medicines were related to reported adherence: higher necessity scores correlated with higher reported adherence (r=0.21, n=324, p<0.01) and higher concerns correlated with lower reported adherence (r=0.33, n=324, p<0.01). For 17% of the total sample, concerns scores exceeded necessity scores and these patients reported significantly lower adherence rates (t=-4.28, p<0.001). Stepwise multiple linear regression analysis showed that higher reported adherence rates were associated with higher necessity-concerns difference scores (beta=0.35, p<0.001), a diagnosis of asthma (beta= -0.31, p<0.001), a diagnosis of heart disease (beta=0.19, p<0.001), and age (beta=0.22, p<0.001). Gender, educational experience, or the number of prescribed medicines did not predict reported adherence. Medication beliefs were more powerful predictors of reported adherence than the clinical and sociodemographic factors, accounting for 19% of the explained variance in adherence. These data were consistent with the hypothesis that many patients engage in an implicit cost-benefit analysis in which beliefs about the necessity of their medication are weighed against concerns about the potential adverse effects of taking it and that these beliefs are related to medication adherence.

Ultrastructural evidence of intestinal mucosal macrophage activation after bone marrow transplantation.

Previous studies have demonstrated upregulation of intestinal mucosal macrophage CD16 (an Fc receptor for IgG) in bone marrow transplant (BMT) recipients with graft-versus-host disease (GVHD). We sought to determine whether there was ultrastructural evidence of mucosal macrophage activation in allogeneic BMT recipients and relate appearances to those seen in autologous BMT patients and to immunohistological findings. Sigmoid colonic mucosal biopsies from five allogeneic and three autologous BMT patients were taken prior to, 30 days after transplant and, in three of the allogeneic patients, 120 days after transplant. These were examined by immunohistochemistry and electron microscopy. Immunohistological analysis revealed upregulation of lamina propria macrophage CD16 after transplant in all patients except one autologous BMT recipient; there were no such changes in total macrophage numbers. Ultrastructural evidence of lamina propria macrophage activation was prominent after both allogeneic and autologous BMT. There was an increase in nuclear size accompanied by increased euchromatin and larger nucleoli. In the cytoplasm there were increased numbers of lysosomes, many of which were small and cylindrical, and cytoplasmic flaps were prominent. Phagosomes were less numerous after transplant. These data confirm that after BMT intestinal mucosal macrophages become activated. However changes in macrophage ultrastructure specific to patients at risk of developing clinical GVHD are lacking.

Effect of arginine vasopressin and parathyroid hormone-related protein on renal function in the ovine foetus.

1. The effects of intravenous infusions of arginine vasopressin (AVP), parathyroid hormone-related protein (PTHrP) and AVP+PTHrP on renal function in intact ovine foetuses at 100-125 days of gestation were examined. 2. A low dose of AVP (5.5 +/- 0.9 pmol/h) increased plasma AVP concentrations from 0.6 pmol/L to 2.1 +/- 0.4 pmol/L (mean +/- s.e.m; n = 8). This dose caused a significant reduction in free water clearance (CH2O; P < 0.001), without any significant change in fetal arterial blood pressure, glomerular filtration rate (GFR), or the urinary excretion rates of sodium, calcium or 3',5'-cyclic adenosine monophosphate (cAMP). 3. Infusions of PTHrP (1 nmol/h), with or without 1 nmol bolus dose, significantly increased (P < 0.05) urine osmolality (UOSM), but did not synergize with AVP in reducing CH2O. 4. It is concluded that AVP and PTHrP do not act synergistically on the kidney of the intact ovine foetus.

Binge eating disorder: its further validation in a multisite study.

Binge eating disorder (BED) is a new eating disorder that describes the eating disturbance of a large number of individuals who suffer from recurrent binge eating but who do not regularly engage in the compensatory behaviors to avoid weight gain seen in bulimia nervosa. This multisite study of BED involved 1,785 subjects drawn from 18 weight control programs, 942 subjects from five nonpatient community samples, and 75 patients with bulimia nervosa. Approximately 29% of subjects in weight control programs met the criteria for BED. In the nonpatient community samples BED was more common than purging bulimia nervosa. The validity of BED was supported by its strong association with (1) impairment in work and social functioning, (2) overconcern with body/shape and weight, (3) general psychopathology, (4) significant amount of time in adult life on diets, (5) a history of depression, alcohol/drug abuse, and treatment for emotional problems.

Effects of thyroparathyroidectomy, parathyroid hormone, and PTHrP on kidneys of ovine fetuses.

The fetal parathyroid glands and parathyroid hormone-related protein (PTHrP) have been shown to be important regulators of fetal calcium metabolism through their actions on the placenta and bone. This study examined the effects of fetal thyroparathyroidectomy (with thyroxine replacement) and exogenous infusion of human parathyroid hormone [PTH-(1-34)], PTHrP-(1-34), and PTHrP-(1-141) on the urinary excretion of calcium in chronically cannulated ovine fetuses during the last one-fifth of gestation. Fetal plasma total and ionized calcium concentrations were significantly lower in thyroparathyroidectomized (TxPTx) fetuses when compared with intact fetuses, but there were no significant differences in urinary excretion rates of total calcium. However, TxPTx produced a significant increase in the fractional excretion rate of total calcium and a significant decrease in the excretion of adenosine 3',5'-cyclic monophosphate (cAMP) compared with intact fetuses. Infusions of PTH-(1-34), PTHrP-(1-34), and PTHrP-(1-141) into the jugular vein of TxPTx fetuses (n = 5) at the rate of 1 nmol/h for 2 h, after a 1-nmol loading dose, significantly decreased the excretion rate of total calcium and increased the excretion rate of cAMP in fetal urine. Infusions of all three peptides resulted in significant increases in the concentration of total calcium in fetal plasma but had no effect on the plasma concentrations or urinary excretion rates of phosphate. Infusion of either PTH-(1-34), PTHrP-(1-34), or PTHrP-(1-141) also resulted in an increase in fetal urine osmolality and pH and a decrease in free water clearance in TxPTx fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory chain defect of myocardial mitochondria in idiopathic dilated cardiomyopathy of Doberman pinscher dogs.

Idiopathic dilated cardiomyopathy (IDCM) is a primary myocardial disease of unknown cause. We tested the hypothesis that IDCM was associated with a myocardial metabolic defect by determining a comprehensive biochemical profile of metabolite concentrations and enzyme activities for the major metabolic pathways of the myocardium. We used the Doberman pinscher breed as a naturally occurring canine model of IDCM and compared its myocardial profile with that of healthy adult mongrels. Compared with controls, myocardium in IDCM had markedly reduced mitochondrial electron transport activity and myoglobin concentration, in association with acidosis and energy depletion following anoxic challenge: 60% decreased NADH dehydrogenase and 50% decreased ATP synthetase activities; 90% decreased myoglobin concentration; and 30% reduced ATP and 50% increased lactate and proton concentrations. Sarcoplasmic reticulum Ca(2+)-transport ATPase was decreased by 42%. There was a 15% compensatory increase in fatty acid oxidation and Krebs cycle activity. Other biochemical changes were mild by comparison with the mitochondrial defects. We conclude that IDCM is associated with a marked impairment of mitochondrial production of ATP, arising from decreased activity of the mitochondrial electron transport system, including myoglobin. These changes may be secondary to an underlying genetic defect or may indicate a deficiency of the mitochondrial respiratory chain that predisposes this breed to heart failure.

Myocardial myoglobin deficiency in various animal models of congestive heart failure.

Myoglobin is known to protect the mechanical function of the heart from hypoxia by acting as a sarcoplasmic oxygen reservoir and shuttle. We postulated a role for myoglobin in the pathogenesis of congestive heart failure. Several models of congestive heart failure were employed to test the hypothesis, including spontaneous inherited dilated cardiomyopathy in Doberman Pinschers, and heart failure produced by rapid ventricular pacing in dogs, volume overload in chickens and furazolidone toxicity in turkeys. Myocardial myoglobin was decreased by approximately 50% for all models (P less than 0.05). In Doberman Pinschers dogs which are predisposed to the development of dilated cardiomyopathy and have mild subclinical depression of cardiac performance, myocardial myoglobin (1.05 +/- 0.22 mg/g) is approximately 50% decreased compared to healthy mongrel dogs (2.15 +/- 0.52 mg/g), approximately twice as much as dobermans with heart failure (0.47 +/- 0.25 mg/g) but similar to the concentration found in dogs paced to heart failure (1.09 +/- 0.34 mg/g). Myocardium from poultry had remarkably decreased myoglobin compared to mammals (34 +/- 4 micrograms/g) with heart failure produced either by furazolidone or salt toxicity causing a further 50% reduction. In the canine models of heart failure, myocardial myoglobin concentration was demonstrated to be correlated with biochemical and physiological indicators of myocardial performance, namely, mitochondrial and sarcoplasmic reticular ATPase activities, and cardiac output, systemic vascular resistance, pulmonary capillary wedge pressure and mean arterial pressure, respectively. Our data implicates a role for myoglobin deficiency in the pathogenesis of congestive heart failure and in the predisposition of doberman pinschers to dilated cardiomyopathy.