Routine exercise-based cardiac rehabilitation does not increase aerobic fitness: A CARE CR study.

BACKGROUND: Recent evidence suggests that routine exercise-based cardiac rehabilitation (CR) may not lead to a substantial increase in estimated peak oxygen uptake (V̇O2peak). This could reduce the potential benefits of CR and explain why CR no longer improves patient survival in recent studies. We aimed to determine whether routine exercise-based CR increases V̇O2peak using gold-standard maximal cardiopulmonary exercise testing (CPET), and to quantify the exercise training stimulus which might be insufficient in patients undertaking CR. METHODS: We studied the effects of a routine, twice weekly, exercise-based CR programme for eight weeks (intervention group) compared with abstention from supervised exercise training (control group) in patients with coronary heart disease. The primary outcome was V̇O2peak measured using CPET. We also measured changes in body composition using dual X-ray absorptiometry, carotid intima-media thickness, hs-CRP and N-terminal pro B-type natriuretic peptide at baseline, 10 weeks and 12 months. We also calculated the Calibre 5-year all-cause mortality risk score. RESULTS: Seventy patients (age 63.1 SD10.0 years; BMI 29.2 SD4.0 kg·m-2; 86% male) were recruited (n = 48 intervention; n = 22 controls). The mean aerobic exercise training duration was 23 min per training session, and the mean exercise training intensity was 45.9% of heart rate reserve. V̇O2peak was 23·3 ml·kg-1·min-1 at baseline, and there were no changes in V̇O2peak between groups at any time point. The intervention had no effect on any of the secondary endpoints. CONCLUSION: Routine CR does not lead to an increase in V̇O2peak and is unlikely to improve long-term physiological outcomes.

Effects of energy intake and body weight on physical and chemical body composition in growing entire male pigs.

Two experiments were conducted to determine independent effects of BW and DE intake on body composition and the partitioning of retained body energy between lipid and protein in pigs with high lean tissue growth potentials and when energy intake limited whole-body protein deposition. In a preliminary N-balance experiment involving 20 entire male pigs at either 30 or 100 kg BW, it was established that whole-body protein deposition increased linearly (P < 0.05) with DE intake at both BW. These results indicate that DE intake controlled whole-body protein deposition and that these pigs did not achieve their maximum whole-body protein deposition when fed semi-ad libitum. In the main serial slaughter experiment, 56 pigs, with a BW of 15 kg, were assigned to one of four DE intake schemes and slaughtered at 40, 65, 90, or 115 kg BW. Within DE intake schemes, DE intake was increased linearly (P < 0.05) with BW, allowing for an assessment of effects of DE intake and slaughter BW on chemical and physical body composition (carcass, viscera, blood). Between 15 and 90 kg BW, average DE intake of 16.1, 20.9, 25.2, and 28.8 MJ/d supported average BW gains of 502, 731, 899, and 951 g/d, respectively. The proportion of whole-body protein present in the carcass increased with BW and decreased with DE intake (P < 0.05), whereas the distribution of whole-body lipid between carcass and viscera was not influenced by BW and DE intake. A mathematical relationship was developed to determine the relationship between DE intake at slaughter (MJ/d) and chemical body composition in these pigs: whole-body lipid-to-protein ratio = 1.236 - 0.056 x (DE intake) + 0.0013 x (DE intake)2, r2 = 0.71. The data suggests that absolute DE intake alone was an adequate predictor of chemical body composition in this population of entire male pigs over the BW and DE intake ranges that were evaluated, simplifying the characterization of this aspect of nutrition partitioning for growth in different pig populations.

Limitations of conventional models and a conceptual framework for a nutrient flow representation of energy utilization by animals.

Conventional models of energy utilization by animals, based on partitioning metabolizable energy (ME) intake or net energy (NE), are reviewed. The limitations of these methods are discussed, including various experimental, analytical and conceptual problems. Variation in the marginal efficiency of utilizing energy can be attributed to various factors: diet nutrient composition; animal effects on diet ME content; diet and animal effects on ME for maintenance (MEm); experimental methodology; and important statistical issues. ME partitioning can account for some of the variation due to animal factors, but not that related to nutrient source. In addition to many of the problems associated with ME, problems with NE pertain to: estimation of NE for maintenance (NEm); experimental and analytical methodology; and an inability to reflect variation in the metabolic use of NE. A conceptual framework is described for a new model of energy utilization by animals, based on representing explicit flows of the main nutrients and the important biochemical and biological transformations associated with their utilization. Differences in energetic efficiency from either dietary or animal factors can be predicted with this model.

A computational framework for a nutrient flow representation of energy utilization by growing monogastric animals.

A computational framework to represent nutrient utilization for body protein and lipid accretion by growing monogastric animals is presented. Nutrient and metabolite flows, and the biochemical and biological processes which transform these, are explicitly represented. A minimal set of calibration parameters is determined to provide five degrees of freedom in the adjustment of the marginal input-output response of this nutritional process model for a particular (monogastric) animal species. These parameters reflect the energy requirements to support the main biological processes: nutrient intake, faecal and urinary excretion, and production in terms of protein and lipid accretion. Complete computational details are developed and presented for these five nutritional processes, as well as a representation of the main biochemical transformations in the metabolic processing of nutrient intake. Absolute model response is determined as the residual nutrient requirements for basal processes. This model can be used to improve the accuracy of predicting the energetic efficiency of utilizing nutrient intake, as this is affected by independent diet and metabolic effects. Model outputs may be used to generate mechanistically predicted values for the net energy of a diet at particular defined metabolic states.

Calibration of a nutrient flow model of energy utilization by growing pigs.

A computational framework to represent energy utilization for body protein and lipid accretion by growing pigs is presented. Nutrient and metabolite flows, and the biochemical and biological processes which transform these, are explicitly represented in this nutritional process model. A calibration procedure to adjust the marginal input-output response is described, and applied, using reported experimental results, to determine a complete set of parameters for representing energy utilization by growing pigs. A reasonable value for minimum basal energy requirements is also determined. Although model inputs and outputs need not at any time be converted to equivalent energy flows, to facilitate comparison of model response with that of conventional energy-based models, a simple means to estimate energy flows from model-predicted nutrient flows is described. The well-known hierarchy of marginal (biological) energetic efficiencies with which pigs use different classes of nutrients is predicted by the model, based only on simple biological and biochemical principles. The significance of independent diet and metabolic effects on both energetic efficiency and maintenance requirements is examined using model predictions from simulated experiments.

What to do about flat heads: preventing and treating positional occipital flattening.

Across Canada there has been an increasing incidence of positional occipital flattening. This increase appears to be related to the recent change in infant sleep position to supine. In this paper, two patterns of positional occipital flattening, positional plagiocephaly and positional brachycephaly, are outlined. While there is no evidence of long-term developmental or neurological problems that result from positional occipital flattening, the infant's appearance can be distressing to parents who will then seek treatment. Prevention of positional occipital flattening requires a community approach with timely screening and early intervention should the infant's skull appear flat. Treatment involves repositioning the infant coupled with physiotherapy if there is neck muscle involvement. Should repositioning alone be ineffective, a helmet or headband program may be implemented. Neuroscience nurses can work in partnership with the community to ensure prevention strategies are implemented and timely interventions initiated.

Inhibition of intracellular Ca2+ mobilisation by low antiproliferative concentrations of thapsigargin in human vascular smooth-muscle cells.

Low nanomolar concentrations of thapsigargin, a modulator of intracellular Ca2+ ([Ca2+]i) pools, inhibit vascular smooth-muscle cell (VSMC) proliferation. Because the mechanisms underlying this effect have not been defined, the effect of antiproliferative concentrations of thapsigargin on [Ca2+]i in fura-2-loaded VSMCs was studied by using dynamic video imaging of [Ca2+]i. After seeding on coverslips, human VSMCs were incubated for 1-48 h with thapsigargin before loading with fura-2 or during imaging. Mobilisation of [Ca2+]i was stimulated with 1 microM ionomycin in Ca2+-free medium and the increase in [Ca2+]i detected by using Ca2+ imaging techniques. Continuous exposure of cells to low concentrations of thapsigargin (which failed measurably to increase in [Ca2+]i) reduced the ionomycin response in a time- and dose-dependent manner (100% inhibition at 10 nM thapsigargin after 1 h exposure). After exposure of cells to 10 nM thapsigargin for 1 h followed by washing and further incubation for < or = 72 h, there was a time-dependent recovery of the ionomycin response. Because the concentrations of thapsigargin and exposure times are identical to those that inhibit replication in VSMCs, it is proposed that depletion of [Ca2+]i pools mediates the inhibitory effect of thapsigargin on VSMC proliferation.

The influence of surgical preparation on cyclic nucleotide synthesis in an organ culture of human saphenous vein.

OBJECTIVES: To investigate adenosine cyclic 3'5' monophosphate (cAMP) and guanosine cyclic 3'5' monophosphate (cGMP) synthesis in freshly isolated and surgically prepared human saphenous vein before and after culture. SETTING: Bristol Heart Institute, Bristol, U.K. METHODS: Freshly isolated and surgically prepared human saphenous vein was obtained from patients undergoing coronary artery bypass graft surgery. cAMP and cGMP synthesis, was assessed by radioimmunoassay in response to specific simulators in segments of saphenous veins after collection and following 14 days culture. RESULTS: Immediately after collection there was a significant reduction in the synthesis of cAMP (forskolin and prostaglandin E1-stimulated) and cGMP (sodium nitroprusside-stimulated) in surgically prepared compared to freshly isolated saphenous veins. In contrast, following 14 days in culture, cAMP and cGMP synthesis was significantly elevated in surgically prepared compared to freshly isolated saphenous veins. CONCLUSIONS: These data indicate that surgical preparation results in a marked reduction in cyclic nucleotide synthesis in saphenous vein which may be relevant to the pathophysiology of early vein graft failure. The normalisation of both cAMP and cGMP synthesis in surgically prepared veins following 14 days culture indicates that cyclic nucleotide synthesising capacity may not be a major determinant of neointima formation in this experimental model.

Changes in the intracellular free amino acid pool in human saphenous vein tissue culture.

The aim of this work was to investigate the effect of tissue culture on the intracellular amino acid pool in both freshly isolated and surgically prepared saphenous vein segments taken from patients undergoing coronary artery bypass surgery (number of patients, n = 8). Viability of freshly isolated vein rings, indicated by ATP concentration, was maintained in culture (321 +/- 41 vs. 277 +/- 31 nmol (g wet wt)-1, 0 vs. 14 days). The initial decrease in ATP concentration in surgically prepared rings was significantly reversed following 14 days in culture from 135 +/- 26 to 201 +/- 18 nmol (g wet wt)-1 (P < 0.05). Freshly isolated vein rings maintained their intracellular free amino acid pool during the 14 days in culture (from 166 +/- 25 to 166 +/- 23 mumol (g protein)-1). Surgical preparation of vein rings induced a decrease in the intracellular free amino acid pool (from 166 +/- 25 to 87 +/- 15 mumol (g protein)-1, P < 0.05). This decrease was partially reversed after 14 days in culture (140 +/- 19 mumol (g protein)-1). Although the total amino acid pool in both types of vein rings after 14 days in culture was similar, there were variations in individual amino acid concentrations. Freshly isolated rings showed an increase in glutamine concentration and a decrease in alanine and aspartate concentrations after 14 days in culture. Surgically prepared vein rings showed a decrease in aspartate concentration and an increase in concentrations of glutamine, asparagine, glutamate and glycine. The changes in individual intracellular free amino acid concentrations, which were largely determined by the corresponding concentrations in the medium, indicates that culture media should be supplemented with taurine, aspartate and alanine.

Reduced prostacyclin and increased leukotriene B4 synthesis in porcine venous-arterial grafts.

BACKGROUND: Migration and proliferation of vascular smooth muscle cells in the intima and superimposed atheroma are the main changes underlying late failure of saphenous vein bypass grafts. There is evidence that these events are partly modulated by complex interactions between inhibitors of vascular smooth muscle cell proliferation, such as prostacyclin (PGI2), and mitogens, such as leukotriene B4 (LTB4). Because the relative balance between these eicosanoids may play a role in vein graft failure, the synthesis of PGI2 and LTB4 was measured in porcine saphenous vein-carotid artery grafts 4 weeks after implantation and compared with ungrafted vein and common carotid artery from the same animal. METHODS: Vessels were cut into 2-mm squares and preincubated in Dulbecco's minimum essential medium for 4 hours at 37 degrees C. Tissues were then further incubated with Dulbecco's minimum essential medium containing a range of concentrations of noradrenaline, arachidonate, and calcium ionophore A23187. Release of PGI2 and LTB4 into the supernatant was then assessed by radioimmunoassay. RESULTS: In response to all stimulators, PGI2 release was markedly diminished in vein grafts compared with ungrafted saphenous veins and carotid arteries. The patterns of responses were similar in each vessel type. In contrast, LTB4 release was significantly enhanced in vein grafts compared to ungrafted saphenous veins and carotid arteries. CONCLUSIONS: These data indicate that there is a down-regulation of cyclooxygenase or PGI2 synthase in porcine vein grafts, which may constitute a further phenotypic change that would augment the hyperplastic process. Local increases in LTB4 synthesis in the vein graft, which indicates an induction of lipoxygenase and LTB4 synthase enzymes (and possibly reflects release from leukocytes which have infiltrated the graft), may contribute to increased intimal proliferation by direct promitogenic effects on smooth muscle cells.

Changes in intracellular concentration of amino acids in human saphenous vein during preparation for coronary artery bypass grafting.

OBJECTIVES: Earlier research on human skeletal and cardiac muscle has shown a fall in the intracellular free amino acid pool, particularly the non-essential amino acids, during surgery. Surgical preparation of the human saphenous vein for coronary artery by pass grafting has been shown to provoke metabolic damage and may therefore induce changes in cellular amino acids which may have long-term implications for the performance of the grafted vein. This work investigates the hypothesis that surgical preparation of saphenous vein induces changes in amino acids. METHODS: Changes in the intracellular free amino acid pool were monitored, using high-performance liquid chromatography (HPLC), in both freshly isolated and surgically prepared human saphenous veins during coronary artery bypass grafting. In order to asses the extent of metabolic damage incurred by surgical preparation, adenosine triphosphate (ATP) levels were also measured. RESULTS: A substantial fall in intracellular free amino acid was associated with surgical preparation of human saphenous vein for coronary artery bypass grafting (190.8 +/- 25 to 106 +/- 18 mumol.g-1 protein, n = 10, P < 0.05). Although the fall was seen in most amino acids detected, it was marked and statistically significant (P < 0.05) for taurine (30.6 +/- 3.1 to 9.0 +/- 2.2 mumol.g-1 protein), glutamate (43.6 +/- 5.6 to 18.2 +/- 4.5 mumol.g-1 protein), glutamine (12.8 +/- 1.6 to 3.3 +/- 1.2 mumol.g-1 protein) and asparagine (9.6 +/- 1.6 to 4.1 +/- 1.0 mumol.g-1 protein). The fall in tissue taurine which would be largely due to transport showed a strong positive correlation with the fall seen in glutamate, glutamine and asparagine. ATP levels significantly decreased as a result of surgical preparation (279 +/- 44 to 96 +/- 21 nmol.g-1 wet weight, P < 0.05). The fall in ATP was accompanied by an increase in alanine/glutamate ratio which may reflect increased glutamate-alanine transaminase activity and therefore metabolic changes. CONCLUSIONS: The metabolic damage associated with surgical preparation of human saphenous vein for coronary artery bypass grafting is accompanied by a fall in the intracellular free amino acid pool which is marked and statistically significant for glutamate, taurine, glutamine and asparagine. The fall is likely to be due to transport metabolism may also contribute. This may have important implications for the functional recovery of the grated vein.

Neuroendocrine and clinical effects of electroconvulsive therapy and their relationship to treatment outcome.

Two groups of variables, endocrine and clinical, have been reported to have predictive value in determining response to electroconvulsive therapy (ECT) in depressed patients. Baseline levels of oxytocin associated neurophysin (OAN) and peak OAN response to ECT may predict clinical outcome, while the presence of delusional symptoms may indicate favourable initial response to ECT. The purpose of this study was to examine the relationship between these variables on initial and longer term response over a course of ECT, using a direct measure of plasma oxytocin concentrations. A substantial and immediate increase in oxytocin was seen after the first ECT, with significantly attenuated responses after the third and fifth ECTs. Increased plasma vasopressin concentrations were seen after all ECT treatments, each response being of similar magnitude. No associations were found between either endocrine baseline levels or peak responses, and clinical outcome. Only clinical variables predicted outcome, as patients with psychotic symptoms had more rapid initial response to ECT, and patients who had relapsed 2 months after the end of ECT had significantly higher depression ratings at day 14 of treatment than treatment responders.

The effects of idazoxan and other alpha 2-adrenoceptor antagonists on urine output in the rat.

1. In normally-hydrated Wistar rats the alpha 2-adrenoceptor antagonist, idazoxan (1, 3, 10 mg kg-1 i.p.), increased urine output during the 6 h following injection. 2. The more selective and specific alpha 2-adrenoceptor antagonist, RX811059 (0.3, 1, 3 mg kg-1 i.p.), and the peripherally-acting alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1 i.p.), had no effect on urine output in normally-hydrated animals. 3. In rats given a 25 ml kg-1 water-load orally, idazoxan (10 mg kg-1, i.p.) produced an initial antidiuretic response which was followed by an increase in urine output which was apparent 4 and 6 h after drug administration. 4. RX811059 (1, 3 mg kg-1 i.p.) and L-659,066 (3, 10 mg kg-1 i.p.) significantly decreased urine output in water-loaded rats in the 2 h after injection. 5. The antidiuretic effects of L-659,066 were attenuated in Brattleboro rats which are deficient in vasopressin; only the highest dose (10 mg kg-1 i.p.) decreased urine output, and this was only a small response in comparison with its virtual abolition of urine output in water-loaded Wistar rats. 6. The results with the selective alpha 2-adrenoceptor antagonists in Wistar and Brattleboro rats suggest that alpha 2-adrenoceptors in the periphery may play a physiological role in the control of water balance through a mechanism which involves vasopressin. 7. The paradoxical diuretic effects of idazoxan contrast with the effects of the other alpha 2-adrenoceptor antagonists and therefore may be attributed to a property of this compound unrelated to alpha 2-adrenoceptor blockade.

The vasopressin precursor in the Brattleboro (di/di) rat.

The vasopressin precursor in the rat hypothalamus has been studied, using trypsin to release desglycinamide vasopressin and coupling it to glycinamide (T & G treatment). The resulting amidated nonapeptide was detected and measured with a radioimmunoassay for vasopressin. The "vasopressin" produced in this way had the full immunoreactivity of the authentic peptide but eluted from an hplc column 1 min earlier and appeared to have a larger molecular weight. It was found that T&G treatment generated vasopressin immunoreactivity in extracts of the supraoptic nucleus (SON) of the Brattleboro rat in just the same way as it did in normal animals. Furthermore, this procedure produced vasopressin immunoreactivity in those hplc fractions from Brattleboro SON extracts that corresponded with the elution time of vasopressin precursor. Similar amounts of "vasopressin" could be generated from Brattleboro and normal SONs. These results support the suggestion that the Brattleboro SON synthesizes an aberrant vasopressin precursor which is not processed by the cell.

Two vasopressin-like peptides in the pig testis?

Vasopressin (VP)-like immunoreactivity (IR) has been located in the testes of several species of mammal. There is evidence that most of this IR in the rat does not represent authentic arginine vasopressin (AVP) and that a second AVP-like peptide may exist. We have studied testis samples from the pig, which produces lysine vasopressin (LVP) in its pituitary, and have found both LVP- and AVP-like IR. High-performance liquid chromatography (HPLC) of testis extracts showed two peaks of VP-IR. The first peak co-eluted with authentic LVP and was recognized only by antisera which cross-reacted with LVP. The second peak co-eluted with authentic AVP and was recognized by antisera raised against AVP. Both VP-like peptides bound to a neurophysin affinity column and the HPLC elution profiles of the bound peptides were similar to those of the authentic hormones. When the LVP-like material was oxidized with performic acid, a peak of IR running in the same position as oxidized authentic LVP on HPLC was produced. Similarly, the performic acid-oxidized AVP-like material co-eluted with oxidized authentic AVP. The presence of both LVP- and AVP-like peptides in the pig testis may mean that more than one gene is involved. A second VP-like gene could also explain the anomalies of VP-IR in other species.