Comfort feeding in hospitalised people with dementia: a retrospective study of survival following comfort feeding recommendations.

OBJECTIVES: Persistent and significant swallowing impairment can occur in individuals with dementia. Determining prognosis and establishing realistic goals of care in this population is complex and comfort feeding may be recommended. This study aimed to establish evidence relating to patient outcomes following recommendation of comfort feeding to aid informed decision making. DESIGN: A multi-centre, retrospective audit was conducted for a two-year period to establish the survival and readmission rates for hospitalised people with dementia, following recommendation of a comfort feeding plan. SETTING: The study was conducted at three acute care hospitals in Adelaide, South Australia. PARTICIPANTS: A total of 163 participants were included, 90 male and 73 female, with a median age of 88 years. MEASUREMENTS: Mortality within 30 and 90 days of admission and readmission rates within 30 days of discharge were calculated. RESULTS: Forty-two percent of participants died during the admission during which a comfort feeding plan was recommended. Overall median survival time and one month survival was 13 days and 25%, respectively. Readmission rates were low (7.4% of those discharged). Comfort feeding recommendations aligned with dysphagia severity and those for whom Nil By Mouth (NBM) or ice chips only were recommended were at highest risk of dying in hospital, those recommended thickened fluids +/- ice chips were most likely to be alive 30 days after their original admission date. CONCLUSION: Dementia and comfort feeding were associated with high mortality rates, high rates of discharge to a supportive care facility and low readmission rates. Dysphagia severity associated with the consistency of fluids recommended.

Light-Intensity Physical Activity and Sedentary Behavior Are Associated With Blood Pressure Levels in Adolescents.

PURPOSE: To investigate the associations between physical activity (PA) intensities, sedentary behavior (SB), and blood pressure (BP) in adolescents, according to sex. METHOD: This cross-sectional study involved 95 male and female adolescents aged 15-18 years. Accelerometry was used to measure time spent in light-intensity PA (LPA), moderate to vigorous PA (MVPA), and vigorous PA, and SB. The BP was determined using an automated sphygmomanometer. Statistical analyses included multiple linear regression and command margins. RESULTS: Significant associations were found between systolic BP (SBP) and time spent in LPA (B = -0.08; 95% CI, -0.15 to -0.01) and SB (B = 0.071; 95% CI, 0.004-0.138), albeit only in boys. Furthermore, an interaction was observed between time spent in SB and MVPA for SBP in boys (B = -0.002; 95% CI, -0.004 to -0.0008). The main interaction effect of increasing SBP was a combination of <75 minutes per day of MVPA and up to 600 minutes per day of SB. CONCLUSIONS: Increased time in LPA and reduced time spent in SB during the day are associated with lower SBP in male adolescents. Additionally, the relation between SB and SBP was attenuated by MVPA. These findings provide crucial insights for PA recommendations to promote cardiovascular health in adolescents.

Angina due to coronary artery spasm (variant angina): diagnosis and intervention strategies.

INTRODUCTION: Since Prinzmetal first described a 'variant' form of angina pectoris, with predominantly resting episodes of pain and cyclic severity variations, it has gradually become apparent that this clinical presentation is caused by episodes of coronary artery spasm (CAS) involving focal or diffuse changes in large and/or small coronary arteries in the presence or absence of 'fixed' coronary artery stenoses. However, most clinicians have only limited understanding of this group of disorders. AREAS COVERED: We examine the clinical presentation of CAS, associated pathologies outside the coronary vasculature, impediments to making the diagnosis, provocative diagnostic tests, available and emerging treatments, and the current understanding of pathogenesis. EXPERT OPINION: CAS is often debilitating and substantially under-diagnosed and occur mainly in women. Many patients presenting with CAS crises have non-diagnostic ECGs and normal serum troponin concentrations, but CAS can be suspected on the basis of history and association with migraine, Raynaud's phenomenon and Kounis syndrome. Definitive diagnosis requires provocative testing at coronary angiography. Treatment still centers around the use of calcium antagonists, but with greater understanding of pathogenesis, new management options are emerging.

Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice.

KEY POINTS: Hearts from type 2 diabetic animals display perturbations in excitation-contraction coupling, impairing myocyte contractility and delaying relaxation, along with altered substrate consumption patterns. Under high glucose and ß-adrenergic stimulation conditions, palmitate can, at least in part, offset left ventricle (LV) dysfunction in hearts from diabetic mice, improving contractility and relaxation while restoring coronary perfusion pressure. Fluxome calculations of central catabolism in diabetic hearts show that, in the presence of palmitate, there is a metabolic remodelling involving tricarboxylic acid cycle, polyol and pentose phosphate pathways, leading to improved redox balance in cytoplasmic and mitochondrial compartments. Under high glucose and increased energy demand, the metabolic/fluxomic redirection leading to restored redox balance imparted by palmitate helps explain maintained LV function and may contribute to designing novel therapeutic approaches to prevent cardiac dysfunction in diabetic patients. ABSTRACT: Type-2 diabetes (T2DM) leads to reduced myocardial performance, and eventually heart failure. Excessive accumulation of lipids and glucose is central to T2DM cardiomyopathy. Previous data showed that palmitate (Palm) or glutathione preserved heart mitochondrial energy/redox balance under excess glucose, rescuing ß-adrenergic-stimulated cardiac excitation-contraction coupling. However, the mechanisms underlying the accompanying improved contractile performance have been largely ignored. Herein we explore in intact heart under substrate excess the metabolic remodelling associated with cardiac function in diabetic db/db mice subjected to stress given by ß-adrenergic stimulation with isoproterenol and high glucose compared to their non-diabetic controls (+/+, WT) under euglycaemic conditions. When perfused with Palm, T2DM hearts exhibited improved contractility/relaxation compared to WT, accompanied by extensive metabolic remodelling as demonstrated by metabolomics-fluxomics combined with bioinformatics and computational modelling. The T2DM heart metabolome showed significant differences in the abundance of metabolites in pathways related to glucose, lipids and redox metabolism. Using a validated computational model of heart's central catabolism, comprising glucose and fatty acid (FA) oxidation in cytoplasmic and mitochondrial compartments, we estimated that fluxes through glucose degradation pathways are ∼2-fold lower in heart from T2DM vs. WT under all conditions studied. Palm addition elicits improvement of the redox status via enhanced ß-oxidation and decreased glucose uptake, leading to flux-redirection away from redox-consuming pathways (e.g. polyol) while maintaining the flux through redox-generating pathways together with glucose-FA 'shared fuelling' of oxidative phosphorylation. Thus, available FAs such as Palm may help improve function via enhanced redox balance in T2DM hearts during peaks of hyperglycaemia and increased workload.

Physical activity moderates the deleterious relationship between cardiovascular disease, or its risk factors, and quality of life: Findings from two population-based cohort studies in Southern Brazil and South Australia.

BACKGROUND: Few studies have investigated the relationship between physical activity (PA) of low intensity and duration with quality of life (QoL) among individuals at risk or with cardiovascular disease (CVD). OBJECTIVES: To investigate whether PA of different intensity and duration moderates the relationship between CVD and its risk factors (obesity, hypertension, diabetes, dyslipidaemia) and QoL in adults. METHODS: Population-based cross-sectional studies using data from the EpiFloripa Cohort Study (Southern Brazil; n = 1,220, 38.8±12.0 years, 48.2% males) and the North West Adelaide Health Study (NWAHS, South Australia; n = 1,661, 43.7±11.1 years, 49.7% males). The physical and psychological domains of QoL were assessed using the WHOQOL-Bref (EpiFloripa) or the SF-36 (NWAHS) questionnaires. The diagnosis of CVD and its risk factors were self-reported. PA was self-reported and quantified by its intensity ["walking" or moderate/vigorous (MVPA)] and duration (none, 1-150, ≥150 min/week). Both studies were analysed separately, and results were adjusted for sociodemographic variables. RESULTS: Participants at risk or with CVD from both studies showed a lower QoL than 'healthy' individuals with a stronger relationship for the physical domain. PA duration showed a direct-trend relationship with QoL, but the associations were stronger for MVPA in both studies. However, when stratified by health status, the magnitude of the association between "walking" duration and a higher physical QoL was greater among those at risk or with CVD compared to 'healthy' individuals. Conversely, among Australians with CVD, MVPA was associated with a better physical QoL only when its duration was ≥150 min/week. All associations were stronger in the NWAHS than in the Brazilian study. CONCLUSIONS: "Walking" was more prevalent than MVPA and was consistently associated with a better physical QoL among those at risk or with CVD. These findings should be considered in the design of public health interventions designed to increase PA and improve QoL.

Removal of Abnormal Myofilament O-GlcNAcylation Restores Ca2+ Sensitivity in Diabetic Cardiac Muscle.

Contractile dysfunction and increased deposition of O-linked ß-N-acetyl-d-glucosamine (O-GlcNAc) in cardiac proteins are a hallmark of the diabetic heart. However, whether and how this posttranslational alteration contributes to lower cardiac function remains unclear. Using a refined ß-elimination/Michael addition with tandem mass tags (TMT)-labeling proteomic technique, we show that CpOGA, a bacterial analog of O-GlcNAcase (OGA) that cleaves O-GlcNAc in vivo, removes site-specific O-GlcNAcylation from myofilaments, restoring Ca(2+) sensitivity in streptozotocin (STZ) diabetic cardiac muscles. We report that in control rat hearts, O-GlcNAc and O-GlcNAc transferase (OGT) are mainly localized at the Z-line, whereas OGA is at the A-band. Conversely, in diabetic hearts O-GlcNAc levels are increased and OGT and OGA delocalized. Consistent changes were found in human diabetic hearts. STZ diabetic hearts display increased physical interactions of OGA with α-actin, tropomyosin, and myosin light chain 1, along with reduced OGT and increased OGA activities. Our study is the first to reveal that specific removal of O-GlcNAcylation restores myofilament response to Ca(2+) in diabetic hearts and that altered O-GlcNAcylation is due to the subcellular redistribution of OGT and OGA rather than to changes in their overall activities. Thus, preventing sarcomeric OGT and OGA displacement represents a new possible strategy for treating diabetic cardiomyopathy.

From metabolomics to fluxomics: a computational procedure to translate metabolite profiles into metabolic fluxes.

We describe a believed-novel procedure for translating metabolite profiles (metabolome) into the set of metabolic fluxes (fluxome) from which they originated. Methodologically, computational modeling is integrated with an analytical platform comprising linear optimization, continuation and dynamic analyses, and metabolic control. The procedure was tested with metabolite profiles obtained from ex vivo mice Langendorff-heart preparations perfused with glucose. The metabolic profiles were analyzed using a detailed kinetic model of the glucose catabolic pathways including glycolysis, pentose phosphate (PP), glycogenolysis, and polyols to translate the glucose metabolome of the heart into the fluxome. After optimization, the ability of the model to simulate the initial metabolite profile was confirmed, and metabolic fluxes as well as the structure of control and regulation of the glucose catabolic network could be calculated. We show that the step catalyzed by phosphofructokinase together with ATP demand and glycogenolysis exert the highest control on the glycolytic flux. The negative flux control exerted by phosphofructokinase on the PP and polyol pathways revealed that the extent of glycolytic flux directly affects flux redirection through these pathways, i.e., the higher the glycolytic flux the lower the PP and polyols. This believed-novel methodological approach represents a step forward that may help in designing therapeutic strategies targeted to diagnose, prevent, and treat metabolic diseases.

Early postnatal rat ventricle resection leads to long-term preserved cardiac function despite tissue hypoperfusion.

One-day-old mice display a brief capacity for heart regeneration after apex resection. We sought to examine this response in a different model and to determine the impact of this early process on long-term tissue perfusion and overall cardiac function in response to stress. Apical resection of postnatal rats at day 1 (P1) and 7 (P7) rendered 18 ± 1.0% and 16 ± 1.3% loss of cardiac area estimated by magnetic resonance imaging (MRI), respectively (P > 0.05). P1 was associated with evidence of cardiac neoformation as indicated by Troponin I and Connexin 43 expression at 21 days postresection, while in the P7 group mainly scar tissue replacement ensued. Interestingly, there was an apparent lack of uniform alignment of newly formed cells in P1, and we detected cardiac tissue hypoperfusion for both groups at 21 and 60 days postresection using SPECT scanning. Direct basal cardiac function at 60 days, when the early lesion is undetectable, was preserved in all groups, whereas under hemodynamic stress the degree of change on LVDEP, Stroke Volume and Stroke Work indicated diminished overall cardiac function in P7 (P < 0.05). Furthermore, the End-Diastolic Pressure-Volume relationship and increased interstitial collagen deposition in P7 is consistent with increased chamber stiffness. Taken together, we provide evidence that early cardiac repair response to apex resection in rats also leads to cardiomyocyte neoformation and is associated to long-term preservation of cardiac function despite tissue hypoperfusion.

Cardioprotective mechanism of S-nitroso-N-acetylcysteine via S-nitrosated betadrenoceptor-2 in the LDLr-/- mice.

Previous studies from our group have demonstrated the protective effect of S-nitroso-N-acetylcysteine (SNAC) on the cardiovascular system in dyslipidemic LDLr-/- mice that develop atheroma and left ventricular hypertrophy after 15 days on a high fat diet. We have shown that SNAC treatment attenuates plaque development via the suppression of vascular oxidative stress and protects the heart from structural and functional myocardial alterations, such as heart arrhythmia, by reducing cardiomyocyte sensitivity to catecholamines. Here we investigate the ability of SNAC to modulate oxidative stress and cell survival in cardiomyocytes during remodeling and correlation with ß2-AR signaling in mediating this protection. Ventricular superoxide (O2⁻) and hydrogen peroxide (H2O2) generation was measured by HPLC methods to allow quantification of dihydroethidium (DHE) products. Ventricular histological sections were stained using terminal dUTP nick-end labeling (TUNEL) to identify nuclei with DNA degradation (apoptosis) and this was confirmed by Western blot for cleaved caspase-3 and caspase-7 protein expression. The findings show that O2⁻ and H2O2 production and also cell apoptosis were increased during left ventricular hypertrophy (LVH). SNAC treatment reduced oxidative stress during on cardiac remodeling, measured by decreased H2O2 and O2⁻ production (65% and 52%, respectively), and a decrease in the ratio of p-Ser1177 eNOS/total eNOS. Left ventricle (LV) from SNAC-treated mice revealed a 4-fold increase in ß2-AR expression associated with coupling change to Gi; ß2-ARs-S-nitrosation (ß2-AR-SNO) increased 61%, while apoptosis decreased by 70%. These results suggest that the cardio-protective effect of SNAC treatment is primarily through its anti-oxidant role and is associated with ß2-ARs overexpression and ß2-AR-SNO via an anti-apoptotic pathway.

Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives.

Structural modifications of nonsteroidal anti-inflammatory drugs (NSAIDs) have successfully reduced the side effect of gastrointestinal ulceration without affecting anti-inflammatory activity, but they may increase the risk of myocardial infarction with chronic use. The fact that nitroxyl (HNO) reduces platelet aggregation, preconditions against myocardial infarction, and enhances contractility led us to synthesize a diazeniumdiolate-based HNO-releasing aspirin and to compare it to an NO-releasing analogue. Here, the decomposition mechanisms are described for these compounds. In addition to protection against stomach ulceration, these prodrugs exhibited significantly enhanced cytotoxcity compared to either aspirin or the parent diazeniumdiolate toward nonsmall cell lung carcinoma cells (A549), but they were not appreciably toxic toward endothelial cells (HUVECs). The HNO-NSAID prodrug inhibited cylcooxgenase-2 and glyceraldehyde 3-phosphate dehydrogenase activity and triggered significant sarcomere shortening on murine ventricular myocytes compared to control. Together, these anti-inflammatory, antineoplasic, and contractile properties suggest the potential of HNO-NSAIDs in the treatment of inflammation, cancer, or heart failure.

HNO enhances SERCA2a activity and cardiomyocyte function by promoting redox-dependent phospholamban oligomerization.

AIMS: Nitroxyl (HNO) interacts with thiols to act as a redox-sensitive modulator of protein function. It enhances sarcoplasmic reticular Ca(2+) uptake and myofilament Ca(2+) sensitivity, improving cardiac contractility. This activity has led to clinical testing of HNO donors for heart failure. Here we tested whether HNO alters the inhibitory interaction between phospholamban (PLN) and the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in a redox-dependent manner, improving Ca(2+) handling in isolated myocytes/hearts. RESULTS: Ventriculocytes, sarcoplasmic reticulum (SR) vesicles, and whole hearts were isolated from control (wildtype [WT]) or PLN knockout (pln(-/-)) mice. Compared to WT, pln(-/-) myocytes displayed enhanced resting sarcomere shortening, peak Ca(2+) transient, and blunted ß-adrenergic responsiveness. HNO stimulated shortening, relaxation, and Ca(2+) transient in WT cardiomyocytes, and evoked positive inotropy/lusitropy in intact hearts. These changes were markedly blunted in pln(-/-) cells/hearts. HNO enhanced SR Ca(2+) uptake in WT but not pln(-/-) SR-vesicles. Spectroscopic studies in insect cell microsomes expressing SERCA2a±PLN showed that HNO increased Ca(2+)-dependent SERCA2a conformational flexibility but only when PLN was present. In cardiomyocytes, HNO achieved this effect by stabilizing PLN in an oligomeric disulfide bond-dependent configuration, decreasing the amount of free inhibitory monomeric PLN available. INNOVATION: HNO-dependent redox changes in myocyte PLN oligomerization relieve PLN inhibition of SERCA2a. CONCLUSIONS: PLN plays a central role in HNO-induced enhancement of SERCA2a activity, leading to increased inotropy/lusitropy in intact myocytes and hearts. PLN remains physically associated with SERCA2a; however, less monomeric PLN is available resulting in decreased inhibition of the enzyme. These findings offer new avenues to improve Ca(2+) handling in failing hearts.

GSH or palmitate preserves mitochondrial energetic/redox balance, preventing mechanical dysfunction in metabolically challenged myocytes/hearts from type 2 diabetic mice.

In type 2 diabetes, hyperglycemia and increased sympathetic drive may alter mitochondria energetic/redox properties, decreasing the organelle's functionality. These perturbations may prompt or sustain basal low-cardiac performance and limited exercise capacity. Yet the precise steps involved in this mitochondrial failure remain elusive. Here, we have identified dysfunctional mitochondrial respiration with substrates of complex I, II, and IV and lowered thioredoxin-2/glutathione (GSH) pools as the main processes accounting for impaired state 4→3 energetic transition shown by mitochondria from hearts of type 2 diabetic db/db mice upon challenge with high glucose (HG) and the ß-agonist isoproterenol (ISO). By mimicking clinically relevant conditions in type 2 diabetic patients, this regimen triggers a major overflow of reactive oxygen species (ROS) from mitochondria that directly perturbs cardiac electro-contraction coupling, ultimately leading to heart dysfunction. Exogenous GSH or, even more so, the fatty acid palmitate rescues basal and ß-stimulated function in db/db myocyte/heart preparations exposed to HG/ISO. This occurs because both interventions provide the reducing equivalents necessary to counter mitochondrial ROS outburst and energetic failure. Thus, in the presence of poor glycemic control, the diabetic patient's inability to cope with increased cardiac work demand largely stems from mitochondrial redox/energetic disarrangements that mutually influence each other, leading to myocyte or whole-heart mechanical dysfunction.

Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved.

ATP is required for normal cardiac contractile function, and it has long been hypothesized that reduced energy delivery contributes to the contractile dysfunction of heart failure (HF). Despite experimental and clinical HF data showing reduced metabolism through cardiac creatine kinase (CK), the major myocardial energy reserve and temporal ATP buffer, a causal relationship between reduced ATP-CK metabolism and contractile dysfunction in HF has never been demonstrated. Here, we generated mice conditionally overexpressing the myofibrillar isoform of CK (CK-M) to test the hypothesis that augmenting impaired CK-related energy metabolism improves contractile function in HF. CK-M overexpression significantly increased ATP flux through CK ex vivo and in vivo but did not alter contractile function in normal mice. It also led to significantly increased contractile function at baseline and during adrenergic stimulation and increased survival after thoracic aortic constriction (TAC) surgery-induced HF. Withdrawal of CK-M overexpression after TAC resulted in a significant decline in contractile function as compared with animals in which CK-M overexpression was maintained. These observations provide direct evidence that the failing heart is "energy starved" as it relates to CK. In addition, these data identify CK as a promising therapeutic target for preventing and treating HF and possibly diseases involving energy-dependent dysfunction in other organs with temporally varying energy demands.

Evidence for two atypical conformations of beta-adrenoceptors and their interaction with Gi proteins.

In this study, we investigated whether the responses of right atria from sinoaortic denervated rats to CGP12177 (4(3-t-butylamino-2-hydroxypropoxy benzidimidazole-2 one, hydrochloride)), isoprenaline and norepinephrine desensitized in parallel and whether CGP12177 interacted with distinct conformations of beta-adrenoceptors. Right atria from rats 48 h after sinoaortic denervation were subsensitive to isoprenaline, norepinephrine and CGP12177. One week after sinoaortic denervation, the sensitivity to CGP12177 had recovered whereas the responses to isoprenaline and norepinephrine were still subsensitive, suggesting that the binding sites for these molecules showed independent behavior. In atria from 48 h sinoaortic-denervated rats, propranolol or 3 microM CGP20712A (2-hydroxy-5(2-((2-hydroxy-3-(4-((methyl-4-trifluormethyl)1H imidazole-2-yl)-phenoxypropyl) amino) ethoxy)-benzamide monomethane sulphonate)) blocked the responses to 10 nM-1 microM CGP12177 and steepened the curves. The concentration-response curves to CGP12177 in the presence of ICI118,551 (erythro-DL-1(-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol) were biphasic, suggesting that CGP12177 interacted with at least two conformations of beta-adrenoceptors that showed negative cooperativism, one acting through beta(2)-adrenoceptor-Gi and the other via beta(1)-adrenoceptor-Gs. This hypothesis was confirmed in right atria from sinoaortic-denervated rats treated with pertussis toxin.

Adolescentes intercambistas: implicacoes no processo de amadurecimento

O objetivo desta pesquisa, foi investigar as implicacoes que a participacao de adolescentes em programas de intercambio traz em seu processo de amadurecimento. O estudo constou de 20 questionarios contendo 45 perguntas estruturadas e a ultima em aberto, aplicados em adolescentes, com idade entre 14 e 18 anos, de ambos os sexos. Os dados foram levantados de modo qualitativo, atraves de quadros-sinteses. Os achados da pesquisa evidenciaram que a participacao no programa, possibilita ao adolescente, uma oportunidade de reavaliar seus valores, relacionamentos e visao quanto aos problemas de seu pais. Parecem adquirir uma visao mais objetiva da realidade que os cerca, demonstrando um crescimento e amadurecimento em alguns aspectos de sua personalidade.