Nurses' preferred end-of-life treatment choices in five countries.

BACKGROUND: Previous research has focused on physician's perspectives of end-of-life (EOL) decision making as well as patient and family EOL decision making. There is a lack of research pertaining to the EOL treatment preferences of nurses and especially nurses working in a variety of care settings. AIM: The aim of this study was to compare nurses' EOL treatment preferences in Hong Kong, Ireland, Israel, Italy and the USA. METHODS: A comparative descriptive design was used with a convenience sample of nurses (n = 1089). A survey questionnaire using EOL hypothetical clinical case scenarios was used to collect data between June 2011 and July 2012. RESULTS: Nurses in every country consistently chose a more aggressive option for patients than for themselves or for a parent. The treatment preferences of nurses varied from country to country. Lack of knowledge of patients' wishes and duty of care were the main influencing factors on treatment preferences. STUDY LIMITATIONS: The study was limited to the hypothetical nature of the scenarios; however, the study highlights numerous future research questions. CONCLUSIONS: This study is the first to examine and compare nurses' preferred EOL treatment choices in five countries from three different continents. The findings of this study raise several important questions for healthcare researchers, for policy development, and highlight the need for further international collaboration.

Reduced hepatocyte fatty acid oxidation in outbred rats prescreened for susceptibility to diet-induced obesity.

Rats vary in their propensity to become obese when eating a high-fat diet, but the factors that make some rats susceptible and others resistant to diet-induced obesity are unclear. Recent studies show that rats predisposed to diet-induced obesity have a preexisting deficit in fat oxidation and suggest that this impairment is due in part to reduced fatty acid oxidation in liver. To determine directly whether rats susceptible to diet-induced obesity are less able to oxidize fatty acids in liver, we measured palmitate oxidation in hepatocytes isolated from outbred Sprague-Dawley rats that were identified while still eating a low-fat diet as obesity-prone or obesity-resistant by using a new screening procedure based on the change in plasma triglyceride concentration produced by an intragastric load of a fat and carbohydrate mixture. The results showed that hepatocytes from rats thus identified as obesity-prone oxidized 44% less palmitate in vitro than did those from obesity-resistant rats. This difference in hepatocyte fatty acid oxidation is consistent with and may explain at least in part the reduced capacity of obesity-prone rats to oxidize fat.

Changes in insulin, glucose and ketone bodies, but not leptin or body fat content precede restoration of luteinising hormone secretion in ewes.

The reproductive system, including pulsatile luteinising hormone (LH) secretion, is inhibited by deficits in energy availability and restored by energy surfeits. Plasma LH, insulin, leptin, ghrelin, glucose, ketone body, and nonesterified fatty acid concentrations were measured in ovariectomised, food-restricted ewes before and after return to ad libitum feeding to determine the factors that change in time to account for the restoration of pulsatile LH secretion. At 07.00 h, blood was sampled every 10 min for 5 h from ovariectomised, hypogonadotrophic, chronically food-restricted and ad libitum-fed ewes (Fed). At 12.00 h, four of the food-restricted sheep were given ad libitum access to food (Re-Fed), while three ewes continued to be food restricted (Restricted). Sampling continued for 5 h and resumed again on the mornings of days 2, 4, and 9. A pulse of LH was seen within 1 h of re-feeding in all Re-Fed ewes, and interpulse interval (IPI) was significantly shorter in Re-Fed compared to Restricted ewes and longer than in Fed ewes during the period after re-feeding. Re-Fed LH IPI was not restored to that of Fed ewes until sometime between days 4 and 9. The first pulse occurred within minutes, whereas restoration of IPI occurred after 4-8 days. Prior to the initial LH pulses seen in Re-Fed ewes, plasma ketone bodies first fell and then rose to levels significantly above those in Restricted ewes. Significant changes in circulating insulin, ghrelin, glucose, and total ketone body concentrations, daily food intake and lean body mass preceded restoration of Re-Fed LH IPI some time between days 4 and 9, but there were no significant changes in adiposity or circulating leptin concentrations, consistent with the hypothesis that LH pulses are reinitiated by changes in the availability of oxidisable metabolic fuels and possibly insulin, but not leptin concentrations.

Hormonal and metabolic defects in a prader-willi syndrome mouse model with neonatal failure to thrive.

Prader-Willi syndrome (PWS) has a biphasic clinical phenotype with failure to thrive in the neonatal period followed by hyperphagia and severe obesity commencing in childhood among other endocrinological and neurobehavioral abnormalities. The syndrome results from loss of function of several clustered, paternally expressed genes in chromosome 15q11-q13. PWS is assumed to result from a hypothalamic defect, but the pathophysiological basis of the disorder is unknown. We hypothesize that a fetal developmental abnormality in PWS leads to the neonatal phenotype, whereas the adult phenotype results from a failure in compensatory mechanisms. To address this hypothesis and better characterize the neonatal failure to thrive phenotype during postnatal life, we studied a transgenic deletion PWS (TgPWS) mouse model that shares similarities with the first stage of the human syndrome. TgPWS mice have fetal and neonatal growth retardation associated with profoundly reduced insulin and glucagon levels. Consistent with growth retardation, TgPWS mice have deregulated liver expression of IGF system components, as revealed by quantitative gene expression studies. Lethality in TgPWS mice appears to result from severe hypoglycemia after postnatal d 2 after depletion of liver glycogen stores. Consistent with hypoglycemia, TgPWS mice appear to have increased fat oxidation. Ghrelin levels increase in TgPWS reciprocally with the falling glucose levels, suggesting that the rise in ghrelin reported in PWS patients may be secondary to a perceived energy deficiency. Together, the data reveal defects in endocrine pancreatic function as well as glucose and hepatic energy metabolism that may underlie the neonatal phenotype of PWS.

Role of vagal afferent innervation in feeding and brain Fos expression produced by metabolic inhibitors.

Hepatic vagal afferent fibers have been implicated in the feeding responses initiated by administration of 2,5-anhydro-D-mannitol (2,5-AM; an inhibitor of hepatic metabolism) and methyl palmoxirate (MP; an inhibitor of fat metabolism). 2,5-AM and MP also increase brain Fos expression, an indicator of neural activity, which suggests that Fos expression can reveal the central neural pathways involved in the stimulation of feeding by these agents. To more closely test the hypothesis that brain Fos expression is related to the effects of 2,5-AM and MP on feeding, the vagus was lesioned by application of capsaicin, which destroys afferent fibers, directly to the cervical vagi. Perivagal capsaicin treatment blocked 2,5-AM-induced eating and attenuated MP-induced eating. Although perivagal capsaicin treatment attenuated MP-induced Fos expression, capsaicin treatment did not affect brain Fos expression produced by 2,5-AM. It is concluded that (1) brain Fos expression is not always related to the effects of 2,5-AM on feeding, (2) capsaicin-sensitive hepatic vagal afferent fibers carry the signal that stimulates feeding following 2,5-AM treatment, and (3) MP-induced feeding and brain Fos expression is mediated in part by capsaicin-sensitive fibers.

Conditioned food aversion in Suncus murinus (house musk shrew) - a new model for the study of nausea in a species with an emetic reflex.

The lack of a small animal model with an emetic reflex in which the relationship between conditioned food aversion and emesis could be investigated prompted a study of the insectivore, Suncus murinus (the house musk shrew). A novel food (either tuna or chicken cat food) was paired (C+) with a single exposure to either nicotine (4 mg/kg sc), motion (1 Hz, 4 cm, 10 min) or lithium chloride (100 mg/kg ip) or was paired (C-) with either saline or sham exposure to motion. Nicotine and motion both induced emesis (retching/vomiting) but lithium chloride did not. All three treatments produced a conditioned food aversion after a single pairing with consumption of C+ food. When given a choice between the two foods, S. murinus given lithium chloride, motion exposure and nicotine consumed, respectively, only 25%, 23% and 1% of their total intake from the C+ food. This study shows that a conditioned food aversion can be readily induced in S. murinus and that the induction of emesis can be uncoupled from food aversion. S. murinus provides a promising new model in which the relationship between emesis, nausea and conditioned food aversion can be investigated.

Metabolic inhibitors synergistically decrease hepatic energy status and increase food intake.

Previous studies indicate that administration of the metabolic inhibitor, 2,5-anhydro-D-mannitol (2,5-AM) or methyl palmoxirate (MP), induces feeding behavior in rats by lowering hepatic energy status. Combined treatment with these agents synergistically increases food intake. The present study was designed to investigate whether combined treatment also has a synergistic effect on hepatic energy status. Rats treated with both inhibitors increased feeding behavior compared with the controls, whereas those treated with 2, 5-AM or MP alone did not. Although 2,5-AM alone lowered hepatic ATP content regardless of MP treatment, only the combination resulted in decreases in hepatic ATP/ADP ratio and phosphorylation potential. MP treatment did not affect the uptake of 2,5-AM into liver. These results suggest that a reduction in hepatic energy status is the common triggering signal for eating behavior induced by 2,5-AM and MP and provide additional evidence for an integrated metabolic control of food intake.

Comparison of verbal and pictorial measures of hunger during fasting in normal weight and obese subjects.

OBJECTIVE: Friedman, Ulrich, and Mattes described a new pictorial instrument for assessing hunger wherein respondents outline areas on a drawing of a human figure to depict the location of their hunger sensations. The present study compared normal weight and obese individuals on the pictorial measure and on more traditional verbal hunger measures during a 22-hour fast. RESEARCH METHODS AND PROCEDURES: The pictorial measure, along with 13 verbal items assessing hunger and hunger-related symptoms, was administered to 29 normal weight college students and 46 overweight clinic patients four times during a 22-hour fast. Factor analyses of verbal hunger items produced Hunger, Somatic Symptoms, and Stomach Symptoms factors. The pictorial measure was divided into peripheral (arms, legs, head) and central (trunk) body areas. RESULTS: The increases in hunger during the fast were greater when measured using the pictorial as opposed to the verbal instrument. Correlations between and within the three verbal hunger measures and two pictorial measures were generally few in number and modest in size. The overall pattern of correlations suggested that the verbally based hunger measures more adequately reflected the experience of hunger in normal weight than in obese individuals. A significant interaction between weight status and assessment period was found for the pictorial measure, indicating that normal weight subjects experienced more bodily hunger than overweight subjects initially but experienced less hunger than obese subjects after a prolonged period of food deprivation. DISCUSSION: Although more testing is needed, these results suggest that the pictorial hunger assessment provides information about the experience of hunger that could complement information provided by traditional verbally based hunger measures.

Metabolic, gastrointestinal, and CNS neuropeptide effects of brain leptin administration in the rat.

To investigate whether brain leptin involves neuropeptidergic pathways influencing ingestion, metabolism, and gastrointestinal functioning, leptin (3.5 micrograms) was infused daily into the third cerebral ventricular of rats for 3 days. To distinguish between direct leptin effects and those secondary to leptin-induced anorexia, we studied vehicle-infused rats with food available ad libitum and those that were pair-fed to leptin-treated animals. Although body weight was comparably reduced (-8%) and plasma glycerol was comparably increased (142 and 17%, respectively) in leptin-treated and pair-fed animals relative to controls, increases in plasma fatty acids and ketones were only detected (132 and 234%, respectively) in pair-fed rats. Resting energy expenditure (-15%) and gastrointestinal fill (-50%) were reduced by pair-feeding relative to the ad libitum group, but they were not reduced by leptin treatment. Relative to controls, leptin increased hypothalamic mRNA for corticotropin-releasing hormone (CRH; 61%) and for proopiomelanocortin (POMC; 31%) but did not reduce mRNA for neuropeptide Y. These results suggest that CNS leptin prevents metabolic/gastrointestinal responses to caloric restriction by activating hypothalamic CRH- and POMC-containing pathways and raise the possibility that these peripheral responses to CNS leptin administration contribute to leptin's anorexigenic action.

A figurative measure of subjective hunger sensations.

In an attempt to better characterize the subjective experience of hunger, we assessed the locus and extent of sensations associated with varying degrees of hunger. In the first study, 83 subjects indicated by marking on a drawing of a human figure where they felt hungry under hypothetical conditions of slight to extreme hunger. Approximately 55% of subjects indicated an abdominal locus with slight hunger, a proportion which increased somewhat with increasing levels of imagined hunger. The proportion of subjects indicating other or additional body sites grew significantly with increasing hunger states; for example, those identifying the head region increased from about 10-35%. In a second study, 14 subjects were fasted for 22 h and then refed. Using the drawn figures, they outlined body areas where they experienced hunger during and after fasting. The size of the abdominal area and the total body area associated with hunger sensations expanded with increasing food deprivation and contracted after refeeding. The size of the area of hunger sensation did not necessarily correlate with the degree of hunger as assessed by standard rating scales. The results indicate that the extent and locus of hunger sensations vary with fasting and feeding, and suggest that the site and size of the body areas associated with hunger sensations may provide qualitative and quantitative measures of the subjective experience of hunger not captured by analogue rating scales.

Fatty acid oxidation affects food intake by altering hepatic energy status.

Inhibition of fatty acid oxidation stimulates feeding behavior in rats. To determine whether a decrease in hepatic fatty acid oxidation triggers this behavioral response, we compared the effects of different doses of methyl palmoxirate (MP), an inhibitor of fatty acid oxidation, on food intake with those on in vivo and in vitro liver and muscle metabolism. Administration of 1 mg/kg MP selectively decreased hepatic fatty acid oxidation but did not stimulate food intake. In contrast, feeding behavior increased in rats given 5 or 10 mg/kg MP, which inhibited hepatic fatty acid oxidation to the same extent as did the low dose but in addition suppressed fatty acid oxidation in muscle and produced a marked depletion of liver glycogen. Dose-related increases in food intake tracked dose-related reductions in liver ATP content, ATP-to-ADP ratio, and phosphorylation potential. The findings suggest that a decrease in hepatic fatty acid oxidation can stimulate feeding behavior by reducing hepatic energy production.

Neural substrate for an integrated metabolic control of feeding behavior.

Evidence indicates that feeding behavior in rats is controlled by a mechanism that integrates information about different aspects of fuel metabolism. We investigated the neural substrate for this integrated control by measuring the effect of metabolic inhibitors given alone and in combination on food intake and neuronal activity as reflected by the expression of c-Fos protein. Combined administration of methyl palmoxirate (5 mg/kg po), an inhibitor of fatty acid oxidation, and 2,5-anhydro-D-mannitol (150 mg/kg ip), which decreases liver ATP content, increased feeding in rats more than expected on the basis of eating responses after treatment with either inhibitor given alone. Combined treatment also produced a synergistic increase in Fos-like immunoreactivity in several brain areas, including the nucleus of the solitary tract, area postrema, and parvocellular portion of the hypothalamic paraventricular nucleus. These findings provide strong evidence for the involvement of selected brain regions in the metabolic control of food intake and suggest that metabolic information used to control feeding behavior is integrated in the periphery or at the level of the brain stem.

Compensatory hyperphagia after fasting tracks recovery of liver energy status.

Studies using metabolic inhibitors suggest that a reduction in hepatic ATP generates a stimulus that triggers feeding behavior. To investigate the relationship between changes in liver ATP and food intake under physiological conditions, we assessed changes in feeding behavior and liver adenine nucleotides during refeeding after 24 h of food deprivation. Deprived rats consumed 14 g of food in the first 3 h of refeeding; the rate of consumption declined markedly thereafter for the next 9 h, but remained higher than that seen in nonfasted rats. Fasting produced substantial reductions in ATP, ATP/ADP, and phosphorylation potential relative to fed levels. Refeeding restored liver ATP by 6 h, whereas ATP/ADP and phosphorylation potential did not fully recover until 12 h of refeeding. Restricting food intake during refeeding limited recovery of liver energy status. These results show that liver energy production recovers slowly during refeeding with a time course that parallels the compensatory change in eating behavior. These findings raise the possibility that changes in hepatic energy status play a role in satiation as well as in hunger.

Do patient data ever exceed the partial volume limit in gated SPECT studies?

BACKGROUND: Some single photon emission computed tomography (SPECT) methods to detect percent myocardial wall thickening (%WT) assume a linear relationship to changes in maximum myocardial counts, predicated on myocardial walls never exceeding the SPECT camera's partial volume limit. Recent studies have challenged such assumptions, reporting that systolic count changes underestimate wall thickening as measured by echocardiography and magnetic resonance imaging. METHODS AND RESULTS: To test whether clinical data ever are observed to exceed the partial volume limit, we examined gated tomograms of 75 patients selected at random and of an additional 25 patients known to have hypertension with electrocardiographic evidence of left ventricular hypertrophy. Image transformations were performed such that for every cinematic frame, radial counts at every angle were automatically normalized to the same maximum count. If no patient's myocardium ever exceeded the partial volume limit, thickness quantified from transformed images would always be the same throughout the cardiac cycle and would just correspond to the camera's line spread function. Thickness was measured by Gaussian fitting of transformed myocardial counts in the epicardial direction only to exclude cavitary count contamination. % WT was computed from thickness differences from diastole to systole. % WT values were assessed from clinical data at lateral, inferior, septal, anterior, and apical territories. Resulting %WT distributions were tested against the null hypothesis of %WT = 0 by the Z-test. Although some distributions were not actually Gaussian, the maximum mean %WT was only +3% +/-5% for the septal wall, in agreement with an observer's impressions of no detectable wall thickening. Thus mean %WT values were trivial compared with expected physiologic normal values of 30% to 50%. CONCLUSION: No convincing evidence was found of thickness above the partial volume limit in this large sample of 75 normotensive and 25 hypertensive patients. Therefore it is likely that relations between myocardial count increases and wall thickening are similar throughout the cardiac cycle, even in patients with left ventricular hypertrophy.

Brain fos-like immunoreactivity in chronic decerebrate and neurologically intact rats given 2,5-anhydro-D-mannitol.

Injection of the fructose analogue, 2,5-anhydro-d-mannitol (2,5-AM), increases food intake and Fos-like immunoreactivity (Fos-li) in both brainstem and forebrain structures. Because of the interconnections between brainstem and forebrain areas, it has not been possible to determine whether or to what extent induction of Fos-li in a given region reflects brainstem-forebrain interactions. We addressed this issue using chronic decerebrate (CD) rats with complete transections of the neuroaxis at the meso-diencephalic juncture. CD and neurologically intact control rats were injected (i.p.) with saline or 400 mg/kg 2,5-AM and brains were examined for Fos-li. Both intact and CD rats showed increased Fos-li in the nucleus of the solitary tract (NTS) after injection of 2,5-AM as compared with saline. 2, 5-AM treatment increased Fos-li in the external lateral division of parabrachial nucleus (PBNel) in intact but not in CD rats, suggesting that descending projections from the forebrain may play a role in the activation of PBNel neurons after 2,5-AM injection. Decerebration eliminated significant 2,5-AM-induced Fos-li responses in forebrain structures, including the paraventricular nucleus, supraoptic nucleus, bed nucleus of the stria terminalis and central nucleus of the amygdala. The results are consistent with the hypothesis that the activation of forebrain structures after 2,5-AM treatment is due to stimulation by ascending projections from the brainstem.

Leptin indirectly affects estrous cycles by increasing metabolic fuel oxidation.

In previous experiments, lean Syrian hamsters fasted on days 1 and 2 of the estrous cycle failed to show sex behavior and ovulation normally expected to occur on the evening of day 4. The first goal of the present experiment was to determine whether systemic treatment with the ob (obese) protein leptin could reverse the effects of fasting on estrous cyclicity, social behaviors, and ovulation rate. Fasting-induced anestrus was reversed and normal sex and social behavior and ovulation rate were restored in hamsters injected intraperitoneally with 5 mg/kg leptin every 12 h during fasting on days 1 and 2 of the estrous cycle. A second goal was to test whether the effects of leptin could be prevented by treatment with pharmacological agents that block the oxidation of metabolic fuels. Glucose oxidation was blocked by treatment with 2-deoxy-d-glucose (2DG) and fatty acid oxidation was blocked by treatment with methyl palmoxirate (MP). 2DG (1000 mg/kg) or MP (20 mg/kg) was administered at doses that did not induce anestrus in hamsters fed ad libitum. As in the first experiment, fasting-induced anestrus was reversed by leptin treatment. However, when each injection of leptin was preceded by an injection of 2DG or MP, leptin treatment did not reverse fasting-induced anestrus. In summary, estrous cyclicity was not restored when oxidation of metabolic fuels was blocked, despite high endogenous levels of leptin. These results are consistent with the hypothesis that leptin acts indirectly on the reproductive system by increasing fuel oxidation.

Metabolic inhibition increases feeding and brain Fos-like immunoreactivity as a function of diet.

Whether administration of 2,5-anhydro-D-mannitol (2,5-AM) or methyl palmoxirate (MP) elicits eating behavior in rats depends on the composition of the maintenance diet. To assess whether specific brain sites are involved in triggering the eating responses to these metabolic inhibitors, we measured food intake and Fos-like immunoreactivity (Fos-li) in rats maintained on either a low-fat/high-carbohydrate (LF/HC) or high-fat/low-carbohydrate (HF/LC) diet. Rats fed the LF/HC diet increased food intake after administration of 2,5-AM (200 mg/kg ip) but not after treatment with MP (10 mg/kg po), whereas rats maintained on the HF/LC diet increased food intake in response to MP administration but not after 2,5-AM injection. The effects of these inhibitors on brain Fos-li in several specific brain nuclei paralleled those on feeding behavior; that is, the number of cells showing Fos-li increased only under dietary conditions in which 2,5-AM or MP stimulated eating. These results suggest that the eating response to metabolic inhibition is tied to increased neuronal activity in brain regions that process vagal afferent signals.

Effect of a high-fat diet on food intake and hypothalamic neuropeptide gene expression in streptozotocin diabetes.

Insulin-deficient diabetic rats are markedly hyperphagic when fed a high-carbohydrate (HC) diet, but normophagic when fed a high-fat (HF) diet. When maintained on a HC diet, diabetic rats also exhibit increased gene expression of the orexigenic peptide neuropeptide Y (NPY) in the hypothalamic arcuate nucleus, and reduced expression of the anorectic peptide corticotropin-releasing hormone (CRH) in the paraventricular nucleus, and these changes are hypothesized to contribute to diabetic hyperphagia. In this experiment we assessed whether the normophagia displayed by HF-fed diabetic rats is associated with the opposite profile of NPY and CRH expression. Our results show that relative to diabetic rats on the HC diet, the diabetic rats on the HF diet exhibited significantly reduced caloric intake (-40%), NPY expression in the arcuate nucleus (-27%), and elevated CRH expression in the paraventricular nucleus (+37%). Insulin and corticosterone, which are known to affect hypothalamic NPY and CRH expression, were not different between these two groups, making it unlikely that they can account for the differences in either feeding behavior or hypothalamic peptide expression. There was a small but significant increase in plasma leptin levels in the diabetic animals maintained on the HF, and large differences in parameters associated with elevated fat oxidation. These observations support the hypothesis that the normalization of food intake observed in diabetic rats consuming a HF diet may in part be mediated by reductions in NPY expression and elevations in CRH expression.

Methyl palmoxirate increases eating behavior and brain Fos-like immunoreactivity in rats.

Administration of methyl palmoxirate (MP), an inhibitor of fatty acid oxidation, stimulates eating behavior in rats. Fos immunohistochemistry was used to determine neural pathways that may play a role in the eating response to MP. The number of cells showing Fos-like immunoreactivity (Fos-li) was quantified by computerized image analysis. MP treatment, at a dose that increased food intake (10 mg/kg, p.o.), induced Fos expression in the nucleus of the solitary tract, area postrema, lateral parabrachial nucleus, central lateral nucleus of the amygdala, dorsal lateral bed nucleus of the stria terminalis, and the paraventricular nucleus of the hypothalamus. The results suggest that MP activates an afferent pathway projecting from the hindbrain to the forebrain, which may be involved in the eating response after MP treatment.