The influence of "bad news" and "neutral/good news" on patients' perception of physician empathy during oncology consultations.

OBJECTIVES: Being met with empathy increases information sharing, treatment coherence, and helps patients to recover faster. However, we do not know how the content of the conversation about disease progression, new treatments, or other issues concerning serious illness affects patients' perceptions of the physician's empathy, and thus, the quality of the conversation. This study aimed to test the hypothesis that patients will rate their physician lower following a "bad news" consultation using the consultation and relational empathy (CARE) measure. METHODS: A total of 186 outpatients from the Department of Oncology were recruited for this study. After meeting with a patient, the physician filled out a form, placing the patient in either the "bad news" group, or the "neutral/good news" group along with information about the patient and the consultation. The patient was given the CARE measure after the visit. RESULTS: The patients who had received bad news rated their physicians a significantly lower score on the CARE measure, even though the effect size was small, than those who had neutral/good news. On average, bad news consultations were 11 min longer. CONCLUSIONS: Physicians need to be aware of the patients' need to be known and understood, in addition to having skills to attend to emotional cues and concerns, since the current study's finding could be a sign either of the content being projected onto the physician or that the physician is focused on the message rather than on the patient.

Physicians' Lived Experience of Breaking Bad News in Clinical Practice: Five Essentials of a Relational Process.

The purpose of this study was to develop deeper knowledge about physicians' lived experiences of breaking bad news by identifying their common meanings and interrelatedness along with their potential alignment with process-oriented and relational aspects. Based on the methodology of descriptive phenomenology, in-depth interviews were conducted with 22 physicians from a wide variety of specialties. The participants were invited to freely reflect upon their experiences of breaking bad news by describing situations that had worked well and less well. Results showed that breaking bad news was fundamentally experienced as a relational process constituted by the five essentials of Becoming the bad messenger, Expecting the unpredictable, Being on stage, Professionally managing hope, and Mindfulness of the emotional relationship. In line with recent research, this study confirms that clinical communication involves much more than just delivering the message. However, it also contributes to existing knowledge by focusing on the phenomenology of physicians' experiences, which enables deeper understanding of the medical profession and the relational process of breaking bad news. As such, our findings are important to enable broader learning in, for example, medical education and continuing courses for clinical staff.

Patterns of Communication About Serious Illness in the Years, Months, and Days before Death.

Background: Communication with patients and families about serious illness impacts quality of life and helps facilitate decision-making. Objective: To elucidate the pattern of communication about serious illness for patients who have died in an inpatient setting. Design: Three hundred patients from the Swedish Registry of Palliative Care 2015-2017 were randomly selected for manual chart review. Setting: Patients who died in a palliative care, oncology, or internal medicine unit in Sweden were selected. Measurements: We report on the frequency of conversations at three time points, 6 months or longer before death ("Years"), 15 days-6 months before death ("Months"), and 0-14 days before death ("Days"). We also report the timing of the conversation about dying. Results: A total of 249 patients were included after exclusions; they had an average of 2.1 conversations (range 1-6). The first conversation took place a median of 53 days before death and the last conversation took place a median of 9 days before death. Separate conversations with the next of kin took place a median of two days before death. We could verify a conversation about dying in only 156/249 (63%) medical records. Conclusions: Communication about serious illness between clinicians, patients, and families occurs iteratively over a period before death. Measuring the quality of communication about serious illness using a years, months, and days framework may help ensure that patients and families have sufficient information for medical and personal decision making.

Co-afflicted but invisible: A qualitative study of perceptions among informal caregivers in cancer care.

This article explores the lived experience of informal caregivers in cancer care, focusing on the perceived burden and needs of individuals seeking support from an informal group for next of kin. A total of 28 individuals who were closely related to a patient with cancer participated in focus group interviews. Three themes were identified: setting aside one's own needs, assuming the role of project manager, and losing one's sense of identity. Together they form the framing theme: being co-afflicted. The characteristics of informal caregivers are shown to be similar to those of people with codependency, motivating development of targeted interventions from this perspective.

[Difficult discussions with patients practiced at course with actors. A carefully planned strategy helps both physician and patient]. / Svåra samtal med patienter tränas på kurs med skådespelare - En medveten strategi hjälper både läkare och patient.

The physician's communication skill influences the patient's mental and physical wellbeing, as well as the physician's own experience of stress. Most patients wish to be informed about their disease, by physicians who are honest, gives time, sustains hope, listens and shows compassion and empathy. Even though there are established guidelines on how to break bad news, the physician must find out and respond to the unique reactions and needs of each individual, in order to communicate successfully. There is no consensus on how to construct and evaluate communication skills training programs for physicians, and more RCT-studies are requested.

Determination of the thrombin inhibitor AZD0837 and its metabolites in human bile using mixed mode solid phase extraction and LC-MS/MS.

A method for the determination of AZD0837 and its two metabolites AR-H069927 and AR-H067637 in human bile was developed and validated. All three analytes and their stable isotope-labeled internal standards were isolated from bile using solid phase extraction on a mixed mode reversed phase/anion exchange column. Elution was done at high ionic strength with 0.125 M ammoniumacetate in 50% methanol. The extraction recoveries were >75%. Due to the high concentration of AR-H067637 a portion of the extract was diluted before injection on to the LC column, while undiluted extract was directly injected for the analysis of AZD0837 and AR-H069927. Chromatographic separation of all three analytes was achieved in a single system utilizing a C18 column based on fused core particle technology at high flow rate. The two metabolites were eluted when a gradient from 30 to 57% methanol was applied while the more hydrophobic pro-drug, AZD0837, eluted during a steeper second gradient from 57 to 80% methanol with the ammonium acetate concentration and acetic acid concentration kept constant at 3.8 mmol/L and 0.1%, respectively. The total cycle time was 3.2 min. Detection was performed using positive electrospray ionization tandem mass spectrometry. The linearity range was 0.02-20 µmol/L for AZD0837 and AR-H069927, and 1-1000 µmol/L for AR-H067637. The repeatability and the overall precision were less than 15% (RSD) and the accuracy was within the interval 93-100%.

Stimulated efflux of amino acids and glutathione from cultured hippocampal slices by omission of extracellular calcium: likely involvement of connexin hemichannels.

Omission of extracellular Ca(2+) for 15 min from the incubation medium of cultured hippocampal slices stimulated the efflux of glutathione, phosphoethanolamine, hypotaurine, and taurine. The efflux was reduced by several blockers of gap junctions, i.e. carbenoxolone, flufenamic acid, and endothelin-1, and by the connexin43 hemichannel blocking peptide Gap26 but was unchanged by the P2X(7) receptor inhibitor oxidized ATP, a pannexin1 hemichannel blocking peptide and an inactive analogue of carbenoxolone. Pretreatment of the slices with the neurotoxin N-methyl-d -aspartate left the efflux by Ca(2+) omission unchanged, indicating that the stimulated efflux primarily originated from glia. Elevated glutamate efflux was detected when Ca(2+) omission was combined with the glutamate uptake blocker l-trans-pyrrolidine-2,4-dicarboxylate and when both Ca(2+) and Mg(2+) were omitted from the medium. Omission of Ca(2+) for 15 min alone did not induce delayed toxicity, but in combination with blocked glutamate uptake, significant cell death was observed 24 h later. Our results indicate that omission of extracellular Ca(2+) stimulates efflux of glutathione and specific amino acids including glutamate via opening of glial hemichannels. This type of efflux may have protective functions via glutathione efflux but can aggravate toxicity in situations when glutamate reuptake is impaired, such as following a stroke.

S-sulfo-cysteine is an endogenous amino acid in neonatal rat brain but an unlikely mediator of cysteine neurotoxicity.

S-sulfo-cysteine (SSC) is an agonist of glutamate receptors which could be involved in cysteine-induced neurotoxicity. Here we analyzed SSC by HPLC and demonstrated that the concentration of SSC in cortex of cysteine-injected rats increased to 1.4 microM, about four times the value of control rats. The neurotoxic effect of SSC was evaluated in slice cultures of rat hippocampus and compared to NMDA and cysteine. The neurotoxicity threshold of SSC was well above the tissue concentration. Our results show that SSC increases in neonatal rat brain after cysteine injection but reaches a tissue concentration far below concentrations that induce neurotoxicity in vitro. Thus, even if all the tissue SSC after cysteine injection was extracellular it would be below the threshold for toxicity, indicating that SSC is not a main excitotoxin involved in cysteine toxicity.

In vitro studies on the putative function of N-acetylaspartate as an osmoregulator.

Efflux and tissue content of N-acetylaspartate (NAA) and amino acids were evaluated from cultured and acutely prepared hippocampal slices in response to changes in osmolarity. The osmoregulator taurine, but not NAA, was lost from both types of slices after moderate reductions in extracellular osmolarity (-60 mOsm) for 10-48 h. Hypoosmotic shock (-166 mOsm) for 5 min resulted in unselective efflux of several amino acids from acutely prepared slices. Notably, the efflux of taurine, but not NAA, was prominent also after the shock. Efflux of NAA was markedly enhanced by NMDA and high K(+), in particular after the stimulation period. The high K(+)-mediated efflux was decreased by high extracellular osmolarity and a NMDA-receptor antagonist. The results indicate that NAA efflux can be induced by a sudden non-physiological decrease in extracellular osmolarity but not by prolonged more moderate changes in osmolarity. The mechanisms behind the efflux of NAA by high K(+) are complex and may involve both swelling and activation of NMDA-receptors.

N-acetylaspartate monomethyl ester increases N-acetylaspartate concentration in cultured rat hippocampal slices: effects on excitotoxicity and levels of amino acids and chloride.

N-acetylaspartate (NAA) was discovered in mammalian brain 50 years ago but its functions remain debated. One reason for the relatively slow progress of NAA research is the paucity of tools to specifically modify NAA concentrations. In this work we evaluated the use of the monomethyl ester of NAA (NAA MME) to increase the relatively low level of NAA in cultured hippocampal slices. When slices were treated with 30 mM NAA MME for 3 days the NAA concentration increased from 31.6 to 185.3 nmol/mg protein. Incubation with NAA alone increased the NAA concentration non-significantly to 65.6 nmol/mg protein. NAA MME treatment increased NAA in neurons and the increase was non-toxic as determined by the low uptake of propidium iodide, a dye that only enters damaged cells. NMDA-mediated excitotoxicity which is initiated by influx of Ca(2+) was unaltered by increased NAA levels indicating poor intracellular Ca(2+)-chelation by NAA.

Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet.

Intrauterine growth restriction (IUGR) represents an important risk factor for perinatal complications and for adult disease. IUGR is associated with a down-regulation of placental amino acid transporters; however, whether these changes are primary events directly contributing to IUGR or a secondary consequence is unknown. We investigated the time course of changes in placental and fetal growth, placental nutrient transport in vivo and the expression of placental nutrient transporters in pregnant rats subjected to protein malnutrition, a model for IUGR. Pregnant rats were given either a low protein (LP) diet (n = 64) or an isocaloric control diet (n = 66) throughout pregnancy. Maternal insulin, leptin and IGF-I levels decreased, whereas maternal amino acid concentrations increased moderately in response to the LP diet. Fetal and placental weights in the LP group were unaltered compared to control diet at gestational day (GD) 15, 18 and 19 but significantly reduced at GD 21. Placental system A transport activity was reduced at GD 19 and 21 in response to a low protein diet. Placental protein expression of SNAT2 was decreased at GD 21. In conclusion, placental amino acid transport is down-regulated prior to the development of IUGR, suggesting that these placental transport changes are a cause, rather than a consequence, of IUGR. Reduced maternal levels of insulin, leptin and IGF-1 may link maternal protein malnutrition to reduced fetal growth by down-regulation of key placental amino acid transporters.

A Caenorhabditis elegans mutant lacking functional nicotinamide nucleotide transhydrogenase displays increased sensitivity to oxidative stress.

Proton-translocating mitochondrial nicotinamide nucleotide transhydrogenase (NNT) was investigated regarding its physiological role in Caenorhabditis elegans. NNT catalyzes the reduction of NADP(+) by NADH driven by the electrochemical proton gradient, Deltap, and is thus a potentially important source of mitochondrial NADPH. Mitochondrial detoxification of reactive oxygen species (ROS) by glutathione-dependent peroxidases depends on NADPH for regeneration of reduced glutathione. Transhydrogenase may therefore be directly involved in the defense against oxidative stress. nnt-1 deletion mutants of C. elegans, nnt-1(sv34), were isolated and shown to grow essentially as wild type under normal laboratory conditions, but with a strongly lowered GSH/GSSG ratio. Under conditions of oxidative stress, caused by the superoxide-generating agent methyl viologen, growth of worms lacking nnt-1 activity was severely impaired. A similar result was obtained by using RNAi. Reintroducing nnt-1 in the nnt-1(sv34) knockout mutant led to a partial rescue of growth under oxidative stress conditions. These results provide evidence for the first time that nnt-1 is important in the defense against mitochondrial oxidative stress.

NMDA-receptor mediated efflux of N-acetylaspartate: physiological and/or pathological importance?

N-Acetylaspartate (NAA) is a largely neuron specific dianionic amino acid present in high concentration in vertebrate brain. Many fundamental questions concerning N-acetylaspartate in brain remain unanswered. One such issue is the predominantly neuronal synthesis and largely glial catabolism which implies the existence of a regulated efflux from neurons. Here we show that transient (5 min) NMDA-receptor activation (60 microM) induces a long lasting Ca2+ -dependent efflux of N-acetylaspartate from organotypic slices of rat hippocampus. The NMDA-receptor stimulated efflux was unaffected by hyper-osmotic conditions (120 mM sucrose) and no efflux of N-acetylaspartate was evoked by high K+ -depolarization (50 mM) or kainate (300 microM). These results indicate that the efflux induced by NMDA is not related directly to either cell swelling or depolarization but is coupled to Ca2+ -influx via the NMDA-receptor. The efflux of N-acetylaspartate persisted at least 20 min after the omission of NMDA, similar to the efflux of the organic anions glutathione and phosphoethanolamine. The efflux of taurine and hypotaurine was also stimulated by NMDA but returned more quickly to basal levels. The NMDA-receptor stimulated efflux of N-acetylaspartate, glutathione, phosphoethanolamine, taurine and hypotaurine correlated with delayed nerve cell death measured 24 h after the transient NMDA-receptor stimulation. However, exogenous administration of high concentrations of N-acetylaspartate to the culture medium was non-toxic. The results suggest that Ca2+ -influx via the NMDA-receptor regulates the efflux of N-acetylaspartate from neurons which may have both physiological and pathological importance.

Searching for mechanisms of N-methyl-D-aspartate-induced glutathione efflux in organotypic hippocampal cultures.

N-Methyl-D-aspartate (NMDA)-receptor stimulation evoked a selective and partly delayed elevated efflux of glutathione, phosphoethanolamine, and taurine from organotypic rat hippocampus slice cultures. The protein kinase inhibitors H9 and staurosporine had no effect on the efflux. The phospholipase A2 inhibitors quinacrine and 4-bromophenacyl bromide, as well as arachidonic acid, a product of phospholipase A2 activity, did not affect the stimulated efflux. Polymyxin B, an antimicrobal agent that inhibits protein kinase C, and quinacrine in high concentration (500 microM), blocked efflux completely. The stimulated efflux after but not during NMDA incubation was attenuated by a calmodulin antagonist (W7) and an anion transport inhibitor (DNDS). Omission of calcium increased the spontaneous efflux with no or small additional effects by NMDA. In conclusion, NMDA receptor stimulation cause an increased selective efflux of glutathione, phosphoethanolamine and taurine in organotypic cultures of rat hippocampus. The efflux may partly be regulated by calmodulin and DNDS sensitive channels.