Documentation of older people's end-of-life care in the context of specialised palliative care: a retrospective review of patient records.

BACKGROUND: Palliative care focuses on identifying, from a holistic perspective, the needs of those experiencing problems associated with life-threatening illnesses. As older people approach the end of their lives, they can experience a complex series of problems that health-care professionals must identify and document in their patients' records. Documentation is thus important for ensuring high-quality patient care. Previous studies of documentation in older people's patient records performed in various care contexts have shown that such documentation almost exclusively concerns physical problems. This study explores, in the context of Swedish specialised palliative care, the content of documentation in older people's patient records, focusing on documented problems, wishes, aspects of wellbeing, use of assessment tools, interventions, and documentation associated with the person's death. METHODS: A retrospective review based on randomly selected records (n = 92) of older people receiving specialised palliative care, at home or in a palliative in-patient ward, who died in 2017. A review template was developed based on the literature and on a review of sampled records of patients who died the preceding year. The template was checked for inter-rater agreement and used to code all clinical notes in the patients' records. Data were processed using descriptive statistics. RESULTS: The most common clinical notes in older people's patient records concerned interventions (n = 16,031, 71%), mostly related to pharmacological interventions (n = 4318, 27%). The second most common clinical notes concerned problems (n = 2804, 12%), pain being the most frequent, followed by circulatory, nutrition, and anxiety problems. Clinical notes concerning people's wishes and wellbeing-related details were documented, but not frequently. Symptom assessment tools, except for pain assessments, were rarely used. More people who received care in palliative in-patient wards died alone than did people who received care in their own homes. CONCLUSIONS: Identifying and documenting the complexity of problems in a more structured and planned way could be a method for implementing a more holistic approach to end-of-life care. Using patient-reported outcome measures capturing more than one symptom or problem, and a systematic documentation structure would help in identifying unmet needs and developing holistic documentation of end-of-life care.

Infliximab as rescue therapy in hospitalised patients with steroid-refractory acute ulcerative colitis: a long-term follow-up of 211 Swedish patients.

BACKGROUND: Rescue therapy with infliximab (IFX) has been proven effective in a steroid-refractory attack of ulcerative colitis (UC). The long-term efficacy is not well described. AIM: To present a retrospective study of IFX as rescue therapy in UC. Primary end points were colectomy-free survival at 3 and 12 months. METHODS: In this multicentre study, 211 adult patients hospitalised between 1999 and 2010 received IFX 5 mg/kg as rescue therapy due to a steroid-refractory, moderate-to-severe attack of UC. Exclusion criteria were duration of current flare for >12 weeks, corticosteroid treatment for >8 weeks before hospitalisation, previous IFX therapy or Crohn's disease. RESULTS: Probability of colectomy-free survival at 3 months was 0.71 (95% CI, 0.64-0.77), at 12 months 0.64 (95% CI, 0.57-0.70), at 3 years 0.59 (95% CI, 0.52-0.66) and at 5 years 0.53 (95% CI, 0.44-0.61). Steroid-free, clinical remission was achieved in 105/211 (50%) and 112/209 (54%) patients at 3 and 12 months respectively. Of 75 colectomies during the first year, 48 (64%) were carried out during the first 14 days, 13 (17%) on days 15-90 and 14 (19%) between 3 and 12 months. There were three (1.4%) deaths during the first 3 months. CONCLUSIONS: Infliximab is an effective rescue treatment, both short- and long-term, in a steroid-refractory attack of UC. Most IFX failures underwent surgery during the first 14 days, which calls for studies on how to optimise induction treatment with IFX. Serious complications, including mortality, were rare.

Effect of hypnotherapy and educational intervention on brain response to visceral stimulus in the irritable bowel syndrome.

BACKGROUND: Gut-directed hypnotherapy can reduce IBS symptoms, but the mechanisms underlying this therapeutic effect remain unknown. AIM: To determine the effect of hypnotherapy and educational intervention on brain responses to cued rectal distensions in IBS patients. METHODS: Forty-four women with moderate-to-severe IBS and 20 healthy controls (HCs) were included. Blood oxygen level dependent (BOLD) signals were measured by functional Magnetic Resonance Imaging (fMRI) during expectation and delivery of high- (45 mmHg) and low-intensity (15 mmHg) rectal distensions. Twenty-five patients were assigned to hypnotherapy (HYP) and 16 to educational intervention (EDU). Thirty-one patients completed treatments and posttreatment fMRI. RESULTS: Similar symptom reduction was achieved in both groups. Clinically successful treatment (all responders) was associated with significant BOLD attenuation during high-intensity distension in the dorsal and ventral anterior insula (cluster size 142, P = 0.006, and cluster size 101, P = 0.005 respectively). Moreover HYP responders demonstrated a pre-post treatment BOLD attenuation in posterior insula (cluster sizes 59, P = 0.05) while EDU responders had a BOLD attenuation in prefrontal cortex (cluster size 60, P = 0.05). Pre-post differences for expectation conditions were almost exclusively seen in the HYP group. Following treatment, the brain response to distension was similar to that observed in HCs, suggesting that the treatment had a normalising effect on the central processing abnormality of visceral signals in IBS. CONCLUSIONS: The abnormal processing and enhanced perception of visceral stimuli in IBS can be normalised by psychological interventions. Symptom improvement in the treatment groups may be mediated by different brain mechanisms. CLINICAL TRIAL NUMBER: NCT01815164.

Psychological problems in children with burns--parents' reports on the Strengths and Difficulties Questionnaire.

Burns may have a devastating effect on psychological health among children, although previous studies report difficulties as well as positive findings. The aims were to describe the rate of psychological problems in children with burns using a standardised instrument and to explore statistical predictors of these problems. Parents (n=94) of children aged 3-18 years who sustained burns 0.3-9.0 years previously answered the Strengths and Difficulties Questionnaire (SDQ) covering Emotional symptoms, Conduct problems, Hyperactivity/Inattention, Peer relationship problems, Prosocial behaviour, and a Total difficulties score. Questions regarding parental psychological health and family situation were also included. The results for three of the SDQ subscales were close to the norm (10%) regarding the rate of cases where clinical problems were indicated, while the rate of cases indicated for Conduct, Peer problems and Total difficulties was 18-20%. Statistical predictors of the SDQ subscales were mainly parents' psychological symptoms, father's education, and changes in living arrangements. Visible scars were relevant for the Total difficulties score and Hyperactivity/Inattention. In summary, a slightly larger proportion of children with burns had psychological problems than is the case among children in general, and family variables exerted the most influence on parental reports of children's psychological problems.

Study of GH sensitivity in chilean patients with idiopathic short stature.

We hypothesized that some children with idiopathic short stature in Chile might bear heterozygous mutations of the GH receptor. We selected 26 patients (3 females, 23 males) from 112 patients who consulted for idiopathic short stature at the University of Chile. Their chronological age was 8.3 +/- 1.9, and bone age was 6.1 +/- 1.0 yr. Their height was -3.0 +/- 0.7 SDS; IGF-I, -1.2 +/- 1.1 SD; IGF binding protein 3, -0.7 +/- 2.0 SDS; and GH binding protein, 0.4 +/- 0.8 SDS. Patients were admitted, and blood samples were obtained every 20 min to determine GH concentrations overnight. Coding sequences and intron-exon boundaries of exons 2-10 of GH receptor gene were amplified by PCR and subsequently analyzed through single-strand conformational analysis. Mean serum GH concentration, over 12-h, was 0.20 +/- 0.08 nM; pulse amplitude, 0.40 +/- 0.15 nM; number of peaks, 5.8 +/-1.5 peaks/12 h; peak value of GH during the 12-h sampling, 1.03 +/- 0.53 nM; and area under the curve, 151.4 +/- 56.1 nM/12 h. There were positive correlations between mean GH vs. area under the curve (P < 0.001) and GH peak (P < 0.01). The single-strand conformational analysis of the GH receptor gene showed abnormal migration for exon 6 in 9 patients and for exon 10 in 9 patients, which (by sequence analysis) corresponded to 2 polymorphisms of the GH receptor gene: an A-to-G transition in third position of codon 168 in exon 6 and a C-to-A transversion in the first position of codon 526 in exon 10. We further sequenced all coding exons and intron-exon boundaries in the most affected patients (nos. 6, 9, 11, 14, 15, 16, and 23). This analysis revealed a C-to-T transition in codon 161 of exon 6 in patient 23, which results in an amino acid change (Arg to Cys) in an heterozygous form in the patient and his father. In conclusion, the results of our study suggest that, in Chilean patients with idiopathic short stature, GH receptor gene mutations are uncommon, although we cannot exclude mutations that were missed by single-strand conformational analysis or mutations within introns or in the promoter regions of the GH receptor gene.

Cross-talk between Stat5b and estrogen receptor-alpha and -beta in mammary epithelial cells.

Both 17beta-estradiol and prolactin play important roles in the mammary gland, raising the possibility of functional cross-talk between the two signaling pathways. Here, we demonstrate that estrogen receptor-alpha (ERalpha) and -beta (ERbeta) are both able to potentiate transcription from a Stat5-responsive promoter when activated by prolactin. Potentiation was observed not only in the presence of 17beta-estradiol, but also in the presence of anti-estrogens such as tamoxifen and ICI 182,780. The magnitude of the response was dependent on cell-type: in the HC11 mouse mammary epithelial cell line ERbeta potentiates transcription efficiently whereas ERalpha showed low activity. Conversely, in COS-7 cells, both estrogen receptors were active. We show that activation domains in the N-terminus (AF-1) and the C-terminus (AF-2) of the ERs are dispensable for potentiation. The effects are dependent on the presence of an intact DNA-binding/hinge domain, which we show is capable of interacting with Stat5b in vitro and in HC11 cell extracts. We conclude that ERalpha and ERbeta act as coactivators for Stat5b through a mechanism which is independent of AF-1 and AF-2.

Mechanical strain and estrogen activate estrogen receptor alpha in bone cells.

Bone cells' early responses to estrogen and mechanical strain were investigated in the ROS 17/2.8 cell line. Immunoblotting with antiphosphorylated estrogen receptor a (ER-alpha) antibody showed that when these cells were exposed for 10 minutes to estrogen (10(-8) M) or a single period of cyclic dynamic strain (peak 3400 microepsilon, 1 Hz, 600 cycles), there was an increase in the intensity of a 66-kDa band, indicating phosphorylation of ser122 in the amino terminus of ER-alpha. Increased phosphorylation was detected within 5 minutes of exposure to estrogen and 5 minutes after the end of the period of strain. Estrogen and strain also activated the mitogen-activated protein kinase (MAPK) family member extracellular regulated kinase-1 (ERK-1). Increases in ERK activation coincided with increased ER-alpha phosphorylation. Activation of ERK-1 and the phosphorylation of ER-alpha, by both estrogen and strain, were prevented by the MAP kinase kinase (MEK) inhibitor U0126 and the protein kinase A (PKA) inhibitor (PKI). These data support previous suggestions that resident bone cells' early responses to strain and estrogen share a common pathway, which involves ER-alpha. This pathway also appears to involve PKA and ERK-mediated phosphorylation of ser122 within the amino terminus of ER-alpha. Reduced availability of this pathway when estrogen levels are reduced could explain diminished effectiveness of mechanically related control of bone architecture after the menopause.

Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain.

The retinoid X receptor (RXR) is a nuclear receptor that functions as a ligand-activated transcription factor. Little is known about the ligands that activate RXR in vivo. Here, we identified a factor in brain tissue from adult mice that activates RXR in cell-based assays. Purification and analysis of the factor by mass spectrometry revealed that it is docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid that is highly enriched in the adult mammalian brain. Previous work has shown that DHA is essential for brain maturation, and deficiency of DHA in both rodents and humans leads to impaired spatial learning and other abnormalities. These data suggest that DHA may influence neural function through activation of an RXR signaling pathway.

Evidence for extensive distribution of oestrogen receptor alpha-immunoreactivity in the cerebral cortex of adult rats.

The presence of oestrogen receptor alpha (ERalpha)-immunoreactivity (IR) in the cerebral cortex of adult rats has been investigated. Previous studies have reported a negligible presence of ERalpha or ERalpha mRNA in this region of the adult rat brain. We have used immunoprecipitation and immunohistochemistry, with various antibodies and fixatives, to detect this protein in the cingulate cortex. When the tissue was fixed using paraformaldehyde alone only faint ERalpha-IR was observed at this site. In contrast, following fixation either with acrolein (with or without paraformaldehyde) or with a mixture of paraformaldehyde and glutaraldehyde there was extensive ERalpha-IR throughout layers II to VI; this was absent when the antibodies were preincubated with the peptide fragment used in their production. The presence of ERalpha-IR in the nonfixed cingulate cortex of adult rats was confirmed by immunoprecipitation.

Evidence for oestrogen receptor alpha-immunoreactivity in gonadotrophin-releasing hormone-expressing neurones.

Having used the cingulate cortex to demonstrate the validity of our methods for detecting hitherto unrecognized oestrogen receptor alpha (ERalpha)-immunoreactive neurones, we have now employed immunoprecipitation and double-label immunohistochemistry to investigate whether the ERalpha protein is present in gonadotrophin-releasing hormone (GnRH)-containing cells. The immortalized GnRH cell line GT1-7 and GnRH neurones within the rat preoptic area were found to possess ERalpha-immunoreactivity (ERalpha-IR). These observations indicate that oestrogen may regulate the synthesis and release of GnRH by direct actions on GnRH neurones.

Competition between thyroid hormone receptor-associated protein (TRAP) 220 and transcriptional intermediary factor (TIF) 2 for binding to nuclear receptors. Implications for the recruitment of TRAP and p160 coactivator complexes.

Transcriptional activation by nuclear receptors (NRs) involves the concerted action of coactivators, chromatin components, and the basal transcription machinery. Crucial NR coactivators, which target primarily the conserved ligand-regulated activation (AF-2) domain, include p160 family members, such as TIF2, as well as p160-associated coactivators, such as CBP/p300. Because these coactivators possess intrinsic histone acetyltransferase activity, they are believed to function mainly by regulating chromatin-dependent transcriptional activation. Recent evidence suggests the existence of an additional NR coactivator complex, referred to as the thyroid hormone receptor-associated protein (TRAP) complex, which may function more directly as a bridging complex to the basal transcription machinery. TRAP220, the 220-kDa NR-binding subunit of the complex, has been identified in independent studies using both biochemical and genetic approaches. In light of the functional differences identified between p160 and TRAP coactivator complexes in NR activation, we have attempted to compare interaction and functional characteristics of TIF 2 and TRAP220. Our findings imply that competition between the NR-binding subunits of distinct coactivator complexes may act as a putative regulatory step in establishing either a sequential activation cascade or the formation of independent coactivator complexes.

The first step: activation of the Semliki Forest virus spike protein precursor causes a localized conformational change in the trimeric spike.

The structure of the particle formed by the SFVmSQL mutant of Semliki Forest virus (SFV) has been defined by cryo-electron microscopy and image reconstruction to a resolution of 21 A. The SQL mutation blocks the cleavage of p62, the precursor of the spike proteins E2 and E3, which normally occurs in the trans-Golgi. The uncleaved spike protein is insensitive to the low pH treatment that triggers membrane fusion during entry of the wild-type virus. The conformation of the spike in the SFVmSQL particle should correspond to that of the inactive precursor found in the early stages of the secretory pathway. Comparison of this "precursor" structure with that of the mature, wild-type, virus allows visualization of the changes that lead to activation, the first step in the pathway toward fusion. We find that the conformational change in the spike is dramatic but localized. The projecting domains of the spikes are completely separated in the precursor and close to generate a cavity in the mature spike. E1, the fusion peptide-bearing protein, interacts only with the p62 in its own third of the trimer before cleavage and then collapses to form a trimer of heterotrimers (E1E2E3)3 surrounding the cavity, poised for the pH-induced conformational change that leads to fusion. The capsid, transmembrane regions and the spike skirts (thin layers of protein that link spikes above the membrane) remain unchanged by cleavage. Similarly, the interactions of the spikes with the nucleocapsid through the transmembrane domains remain constant. Hence, the interactions that lead to virus assembly are unaffected by the SFVmSQL mutation.

Spectral analysis of heart rate variability in patients with irritable bowel syndrome.

BACKGROUND: Autonomic dysfunction, both adrenergic and cholinergic, has been associated with the irritable bowel syndrome (IBS). The accuracy of the methods in use, however, has been limited by the need for active co-operation by the patients, with consequent difficulties in standardization. The aim of this study was to investigate the function of the autonomic nervous system in patients with IBS by using spectral analysis of the heart rate variability, an accurate method depending very little on patient cooperation. METHODS: Eighteen patients with IBS were compared with 36 sex- and age-matched controls. Spectral analysis of heart rate variability was performed to quantify sympathetic and parasympathetic nerve activity. RESULTS: The patients with IBS had significantly higher sympathetic activity than controls (P = 0.005). There was no significant (P = 0.308) increase in parasympathetic activity. There were no significant differences in heart rate or blood pressure between the patients and controls. CONCLUSION: Spectral analysis of heart rate variability has been used to assess the function of the autonomic nervous system in patients with IBS. IBS patients have significantly increased symphathetic activity, whereas parasympathetic activity does not differ from that of controls.

Ligand-independent activation of the oestrogen receptor by mutation of a conserved tyrosine.

The oestrogen receptor is a member of the nuclear receptor family of transcription factors which, on binding the steroid hormone 17beta-oestradiol, interacts with co-activator proteins and stimulates gene expression. Replacement of a single tyrosine in the hormone-binding domain generated activated forms of the receptor which stimulated transcription in the absence of hormone. This increased activation is related to a decrease in hydrophobicity and a reduction in size of the side chain of the amino acid with which the tyrosine is replaced. Ligand-independent, in common with ligand-dependent transcriptional activation, requires an amphipathic alpha-helix at the C-terminus of the ligand-binding domain which is essential for the interaction of the receptor with a number of potential co-activator proteins. In contrast to the wild-type protein, constitutively active receptors were able to bind both the receptor-interacting protein RIP-140 and the steroid receptor co-activator SRC-1 in a ligand-independent manner, although in the case of SRC-1 this was only evident when the receptors were prebound to DNA. We propose, therefore, that this tyrosine is required to maintain the receptor in a transcriptionally inactive state in the absence of hormone. Modification of this residue may generate a conformational change in the ligand-binding domain of the receptor to form an interacting surface which allows the recruitment of co-activators independent of hormone binding. This suggests that this tyrosine may be a target for a different signalling pathway which forms an alternative mechanism of activating oestrogen receptor-mediated transcription.

Spinal epidural metastasis: implications for spinal analgesia to treat "refractory" cancer pain.

Two hundred one consecutive patients with cancer pain who received intrathecal pain treatment between 1985 and 1993 were included in this retrospective study undertaken to test the hypothesis that epidural metastasis is a common cause of "refractory" cancer pain and that its presence may affect the efficacy and the complication rates of intraspinal pain treatment. Fifty-seven (approximately 28%) patients were investigated by metrizamide myelography, computerized tomography (CT), magnetic resonance imaging (MRI), laminectomy, or neurohistopathology. Epidural metastases were found in 40 (70%) and spinal stenosis in 33 (approximately 58%); 7 patients with total and 26 with partial occlusion of the spinal canal. Presence of epidural metastasis affected catheter insertion complications, daily dosages, and complications of the intrathecal pain treatment only when it was associated with spinal canal stenosis (partial or total). During the period of the intrathecal treatment, the patients with confirmed epidural metastasis and total spinal canal stenosis needed significantly (P < 0.05) higher daily doses of opioid (means = 77 +/- 103 versus 22 +/- 29 mg) and intrathecal bupivacaine (means = 65 +/- 44 versus 33 +/- 20 mg) and had significantly (P < 0.05) higher rates (14% versus 0%) of radicular pain at injection and poor distribution of analgesia than those without epidural metastasis and spinal canal stenosis. In contrast, the rate of occurrence of post-dural puncture headache was significantly (P < 0.05) lower in patients with partial (4%) and total (14%) spinal stenosis than in those without (29%). Unexpected paraplegia occurred in four patients and was due to accidental injury during attempted dural puncture (N = 1) and collapse (due to cerebrospinal fluid leakage leading to "medullary coning" of an unknown epidural metastasis (N = 3).

Ligand-dependent and -independent transactivation by thyroid hormone receptor beta 2 is determined by the structure of the hormone response element.

Chicken thyroid hormone receptor beta 2 (cTR beta 2) is likely to serve specific functions in gene regulation since it possesses a unique N-terminal domain and is expressed in very few tissues. We demonstrate here that TR beta 2 exhibits distinct transactivation properties which are dependent on the availability of ligand and on the structure of the hormone response element. First, a strong ligand-independent transactivation was observed with hormone response elements composed of direct repeats and everted repeats. Second, TR beta 2 was induced by triiodothyronine to transactivate more efficiently than TR beta 0 on palindromic and everted-repeat types of hormone response elements. However, coexpression of the retinoid X receptor reduced the strong transactivation by TR beta 2 but not by TR beta 0 via palindromic response elements, suggesting that TR beta 2 can transactivate as a homodimer. Finally, the N terminus of TR beta 2 contains two distinct transactivation regions rich in tyrosines, which are essential for transactivation. Our results thus show that the activity of the novel transactivating region of TR beta 2 is dependent on the organization of the half-sites in the response element.

Complications of intrathecal opioids and bupivacaine in the treatment of "refractory" cancer pain.

OBJECTIVE: To test the concept that externalized tunneled intrathecal catheters lead to a high risk of complications, such as meningitis and epidural abscess, and therefore should not be used for durations of intrathecal pain treatment of > 1 week. DESIGN: Prospective, cohort, nonrandomized, consecutive, historical control trial. SETTING: Tertiary care center, institutional practice, hospitalized and ambulatory care. PATIENTS: Two hundred adults (107 women, 93 men) with refractory cancer pain treated for 1-575 (median, 33; total, 14,485) days; 79 patients were treated at home for 2-226 (median, 36; total, 4,711) days. All patients had died by the close of the study. INTERVENTIONS: Insertion of intrathecal tunneled nylon (Portex) catheters (223 in 200 patients) with Millipore filters. The catheter hubs were securely fixed to the skin with steel sutures. Standardized care after insertion: (a) daily phone contact with the patients, their families, or the nurses in charge; (b) weekly dressing change at the tunnel outlet by the nurses; (c) refilling of the infusion containers by the nurses; (d) exchange of the infusion systems when empty (within 1 month) and of the antibacterial filter once a month by specially instructed Pain Department nurses. All contact between the connections of the syringes, cassettes, and needles with the operator's hands was carefully avoided during filling and refilling of the infusion containers and exchange of the antibacterial filters; no other aseptic precautions were taken. MAIN OUTCOME MEASURES: We recorded the rates of perfect function and complications of the systems. The rates of complications recorded in this study with externalized tunneled intrathecal catheters are discussed and compared with the rates reported in the literature with externalized (tunneled and non-tunneled) epidural and intrathecal catheters, as well as with internalized (both epidural and intrathecal) catheters connected to subcutaneous ports, reservoirs, and pumps. RESULTS: The following rates (as a percentage of number of patients) of perfect function and complications of the systems were recorded (the ranges of rates reported in the literature are given in parentheses): perfect function of the system, 93% (31-90%); accidental injury of an unknown epidural tumor followed by an epidural hematoma, 0.5% (0-6%); skin breakdown at the insertion site, 2% (2-50%); postdural puncture headache, 15.5% (10%); external leakage of CSF, 3.5% (4-27%); CSF hygroma ("pseudomeningocele"), 1.5% (4-6.25%); hearing loss and Ménière-like syndrome, 0% (12%); pain on injection, 0% with continuous infusion and 4.5% with intermittent injections (3-36% with intermittent injections); catheter tip dislodgement, 1.5% (6-33%); catheter (system) occlusion, 1% (3-12%); accidental catheter withdrawal, 4% (3-22%); catheter (system) leakage, 1.5% (2.1-26.6%); all mechanical complications, 8.5% (10-44%); local (catheter entry site) infection, 0.5% (2-33%); catheter track infection, 0% (6-25%); epidural abscess, 0% (0.6-25%); meningitis, 0.5% (1-25%); systemic infection, 0% (3%); incidence of all infections (n/treatment days), 1/7,242 (1/168-1/2,446). CONCLUSIONS: In our population and with the technique of insertion and care reported here, the use of externalized tunneled intrathecal catheters has not been associated with higher rates of complications when compared with earlier reported rates of externalized epidural catheters and internalized (both epidural and intrathecal) catheters connected to subcutaneously implanted ports, reservoirs, and pumps. The opinion that the use of externalized tunneled intrathecal catheters should be restricted only to patients who need pain treatment for < 1 week (because of the potential risk of infection, particularly meningitis and epidural abscess) is unfounded.