Patient-reported perceptions of care after the introduction of a new advanced cancer nursing role in Sweden.

PURPOSE: Extensive research results show quality improvements associated with advanced cancer nursing roles. Despite this, these roles are not implemented in many countries. The aim of this cross-sectional, population-based study was to compare patients' perception of care, before and after the introduction of a new advanced nursing role, the coordination contact nurse (CCN), in a region in Sweden. METHOD: All patients (with gynaecological, haematological, Head & Neck, upper gastrointestinal cancers) diagnosed in the region the year prior and one-year post introducing the new CCN role were identified from the Swedish Cancer Register. Data were collected using the European Organization of Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire (QLQ-C30 and QLQ-INFO25) and a study specific questionnaire. RESULT: The results, based on baseline (n = 869) and follow-up data (n = 1003), show statistically significant patient-reported improvements after the introduction of the CCN role, regarding health-related patient information (EORTC QLQ- INFO25 global mean score increased from 41.23 to 44.16, p = 0.0006). We found statistically significant improvements related to availability of supportive care resources, e.g. increased reported access to contact nurse (from 53% to 66%, p ≤ 0.0001) and individual written care plans (from 40% to 54%, p < 0.0001). We also found some improvements related to patient involvement and care coordination, but also room for further developments. CONCLUSION: The implementation of the new advanced cancer nursing role may have contributed to important improvements, but it has also identified areas in need of development. Further research with long-term evaluations of CCN roles in other contexts, are both needed and on-going.

The betaine-GABA transporter (BGT1, slc6a12) is predominantly expressed in the liver and at lower levels in the kidneys and at the brain surface.

The Na(+)- and Cl(-)-dependent GABA-betaine transporter (BGT1) has received attention mostly as a protector against osmolarity changes in the kidney and as a potential controller of the neurotransmitter GABA in the brain. Nevertheless, the cellular distribution of BGT1, and its physiological importance, is not fully understood. Here we have quantified mRNA levels using TaqMan real-time PCR, produced a number of BGT1 antibodies, and used these to study BGT1 distribution in mice. BGT1 (protein and mRNA) is predominantly expressed in the liver (sinusoidal hepatocyte plasma membranes) and not in the endothelium. BGT1 is also present in the renal medulla, where it localizes to the basolateral membranes of collecting ducts (particularly at the papilla tip) and the thick ascending limbs of Henle. There is some BGT1 in the leptomeninges, but brain parenchyma, brain blood vessels, ependymal cells, the renal cortex, and the intestine are virtually BGT1 deficient in 1- to 3-mo-old mice. Labeling specificity was assured by processing tissue from BGT1-deficient littermates in parallel as negative controls. Addition of 2.5% sodium chloride to the drinking water for 48 h induced a two- to threefold upregulation of BGT1, tonicity-responsive enhancer binding protein, and sodium-myo-inositol cotransporter 1 (slc5a3) in the renal medulla, but not in the brain and barely in the liver. BGT1-deficient and wild-type mice appeared to tolerate the salt treatment equally well, possibly because betaine is one of several osmolytes. In conclusion, this study suggests that BGT1 plays its main role in the liver, thereby complementing other betaine-transporting carrier proteins (e.g., slc6a20) that are predominantly expressed in the small intestine or kidney rather than the liver.

Deletion of the betaine-GABA transporter (BGT1; slc6a12) gene does not affect seizure thresholds of adult mice.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Once released, it is removed from the extracellular space by cellular uptake catalyzed by GABA transporter proteins. Four GABA transporters (GAT1, GAT2, GAT3 and BGT1) have been identified. Inhibition of the GAT1 by the clinically available anti-epileptic drug tiagabine has been an effective strategy for the treatment of some patients with partial seizures. Recently, the investigational drug EF1502, which inhibits both GAT1 and BGT1, was found to exert an anti-convulsant action synergistic to that of tiagabine, supposedly due to inhibition of BGT1. The present study addresses the role of BGT1 in seizure control and the effect of EF1502 by developing and exploring a new mouse line lacking exons 3-5 of the BGT1 (slc6a12) gene. The deletion of this sequence abolishes the expression of BGT1 mRNA. However, homozygous BGT1-deficient mice have normal development and show seizure susceptibility indistinguishable from that in wild-type mice in a variety of seizure threshold models including: corneal kindling, the minimal clonic and minimal tonic extension seizure threshold tests, the 6Hz seizure threshold test, and the i.v. pentylenetetrazol threshold test. We confirm that BGT1 mRNA is present in the brain, but find that the levels are several hundred times lower than those of GAT1 mRNA; possibly explaining the apparent lack of phenotype. In conclusion, the present results do not support a role for BGT1 in the control of seizure susceptibility and cannot provide a mechanistic understanding of the synergism that has been previously reported with tiagabine and EF1502.

Designed fluorescent probes reveal interactions between amyloid-beta(1-40) peptides and GM1 gangliosides in micelles and lipid vesicles.

A hallmark of the common Alzheimer's disease (AD) is the pathological conversion of its amphiphatic amyloid-beta (Abeta) peptide into neurotoxic aggregates. In AD patients, these aggregates are often found to be tightly associated with neuronal G(M1) ganglioside lipids, suggesting an involvement of G(M1) not only in aggregate formation but also in neurotoxic events. Significant interactions were found between micelles made of newly synthesized fluorescent G(M1) gangliosides labeled in the polar headgroup or the hydrophobic chain and Abeta(1-40) peptide labeled with a BODIPY-FL-C1 fluorophore at positions 12 and 26, respectively. From an analysis of energy transfer between the different fluorescence labels and their location in the molecules, we were able to place the Abeta peptide inside G(M1) micelles, close to the hydrophobic-hydrophilic interface. Large unilamellar vesicles composed of a raftlike G(M1)/bSM/cholesterol lipid composition doped with labeled G(M1) at various positions also interact with labeled Abeta peptide tagged to amino acids 2 or 26. A faster energy transfer was observed from the Abeta peptide to bilayers doped with 581/591-BODIPY-C(11)-G(M1) in the nonpolar part of the lipid compared with 581/591-BODIPY-C(5)-G(M1) residing in the polar headgroup. These data are compatible with a clustering process of G(M1) molecules, an effect that not only increases the Abeta peptide affinity, but also causes a pronounced Abeta peptide penetration deeper into the lipid membrane; all these factors are potentially involved in Abeta peptide aggregate formation due to an altered ganglioside metabolism found in AD patients.

The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-kappaB target genes by interaction with NFKBIZ.

FUS (also called TLS), EWSR1 and TAF15 (also called TAF2N) are related genes involved in tumor type-specific fusion oncogenes in human malignancies. The FUS-DDIT3 fusion oncogene results from a t(12;16)(q13;p11) chromosome translocation and has a causative role in the initiation of myxoid/round cell liposarcomas (MLS/RCLS). The FUS-DDIT3 protein induces increased expression of the CAAT/enhancer-binding protein (C/EBP) and nuclear factor-kappaB (NF-kappaB)-controlled gene IL8, and the N-terminal FUS part is required for this activation. Chromatin immunoprecipitation analysis showed that FUS-DDIT3 binds the IL8 promoter. Expression studies of the IL8 promoter harboring a C/EBP-NF-kappaB composite site pinpointed the importance of NF-kappaB for IL8 expression in FUS-DDIT3-expressing cells. We therefore probed for possible interaction of FUS-DDIT3 with members of the NF-kappaB family. The nuclear factor NFKBIZ colocalizes with FUS-DDIT3 in nuclear structures, and immunoprecipitation experiments showed that FUS-DDIT3 binds the C-terminal of NFKBIZ. We also report that additional NF-kappaB-controlled genes are upregulated at the mRNA level in FUS-DDIT3-expressing cell lines and they can be induced by NFKBIZ. Taken together, the results indicate that FUS-DDIT3 deregulates some NF-kappaB-controlled genes through interactions with NFKBIZ. Similar mechanisms may be a part of the transformation process in other tumor types carrying FUS, EWSR1 and TAF15 containing fusion oncogenes.

Formation of cytotoxic transthyretin is not dependent on inter-molecular disulphide bridges commonly found within the amyloid form.

Familial amyloidotic polyneuropathy (FAP) is linked to destabilising point mutations in the human plasma protein transthyretin (TTR). Consistent with similar amyloid disorders, low molecular weight TTR oligomers have been shown to exert the major cytotoxic effect. The amyloid structure of TTR contains non-native inter-molecular disulphide linkages via the cysteine at position 10 (Cys10). Moreover, substitution of Cys10 in a mouse model for TTR-amyloidosis abolishes TTR deposits, indicating an important role of Cys10 in FAP pathogenesis. However, the role of disulphide bridges in TTR cytotoxicity has not been elucidated. By probing Cys10Ser TTR variants to the human neuroblastoma SH-SY5Y cell line, we have addressed this question, and our results clearly show that formation of an inter-molecular disulphide bridge is not a pre-requisite for TTR cytotoxicity. This finding suggests that prevention of inter-molecular TTR disulphide bridges as a therapeutic intervention will not impair the cytotoxic potential of TTR.

'If only I manage to get home I'll get better'--interviews with stroke patients after emergency stay in hospital on their experiences and needs.

OBJECTIVE: To find out about the experiences of stroke patients concerning their falling ill, their stay in hospital, discharge and homecoming. DESIGN: Qualitative methods using in-depth interviews. SUBJECTS AND SETTING: Nine strategically chosen patients and in five cases near family members were interviewed in their homes four months post stroke and following care at the Stroke Centre, University Hospital of Northern Sweden, Umeå. RESULTS: Three main categories with subcategories were brought to the fore from the interviews: 'Responsible and implicated', 'Depersonalized object for caring measures' and 'The striving for repersonalization and autonomy'. The patients got the most important insights and understanding about their state and the consequences when they came home. CONCLUSION: The three main categories that were found mirror the crisis which becoming ill entails and the process gone through when the individual takes control again of his or her life. The patients saw coming home as an important factor for their recovery and rehabilitation. The health care system needs to develop strategies to make use of the power of this attitude with the patients and to use the patients' own milieu in rehabilitation after stroke.

Menopausal transition and psychological development.

OBJECTIVE: To study women's psychological development during menopause and to examine the relationship between women's appraisal of menopause and symptom reporting. DESIGN: A population-based sample of 130 healthy women was assessed annually for 5 consecutive years using semistructured interviews, a menopausal symptom rating scale, and the Symptom Checklist-90 rating scale. RESULTS: Qualitative analyses of the interviews showed that the majority of the women (57%) had neutral beliefs about menopause, whereas 31% were pessimistic and 12% were optimistic. Optimistic and neutral expectations were associated with low levels of symptom reporting, whereas the pessimistic appraisal was significantly related to elevated symptom scores. The majority of the neutral and pessimistic women reappraised menopause during the study period, and at the last follow-up, 67% appraised menopause positively. A positive reappraisal among the initially pessimistic women was associated with more frequent statements about personal growth compared with the other subgroups. CONCLUSIONS: Menopause has a developmental potential and is a positive period for most women.

Relationship between fibrinolytic activity and gingival inflammatory reaction in young individuals.

The fibrinolytic system (the plasminogen activating system) is involved in several physiological and pathological processes. Through the transformation of plasminogen to the aggressive broad spectrum protease plasmin, potent enzymatic activity is released. Plasmin acts directly on connective tissue components, and indirectly by activating proforms of the metalloproteinases. The destructive potential of the fibrinolytic system may thus be of importance for the initiation and progression of periodontal diseases. Earlier studies have shown high concentrations of the plasminogen activator t-PA and its inhibitor PAI-2 in gingival crevicular fluid (GCF) as well as enhanced concentrations in areas of gingival inflammation. The aim of this study was to investigate a possible relationship between the gingival inflammatory reactivity and the fibrinolytic activity in gingival crevicular fluid. Thirty-one young individuals took part in the study. Gingival Index scores and Plaque Index scores were assessed and used to formulate a score expressing an individuals' inflammatory response to microbial plaque levels (Relative G/P score). The fibrinolytic activity of GCF was assessed with a fibrin gel lysis assay, and the levels of t-PA and PAI-2 were assayed with ELISAs. All samples showed fibrinolytic activity. A positive correlation between the fibrinolytic activity and Relative G/P score was found. Thus, in individuals with an enhanced reactivity to dental plaque, a higher plasminogen activating activity in GCF was seen. This indicates a higher potential for tissue proteolysis in these individuals, possibly facilitating spread and deeper involvement of the lesions.

Heparin-binding protein (HBP/CAP37): a missing link in neutrophil-evoked alteration of vascular permeability.

Polymorphonuclear leukocyte infiltration into tissues in host defense and inflammatory disease causes increased vascular permeability and edema formation through unknown mechanisms. Here, we report the involvement of a paracrine mechanism in neutrophil-evoked alteration in endothelial barrier function. We show that upon neutrophil adhesion to the endothelial lining, leukocytic beta2 integrin signaling triggers the release of neutrophil-borne heparin-binding protein (HBP), also known as CAP37/azurocidin, a member of the serprocidin family of neutrophil cationic proteins. HBP induced Ca++-dependent cytoskeletal rearrangement and intercellular gap formation in endothelial-cell monolayers in vitro, and increased macromolecular efflux in microvessels in vivo. Moreover, selective inactivation of HBP prevented the neutrophils from inducing endothelial hyperpermeability. Our data suggest a fundamental role of neutrophil-derived HBP in the vascular response to neutrophil trafficking in inflammation. Targeting this molecule in inflammatory disease conditions offers a new strategy for prevention of endothelial barrier dysfunction caused by misdirected leukocyte activation.

Restorations with extensive dentin/enamel-bonded ceramic coverage. A 5-year follow-up.

The durability of restorations with extensive dentin/enamel-bonded posterior partial and complete ceramic coverages were investigated. The effect of luting with a dual-cured and a self-cured luting agent was also studied. In 110 patients, 182 ceramic coverages (IPS Empress) were placed. In 58 restorations, Syntac was used in combination with the dual-cured resin composite Variolink. In the other restorations luted with the chemically cured resin composite Bisfil 2B, 25 were bonded with Gluma, 57 with Allbond 2, and 42 with Syntac. Of the 182 ceramics, 13 (7.1%) were assessed as non-acceptable after a mean observation period of 4.9 yr (range 4.3 7.5 yr). The reasons for failure were fracture (5), lost restorations (4), secondary caries (3) and endodontic treatment (1). No significant differences in failure rate were seen between the two luting agents or between the three dentin-bonding agents. Ceramic coverages placed on non-vital teeth failed in 9.7% of cases (3/31) and on vital teeth in 6.6% (10/151). The success rate of the dentin-enamel-bonded ceramic coverages reduces the need for a traditional full-coverage therapy and/or post or pin(s) and core placement. The technique investigated showed many clinical advantages such as less destruction of healthy tissue, and avoidance of endodontic treatment and/or deep cervical placement of restoration margins.

Capture of a dimeric intermediate during transthyretin amyloid formation.

Point mutations in the human plasma protein transthyretin are associated with the neurological disorder familial amyloidosis with polyneuropathy type 1. The disease is characterized by amyloid fibril deposits causing damage at the site of deposition. Substitution of two amino acids in the hydrophobic core of transthyretin lead to a mutant that was very prone to form amyloid. In addition, this mutant has also been shown to induce a toxic response on a neuroblastoma cell line. Renaturation of the transthyretin mutant at low temperature facilitated the isolation of an amyloid-forming intermediate state having the apparent size of a dimer. Increasing the temperature effectively enhanced the rate of interconversion from a partly denatured protein to mature amyloid. Using circular dichroism the beta-sheet content of the formed mature fibrils was significantly lower than that of the native fold of transthyretin. Morphology studies using electron microscopy also indicated a temperature-dependent transformation from amorphous aggregates toward mature amyloid fibrils. In addition, 1-anilino-8-naphtalenesulfonate fluorescence studies suggested the loss of the thyroxin-binding channel within both the isolated intermediate and the mature fibrils.

Antibody recognition of amyloidogenic transthyretin variants in serum of patients with familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy (FAP) is a late-onset inherited disease characterized by the deposition of amyloid fibrils. FAP is associated with mutations on the transthyretin (TTR) gene. A monoclonal antibody, MAb 39-44, reacting with high molecular weight aggregates of TTR but not with tetrameric TTR has recently been generated and characterized. This antibody recognizes a cryptic epitope that is expressed in isolated recombinant amyloidogenic mutants and in ex vivo amyloid. In the present work we show that this amyloid-specific antibody specifically recognizes in a direct enzyme-linked immunoassay (ELISA) plasma TTR from carriers of various mutations associated with FAP, both in asymptomatic individuals and in patients. In contrast, it does not react with plasma TTR from healthy individuals or that from carriers of nonpathogenic mutations. Using the ELISA developed in this study we identified three different TTR mutations in Portuguese patients with neuropathy of unknown cause, later shown to have amyloid tissue deposition. This antibody recognizes conformations that express cryptic epitopes shared by amyloidogenic TTR variants associated with FAP, not present among nonpathogenic TTR molecules. This antibody will contribute to further identify and characterize intermediates of the amyloidogenic cascade. In addition, it will also be useful for screening amyloidogenic TTR mutations in patients with neuropathy of unknown cause, prior to precise molecular diagnosis using protein and/or DNA analysis.

Kinetics of the AHL regulatory system in a model biofilm system: how many bacteria constitute a "quorum"?

Acylated homoserine lactones (AHLs) regulate a wide variety of phenotypes in Gram-negative bacteria. Most research suggests that AHL-mediated phenotypes are not expressed in populations until late logarithmic phase or stationary phase. Here, we model how the concentration of AHLs inside bacterial cells and in a biofilm changes over time as a function of population growth rate, diffusion of AHLs and the rate of autoinduction. Our theoretical results show that the concentration of AHLs inside a single bacterium (and by implication induction of a phenotype) has a non-trivial behaviour over time, and often exhibits a rapid increase early in population growth. This rapid increase is followed by a plateau, followed by another rise in the concentration of AHLs, to a second plateau. High concentrations of AHLs inside the bacterial cell early in population growth are positively affected by slow diffusion rates out of the cell and the biofilm, slow bacterial growth rates and fast autoinduction. In contrast, fast growth rates, slow autoinduction rates and high diffusion rates result in a high concentration plateau in stationary phase. More generally, the density-dependent nature of AHL regulation can be viewed as a trade-off between factors that dilute intracellular concentrations of AHLs (diffusion out of the cell, cell division), and those that increase concentrations (a slowing or restriction of diffusion or growth, or autoinduction). These results suggest that expression of AHL-mediated phenotypes can occur at relatively low cell densities and low external/environmental AHL concentrations.

The beta-slip: a novel concept in transthyretin amyloidosis.

Transthyretin is a tetrameric plasma protein associated with two forms of amyloid disease. The structure of the highly amyloidogenic transthyretin triple mutant TTRG53S/E54D/L55S determined at 2.3 A resolution reveals a novel conformation: the beta-slip. A three-residue shift in beta strand D places Leu-58 at the position normally occupied by Leu-55 now mutated to serine. The beta-slip is best defined in two of the four monomers, where it makes new protein-protein interactions to an area normally involved in complex formation with retinol-binding protein. This interaction creates unique packing arrangements, where two protein helices combine to form a double helix in agreement with fiber diffraction and electron microscopy data. Based on these findings, a novel model for transthyretin amyloid formation is presented.

Analysis of magnetic resonance imaging acoustic noise generated by a 4.7 T experimental system.

High intensity acoustic noise is an undesirable side-effect in magnetic resonance imaging (MRI) that can cause discomfort and hearing loss in patients and may be an impediment in functional MRI (fMRI) studies of the auditory system. Experimental MRI systems with high magnetic field strengths may generate acoustic noise of higher sound pressure levels (SPLs) than conventional 1.0 and 1.5 T clinical systems. We measured the SPL and spectral content of the acoustic noise generated by the Bruker Biospect 47/40 4.7 T experimental MRI system during scanning sequences commonly used in animal testing. Each sequence generated acoustic noise of high SPL, rapid pulse rates, amplitude-modulated pulse envelopes and multi-peaked spectra. The rapid acquisition with enhancement sequence with a 0.25 mm slice thickness generated SPLs of up to 129 dB peak SPL and 130 dB (A). Fourier analysis of the spectral content of the acoustic noise generated by each MRI sequence showed a wide band of acoustic energy with spectral peaks from 0.2-5 kHz. The intense MRI acoustic impulse noise generated by the 4.7 T system may cause masking of stimuli used in fMRI of the auditory cortex, reduce the hearing acuity of experimental animals and present a risk for unprotected human ears.

Search for intermediate structures in transthyretin fibrillogenesis: soluble tetrameric Tyr78Phe TTR expresses a specific epitope present only in amyloid fibrils.

Familial Amyloidotic Polyneuropathy (FAP) is caused by the assembly of TTR into an insoluble beta-sheet. The TTR tetramer is thought to dissociate into monomeric intermediates and subsequently polymerise into the pathogenic amyloid form. The biochemical mechanism behind this transformation is unknown. We characterised intermediate TTR structures in the in vitro amyloidogenesis pathway by destabilising the AB loop through substitution of residue 78. Changes at this residue, should destabilise the TTR tetrameric fold, based on the known crystallographic structure of a Leu55Pro transthyretin variant. We generated a soluble tetrameric form of TTR that is recognised by a monoclonal antibody, previously reported to react only with highly amyloidogenic mutant proteins lacking the tetrameric native fold and with amyloid fibrils. BIAcore system analysis showed that Tyr78Phe had similar binding properties as synthetic fibrils. The affinity of this interaction was 10(7) M(-1). We suggest that the tetrameric structure of Tyr78Phe is altered due to the loosening of the AB loops of the tetramer, leading to a structure that might represent an early intermediate in the fibrillogenesis pathway.

A comparative analysis of 23 structures of the amyloidogenic protein transthyretin.

Self-assembly of the human plasma protein transthyretin (TTR) into unbranched insoluble amyloid fibrils occurs as a result of point mutations that destabilize the molecule, leading to conformational changes. The tertiary structure of native soluble TTR and many of its disease-causing mutants have been determined. Several independent studies by X-ray crystallography have suggested structural differences between TTR variants which are claimed to be of significance for amyloid formation. As these changes are minor and not consistent between the studies, we have compared all TTR structures available at the protein data bank including three wild-types, three non-amyloidogenic mutants, seven amyloidogenic mutants and nine complexes. The reference for this study is a new 1.5 A resolution structure of human wild-type TTR refined to an R-factor/R-free of 18.6 %/21.6 %. The present findings are discussed in the light of the previous structural studies of TTR variants, and show the reported structural differences to be non-significant.

Naming speed, phonological awareness and the initial stage of learning to read.

Phonological awareness in kindergarten and rapid naming of objects in Grade 1 were used as predictors of reading achievement in Grade 1. Two reading measures were used: oral decoding of both words and pseudowords. They were found to be highly correlated. Both rapid naming and phonological awareness accounted for independent variance in reading achievement except for pseudoword reading, where rapid naming did not contribute significantly after the effect of phonemic awareness had been accounted for. Phonological awareness was the stronger predictor and a large part of the variance was shared between it and rapid naming. The rapid naming testing procedure functioned well and its potential as a research and diagnostic tool is discussed.

Defective heparan sulfate biosynthesis and neonatal lethality in mice lacking N-deacetylase/N-sulfotransferase-1.

Heparan sulfate is a sulfated polysaccharide present on most cell surfaces and in the extracellular matrix. In vivo functions of heparan sulfate can be studied in mouse strains lacking enzymes involved in the biosynthesis of heparan sulfate. Glucosaminyl N-deacetylase/N-sulfotransferase (NDST) catalyzes the first modifying step in the biosynthesis of the polysaccharide. This bifunctional enzyme occurs in several isoforms. We here report that targeted gene disruption of NDST-1 in the mouse results in a structural alteration of heparan sulfate in most basement membranes as revealed by immunohistochemical staining of fetal tissue sections using antibodies raised against heparan sulfate. Biochemical analysis of heparan sulfate purified from fibroblast cultures, lung, and liver of NDST-1-deficient embryos demonstrated a dramatic reduction in N-sulfate content. Most NDST-1-deficient embryos survive until birth; however, they turn out to be cyanotic and die neonatally in a condition resembling respiratory distress syndrome. In addition, a minor proportion of NDST-1-deficient embryos die during the embryonic period. The cause of the embryonic lethality is still obscure, but incompletely penetrant defects of the skull and the eyes have been observed.