Comparison of independent and combined effects of the neurotensin receptor agonist, JMV-449, and incretin mimetics on pancreatic islet function, glucose homeostasis and appetite control.

BACKGROUND: Neurotensin receptor activation augments the biosctivity of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). JMV-449, a C-terminal neurotensin-like fragment with a reduced peptide bond, represents a neurotensin receptor agonist. METHODS: The present study assessed the actions of JMV-449 on pancreatic beta-cells alone, and in combination with GIP and GLP-1. Further studies examined the impact of JMV-449 and incretin mimetics on glucose homeostasis and appetite control in mice. RESULTS: JMV-449 was resistant to plasma enzyme degradation and induced noticeable dose-dependent insulin-releasing actions in BRIN-BD11 beta-cells. In combination with either GIP or GLP-1, JMV-449 augmented (P < 0.05) the insulinotropic actions of both hormones, as well as enhancing (P < 0.001) insulin secretory activity of both incretin peptides. JMV-449 also increased beta-cell proliferation and induced significant benefits on beta-cell survival in response to cytokine-induced apoptosis. JMV-449 (25 nmol/kg) inhibited (P < 0.05-P < 0.001) food intake in overnight fasted lean mice, and enhanced (P < 0.01) the appetite supressing effects of an enzymatically stable GLP-1 mimetic. When injected co-jointly with glucose, JMV-449 evoked glucose lowering actions, but more interestingly significantly augmented (P < 0.05) the glucose lowering effects of established long-acting GIP and GLP-1 receptor mimetics. In terms of glucose-induced insulin secretion, only GIP receptor signalling was associated with increases in insulin concentrations, and this was not enhanced by JMV-449. CONCLUSION: JMV-449 is a neurotensin receptor agonist that positively augments key aspects of the biological action profile of GIP and GLP-1. GENERAL SIGNIFICANCE: These observations emphasise the, yet untapped, therapeutic potential of combined neurotensin and incretin receptor signalling for diabetes.

Understanding the non-pharmacological correlates of self-reported efficacy of antidepressants.

OBJECTIVE: To explore the non-pharmacological correlates of the perceived effectiveness of antidepressants (ADs), thereby enhancing understanding of the mechanisms involved in recovery from depression while taking ADs. METHOD: An online survey was completed by 1781 New Zealand adults who had taken ADs in the previous 5 years. RESULTS: All 18 psychosocial variables measured were associated with depression reduction, and 16 with improved quality of life (QoL). Logistic regression models revealed that the quality of the relationship with the prescriber was related to both depression reduction and improved QoL. In addition, depression reduction was related to younger age, higher income, being fully informed about ADs by the prescriber, fewer social causal beliefs for depression and not having lost a loved one in the 2 months prior to prescription. Furthermore, both outcome measures were positively related to belief in 'chemical' rather than 'placebo' effects. CONCLUSION: There are multiple non-pharmacological processes involved in recovery while taking ADs. Enhancing them, for example focusing on the prescriber-patient relationship and giving more information, may enhance recovery rates, with or without ADs.

Predicting long-term recovery from depression in community settings in Western Europe: evidence from ODIN.

OBJECTIVE: To test the impact of socio-economic and psychological adversity and healthcare on long-term recovery from depression. METHOD: A community sample of 347 people with depressive disorders was followed up after 9 years. Baseline socio-economic adversity, social support, healthcare use, and psychiatric history were identified. Respondents completed self-report instruments on current depressive status (Beck depression inventory) and longstanding psychosocial adversity (sexual, physical or emotional abuse). Univariate analyses tested for association between recovery and respondent characteristics. RESULTS: Follow-up was achieved for 182 (52%) of the sample, of whom 75 (41%) indicated recovery from depression. Psychological adversity definitely and socio-economic adversity probably were associated with lack of recovery. Baseline healthcare had no apparent impact on outcome. Rurality and support after life events were associated with recovery. History of depression was associated with non-recovery. CONCLUSION: Psychological adversity is, and socio-economic adversity may be, associated with long-term non-recovery from depression in community settings.

Recruitment difficulties in a home telecare trial.

We analysed the difficulties encountered in recruiting predominantly older patients, suffering from an acute exacerbation of a chronic illness, to a randomized controlled trial of home telecare. Of 653 patients approached for study participation, after full assessment, 80% (519) met the trial eligibility criteria. Of these, 104 (20%) consented to study participation and 415 (80%) refused. A logistic regression model was constructed to examine independent effects of patient factors on probability of trial participation. Only two independent variables were associated with decreased likelihood of consent: increasing age (1 year older: odds ratio [OR] = 0.96); and being on inhaled steroid medication (OR = 0.60). The most common reason for refusal to participate, accounting for almost one-third of respondents, was a stated preference for a face-to-face nurse visiting service rather than a telecare service. Perhaps home telecare services should continue to be targeted at the more stable chronically ill population and not at those suffering from acute illness.

Patient and provider perspectives on home telecare: preliminary results from a randomized controlled trial.

A randomized controlled trial of home telecare for the management of acute exacerbations of chronic obstructive pulmonary disease has been undertaken in the north-west of England. A videophone was used that communicates via the ordinary telephone network. The intervention period for each participant was two weeks. Participants in the telecare arm of the trial were asked to complete logbooks to record their experiences of each telecare encounter. A simple, self-completed, 10-item questionnaire was used that consisted of a Likert scale, ranging from 1 (totally disagree) to 5 (totally agree). Fourteen nurses completed 150 logbooks and 22 patients completed 145 logbooks. These results demonstrate significant differences in perception between patients and their health-care providers with regard to telecare encounters across all the domains addressed. Participating patients consistently demonstrated more positive views of the telecare encounters than their healthcare providers.

Lessons from the implementation of a home telecare service.

We conducted a qualitative evaluation of the introduction of a telenursing service. The service used an analogue videophone linked with a physiological monitoring device, which allowed the transmission of data between the patient's home and the hospital. A researcher kept a detailed diary of day-to-day activity for the first year of the project. Computer software for qualitative data analysis was used to code the text and the analysis followed the principles of constant comparison. The diary entries documented how the commercially available equipment was adapted to suit the organization and content of the nurses' work. The nurses made a number of suggestions to improve the user-friendliness of the equipment. The technology, the existing home care service (the comparison arm of the study) and the randomized controlled trial itself all underwent continuous change. The traditional randomized control design of trial has limitations in this situation, and there is a need for more realistic trial designs.

Patient-practitioner agreement: does it matter?

BACKGROUND: Good communication is a crucial clinical skill. Previous research demonstrated better clinical outcomes when practitioners and patients agree about the nature of patients' core presenting complaints. We investigated the nature of this agreement and its impact on outcome among depressed primary care patients. METHOD: We compared presenting problem formulations completed by patients, GPs and therapists in a primary care randomized controlled trial of cognitive-behavioural therapy and non-directive counselling for depression. Participants compiled formulations from a list of 13 potential problems of self-completed questionnaires. Subjects scored at least 14 on the Beck Depression Inventory (BDI) at baseline. Outcome measure for this study included BDI at 4 and 12 months, failure to attend for therapy when referred, dropout from therapy and patient satisfaction. RESULTS: Among 464 trial patients, 395 received therapy. Patient baseline problem formulations included significantly more items than GPs, who identified significantly more items than therapists. Agreement levels varied according to a range of patient and professional variables. While patients in complete agreement with their therapists about their main problem after assessment had lower average BDI scores at 12 months (9.7 v. 12.8, P=0.03); we found no other significant associations between the extent of agreement and clinical outcome. There were significant (but relatively weak) associations between agreement and aspects of patient satisfaction. CONCLUSION: Our results suggest that detailed mutual understanding of the presenting complaints may be less important than agreement that the core problem is psychological, and that referral for psychological therapy is appropriate.

PML bodies associate specifically with the MHC gene cluster in interphase nuclei.

Promyelocytic leukemia (PML) bodies are nuclear multi-protein domains. The observations that viruses transcribe their genomes adjacent to PML bodies and that nascent RNA accumulates at their periphery suggest that PML bodies function in transcription. We have used immuno-FISH in primary human fibroblasts to determine the 3D spatial organisation of gene-rich and gene-poor chromosomal regions relative to PML bodies. We find a highly non-random association of the gene-rich major histocompatibilty complex (MHC) on chromosome 6 with PML bodies. This association is specific for the centromeric end of the MHC and extends over a genomic region of at least 1.6 megabases. We also show that PML association is maintained when a subsection of this region is integrated into another chromosomal location. This is the first demonstration that PML bodies have specific chromosomal associations and supports a model for PML bodies as part of a functional nuclear compartment.

PML protein isoforms and the RBCC/TRIM motif.

PML is a component of a multiprotein complex, termed nuclear bodies, and the PML protein was originally discovered in patients suffering from acute promyelocytic leukaemia (APL). APL is associated with a reciprocal chromosomal translocation of chromosomes 15 and 17, which results in a fusion protein comprising PML and the retinoic acid receptor alpha. The PML genomic locus is approximately 35 kb and is subdivided into nine exons. A large number of alternative spliced transcripts are synthesized from the PML gene, resulting in a variety of PML proteins ranging in molecular weight from 48-97 kDa. In this review we summarize the data on the known PML isoforms and splice variants and present a new unifying nomenclature. Although, the function/s of the PML variants are unclear, all PML isoforms contain an identical N-terminal region, suggesting that these sequences are indispensable for function, but differ in their C-terminal sequences. The N-terminal region harbours a RING-finger, two B-boxes and a predicted alpha-helical Coiled-Coil domain, that together form the RBCC/TRIM motif found in a large family of proteins. In PML this motif is essential for PML nuclear body formation in vivo and PML-homo and hetero interactions conferring growth suppressor, apoptotic and anti-viral activities. In APL oligomerization mediated by the RBCC/TRIM motif is essential for the transformation potential of the PML-RARalpha fusion protein.

What proportion of patients refuse consent to data collection from their records for research purposes?

In a randomised trial of the implementation of guidelines for asthma and angina, we sent questionnaires that included a request for consent to collect data from the patient's clinical records to 5069 patients in 81 general practices. Of these 3429 (67.6%) responded, of whom 335 (9.8% [95%, CI = 8.8%-10.8%]) refused consent. We conclude that consent should always be sought unless a research ethics committee has waived this requirement for pressing reasons.

Pressure sore care.

Christopher Shiels and Brenda Roe report on a survey into the prevalence and care of pressure sores among older people living in residential care and nursing homes in Liverpool. Setting up appropriate information systems and auditing available pressure-relieving equipment are just two of a number of important recommendations arising from the survey.

Pressure sore care.

This paper reports the conduct, results and implications of a survey of residential and nursing homes for elderly people in Liverpool, with particular reference to the prevalence and care of pressure sores. The objectives of the survey were to establish prevalence rates, to collect data on the process of preventing and managing pressure sores, and to look at differences between the two types of home sector in terms of care policy and practice.

The human polycomb group complex associates with pericentromeric heterochromatin to form a novel nuclear domain.

The Polycomb group (PcG) complex is a chromatin-associated multiprotein complex, involved in the stable repression of homeotic gene activity in Drosophila. Recently, a mammalian PcG complex has been identified with several PcG proteins implicated in the regulation of Hox gene expression. Although the mammalian PcG complex appears analogous to the complex in Drosophila, the molecular mechanisms and functions for the mammalian PcG complex remain unknown. Here we describe a detailed characterization of the human PcG complex in terms of cellular localization and chromosomal association. By using antibodies that specifically recognize three human PcG proteins- RING1, BMI1, and hPc2-we demonstrate in a number of human cell lines that the PcG complex forms a unique discrete nuclear structure that we term PcG bodies. PcG bodies are prominent novel nuclear structures with the larger PcG foci generally localized near the centromeres, as visualized with a kinetochore antibody marker. In both normal fetal and adult fibroblasts, PcG bodies are not randomly dispersed, but appear clustered into defined areas within the nucleus. We show in three different human cell lines that the PcG complex can tightly associate with large pericentromeric heterochromatin regions (1q12) on chromosome 1, and with related pericentromeric sequences on different chromosomes, providing evidence for a mammalian PcG-heterochromatin association. Furthermore, these heterochromatin-bound PcG complexes remain stably associated throughout mitosis, thereby allowing the potential inheritance of the PcG complex through successive cell divisions. We discuss these results in terms of the known function of the PcG complex as a transcriptional repression complex.

Contiguous arrays of satellites 1, 3, and beta form a 1.5-Mb domain on chromosome 22p.

The centromeric heterochromatin of all the human chromosomes is composed of megabases of tandemly repeated satellite DNA. Some of these sequences have been implicated in centromere formation and/or segregation but the arrangement of most of them on a large scale remains largely uncharacterized because of the difficulties in analyzing repetitive DNA. The alpha satellite is the best studied and is present in large tandem arrays at all centromeres, but satellites 1, 3, and beta have also been detected on a number of chromosomes. Here we have used FISH to extended DNA fibers to analyze these satellites on the short arm of the acrocentric chromosome 22. The satellite sequences were found to form a continuous domain spanning about 1.5 Mb and consisting of a major block of satellite 1 flanked by two blocks of beta satellite and three blocks of satellite 3. These six blocks of satellite DNA appear to form contiguous arrays with little intervening DNA.

Analysis of ribosomal and alphoid repetitive DNA by fiber-FISH.

We have used fluorescence in situ hybridization to extended DNA fibers (fiber-FISH) to analyse the alpha-satellite and rDNA arrays on a human chromosome 22. The rDNA could be seen as a string of signals spanning about 430 kb. The bulk of the alphoid DNA was found in a single large array of about 2.6 Mb.

The inter-rate reliability of a generic measure of severity of illness.

BACKGROUND: There has been increasing interest in the development of measures to quantify baseline severity of illness and thus provide a more meaningful interpretation of health outcomes. OBJECTIVE: We aimed to assess the inter-rater reliability of a generic measure of illness severity, the Duke University Severity of Illness (DUSOI) checklist. METHODS: Selected general practices and hospital outpatient departments across Tyneside and Humberside in the UK were used as the setting. Thirty-three clinicians were posted copies of the same set of 14 patient records and asked to rate the severity of illness of each patient using the DUSOI. The subjects were 27 GPs, three consultant chest physicians and three diabetologists. The main outcome measures were: (i) intraclass correlation coefficients used to express clinician agreement upon severity scores; and (ii) a 'gold standard', constructed in order to assess clinician agreement upon the health problems identified in the patient record to be considered as constituents of overall severity. RESULTS: It was found that the degree of inter-rater reliability of severity scoring was satisfactory, with an intraclass correlation coefficient of 0.43. In terms of identification of problems to be rated, there was considerable agreement between raters and a specially compiled 'gold standard' of health problems. CONCLUSION: The DUSOI has potential use in routine clinical practice, but strategies should be developed in order to maximize the reliability of rating illness severity on such a generic measure.

Accuracy and reliability of assessment of severity of illness before and after an educational intervention.

Severity-of-illness measurement is considered to be an important factor in the risk adjustment of medical outcomes. However, for those measures that involve a high level of clinical judgment, strategies have to be developed to maximize the consistency of rating severity that can be implemented, especially when rating is based upon medical record review. A group of 25 clinicians were sent the same set of 14 patient records, and requested to use the Duke University Severity of Illness (DUSOI) checklist to rate the severity of patients' illness. Written instructions for the use of this instrument were provided. A short educational intervention was than made by the research team, and the clinicians were sent the same set of records to be rated again. Any improvement in the accuracy and reliability of severity assessment over the two ratings was then studied. The educational intervention resulted in identification of fewer irrelevant health problems. However, it had little impact upon the reliability of severity scoring itself, as measured by the intraclass correlation coefficient. Measuring severity of illness is a conceptually complex procedure. However, given its role in outcome interpretation, it may be worth pursuing strategies aimed at maximizing consistency of clinician rating. There are a number of options, including improved written instructions and more intensive training, that could be implemented.

The Diabetes Health Profile (DHP): a new instrument for assessing the psychosocial profile of insulin requiring patients--development and psychometric evaluation.

The aim of the studies was to evaluate the psychometric properties and construct validity of the Diabetes Health Profile (DHP-1). Content for the DHP-1 was derived following in-depth interviews with 25 insulin dependent and insulin requiring patients, a review of the literature and discussions with health care professionals. Initial analysis of the factor structure of the DHP-1 was carried out on the responses of 239 insulin dependent and insulin requiring patients, with a mean age of 40.85 years (SD = 13.0), resulting in a 43 item three factor solution. The 43 item version of the DHP-1 was completed by 2,239 insulin dependent/requiring patients (mean age = 39.8, SD = 10) years. Fifty-one per cent were men. A forced three factor Principal Factoring Analysis with varimax rotation was carried out. Eleven items were excluded with item factor cross loadings > 0.30 or item factor loadings < 0.30. PAF analysis of the 32 items resulted in a three factor solution accounting for 33% of the total explained variance. The three factors were interpreted as Psychological Distress, Barriers to Activity and Disinhibited Eating. Factor congruence between subsamples were: Psychological distress (0.93), Barriers to Activity (0.93) and Disinhibited Eating (0.99). Coefficients of congruence between men and women were 0.94, 0.92 and 0.99 for Psychological Distress, Barriers to Activity and Disinhibited Eating respectively. Internal consistency of the three factors (Cronbach's alpha) were: Psychological Distress (0.86), Barriers to Activity (0.82), and Disinhibited Eating (0.77). Construct-convergent validity was investigated on a sample of 233 insulin dependent and insulin requiring patients (mean age = 51.46 years). Psychological Distress and Barriers to Activity subscales correlated with the Hospital Depression and Anxiety Scale = 0.50 to 0.62, p < 0.01) and subscales of the SF-36 (range: r = -0.17 to -0.62, p < 0.01). These findings lend support to the construct validity and reliability of the DHP-1 and that it is suitable for further development.

Measuring psychological well-being. The adapted General Well-Being Index in a primary care setting: a test of validity.

The measurement of health outcomes is central to the development of health services. Many acute and chronic illnesses and health interventions have implications for mental health. This study tests the validity of a 22 item measure of psychological well-being, the adapted general well-being index (AGWBI). A postal health survey, including the AGWBI, was sent to a 10% random sample of patients aged 16 or over drawn from the computerized list of one general practice. Two hundred and sixty-six respondents returned questionnaires (a response rate of 76%). The AGWBI was fully completed by 94% (249) of the respondents who returned their questionnaires. Only respondents who fully completed the AGWBI are included in the analysis. The AGWBI significantly discriminated people with a limiting long term illness, those reporting suffering from anxiety, depression or bad nerves, users of general practitioner services over the previous two weeks and respondents reporting taking anti-depressants, tranquillizers or sleeping tablets. It was also able to discriminate respondents with psychosocial difficulties in a small sub-sample who reported that they were in excellent health and did not have a limiting long term health problem or psychological illness. The results are broadly supportive of the validity of the AGWBI and suggest it may be appropriate for use in the evaluation of several developing areas of primary care. Further research is needed to test concurrent validity, responsiveness and to establish population norms.