Search

Peer reviewed: True, BACKGROUND: The need for end-of-life care in the community increased significantly during the COVID-19 pandemic. Primary care services, including general practitioners and community nurses, had a critical role in providing such care, rapidly changing their working practices to meet demand. Little is known about primary care responses to a major change in place of care towards the end of life, or the implications for future end-of-life care services. AIM: To gather general practitioner and community nurse perspectives on factors that facilitated community end-of-life care during the COVID-19 pandemic, and to use this to develop recommendations to improve future delivery of end-of-life care. DESIGN: Qualitative interview study with thematic analysis, followed by refinement of themes and recommendations in consultation with an expert advisory group. PARTICIPANTS: General practitioners (n = 8) and community nurses (n = 17) working in primary care in the UK. RESULTS: General practitioner and community nurse perspectives on factors critical to sustaining community end-of-life care were identified under three themes: (1) partnership working is key, (2) care planning for end-of-life needs improvement, and (3) importance of the physical presence of primary care professionals. Drawing on participants' experiences and behaviour change theory, recommendations are proposed to improve end-of-life care in primary care. CONCLUSIONS: To sustain and embed positive change, an increased policy focus on primary care in end-of-life care is required. Targeted interventions developed during COVID-19, including online team meetings and education, new prescribing systems and unified guidance, could increase capacity and capability of the primary care workforce to deliver community end-of-life care.

Anticipatory/advance care planning (ACP) conversations are often known to be challenging and should be undertaken sensitively. A qualitative service evaluation was undertaken with the elderly care department at The Leeds Teaching Hospitals NHS Trust by medical students to explore the thoughts and experiences of foundation doctors. ACP discussions include consideration of future treatment options and preferences; however, foundation doctors were not confident to discuss issues beyond resuscitation status. The key themes identified include understanding of and confidence in ACP, variation across specialty and medical educational needs. The analysis highlights a further need for qualitative research into prevalent attitudes towards ACP discussions across the range of specialties.

Community nursing caseloads are vast, with differing complexities. The Sheffield Caseload Classification Tool (SCCT) was co-produced with community nurses and nurse managers to help assign patients on a community caseload according to nursing need and complexity of care. The tool comprises 12 packages of care and three complexities. The present study aimed to test the inter-rater reliability of the tool. This was a table top validation exercise conducted in one city in South Yorkshire. A purposive sample of six community nurses assessed 69 case studies using the tool and assigned a package of care and complexity of need to each. These were compared with pre-determined answers. Cronbach's alpha for the care package was 0.979, indicating very good reliability, with individual nurse reliability values also being high. Fleiss's kappa coefficient for the care packages was 0.771, indicating substantial agreement among nurses; it was 0.423 for complexity ratings, indicating moderate agreement. The SCCT can reliably assign patients to the appropriate skilled nurse and care package. It helps prioritise and plan a community nursing caseload, ensuring efficient use of staff time to deliver appropriate care to patients with differing needs.

Editorial, 19 June Higginson and colleagues highlight the need for high quality, community end-of-life care as a significant ongoing concern for the NHS.1 The role of primary care in end-of-life care needs much more attention, as reported by The BMJ over the past two decades.23 Primary care has had a key role in the delivery of end-of-life care to patients dying at home during the covid-19 pandemic, adapting rapidly to meet increased need. …

End-of-life (EoL) care is an important role in community nursing. In order to assess a community nursing team's performance in the delivery of EoL care, an evaluation of the EoL care template was undertaken from electronic patient records. Records were assessed against a set of four care priorities across 23 nursing teams in a large acute/community trust. Some 103 electronic patient records were evaluated out of a convenience sample of 110 (94% response rate). The results demonstrated that patients' wishes are being discussed and documented and the priorities of care are being considered with patients needing EoL care. Thus, patients and their families are being supported by the community nursing service, which is communicating with them sensitively and involving patients in the decision-making process. In some cases, the EoL Care Template was not fully completed, which would result in poorer communication across teams and organisations of practice within the wider community. Future action will be focused on continuing to encourage and improve the use of the EoL care template as well as the local online e-learning package for EoL care.

Background Rapid, dramatic changes in primary healthcare services occurred during the COVID-19 pandemic. More palliative and end-of-life care (PEOLC) in the community and care homes needed delivered in new ways. This study sought General Practitioner (GP) and community nursing views about changes related to PEOLC during the COVID-19 pandemic. Methods A national online survey was developed from current literature, patient, public and key stakeholder involvement and disseminated to GPs and community nurses between 01.09.2020 and 16.10.2020. Fixed response and open free text questions addressed demographics, PEOLC provision, changes, challenges and exemplars of good practice. Results There were 559 responses (387 (71.3%) community nurses; 156 (28.7%) GPs; 6 ‘role not specified’) from all UK countries. Over half (296, 53.1%) cared for patients dying with ‘confirmed’ COVID-19 and provided PEOLC ‘a lot more’ or ‘a bit more than usual’ to non-COVID patients (322, 58.2%). All respondents reported increased need to provide family support (339, 60.9% providing ‘a lot’/’a bit more than usual’); a larger proportion of community nurses (252, 66.0%) reported this role change compared with doctors (75, 48.1%, p=0.01). Over forty percent of all respondents reported they were undertaking more advance care planning (266, 53.0%), anticipatory prescribing (227, 56.4%), symptom management (275, 51.1%), death verification (222, 47.8%) and bereavement support (237, 44.6%). Over three-quarters (211, 77.0%) of community nurses had conducted ‘more’/‘a lot more’ face-to-face visits, whereas 53 (34.0%) of GPs had done ‘less’ or ‘a lot less’ ( Qualitative free-text themes relate to increasing end-of-life care workload; changing roles and models of consultation; and emotional impact. Conclusions Contrasting and potentially conflicting roles emerged between GPs and community nurses concerning their response to the increased demand and complexity of PEOLC during the pandemic. The significant emotional impact, especially for community nurses, needs addressing alongside rebuilding trusting and supportive team dynamics.

BackgroundThousands of people in the UK have required end-of-life care in the community during the COVID-19 pandemic. Primary healthcare teams (general practice and community nursing services) have provided the majority of this care, alongside specialist colleagues. There is a need to learn from this experience in order to inform future service delivery and planning.AimTo understand the views of general practitioners and community nurses providing end-of-life care during the first wave of the COVID-19 pandemic.Design and SettingA web-based, UK-wide questionnaire survey circulated via professional general practice and community nursing networks during September and October 2020.MethodResponses were analysed using descriptive statistics and an inductive thematic analysis.ResultsValid responses were received from 559 individuals (387 community nurses, 156 General Practitioners (GPs) and 16 unspecified role), from all regions of the UK. The majority reported increased involvement in providing community end-of-life care. Contrasting and potentially conflicting roles emerged between GPs and community nurses. There was increased use of remote consultations, particularly by GPs. Community nurses took greater responsibility in most aspects of end-of-life care practice, particularly face-to-face care, but reported feeling isolated. For some GPs and community nurses, there has been considerable emotional distress.ConclusionPrimary healthcare services are playing a critical role in meeting increased need for end-of-life care in the community during the COVID-19 pandemic. They have adapted rapidly, but the significant emotional impact, especially for community nurses, needs addressing alongside rebuilding trusting and supportive team dynamics.How this fits in (4 sentences)This study provides insights into experiences of delivering end-of-life care in the community during the first wave of the COVID-19 pandemic from the perspectives of UK general practitioners (GPs) and community nurses.Services have changed and adapted rapidly to meet increased need in terms of both volume and complexity, with community nurses taking greater responsibility for most areas of palliative care clinical practice, and GPs undertaking more care planning conversations.While GPs and specialist palliative care services conducted more remote consultations, community nurses carried out face-to-face end-of-life care and reported a feeling of isolation.As the pandemic progresses, and the increased need for end-of-life care in the community persists, more effective service models and multi-disciplinary teamwork in primary care are urgently needed.

Advances in genome sequencing and assembly technologies are generating many high quality genome sequences, but assemblies of large, repeat-rich polyploid genomes, such as that of bread wheat, remain fragmented and incomplete. We have generated a new wheat whole-genome shotgun sequence assembly using a combination of optimised data types and an assembly algorithm designed to deal with large and complex genomes. The new assembly represents more than 78% of the genome with a scaffold N50 of 88.8kbp that has a high fidelity to the input data. Our new annotation combines strand-specific Illumina RNAseq and PacBio full-length cDNAs to identify 104,091 high confidence protein-coding genes and 10,156 non-coding RNA genes. We confirmed three known and identified one novel genome rearrangements. Our approach enables the rapid and scalable assembly of wheat genomes, the identification of structural variants, and the definition of complete gene models, all powerful resources for trait analysis and breeding of this key global crop. [Supplemental material is available for this article.]

BackgroundThousands of people in the UK have required end-of-life care in the community during the COVID-19 pandemic. Primary healthcare teams (general practice and community nursing services) have provided the majority of this care, alongside specialist colleagues. There is a need to learn from this experience in order to inform future service delivery and planning.AimTo understand the views of GPs and community nurses providing end-of-life care during the first wave of the COVID-19 pandemic.Design & settingA web-based, UK-wide questionnaire survey circulated via professional general practice and community nursing networks, during September and October 2020.MethodResponses were analysed using descriptive statistics and an inductive thematic analysis.ResultsValid responses were received from 559 individuals (387 community nurses, 156 GPs, and 16 unspecified roles), from all regions of the UK. The majority reported increased involvement in providing community end-of-life care. Contrasting and potentially conflicting roles emerged between GPs and community nurses. There was increased use of remote consultations, particularly by GPs. Community nurses took greater responsibility in most aspects of end-of-life care practice, particularly face-to-face care, but reported feeling isolated. For some GPs and community nurses, there has been considerable emotional distress.ConclusionPrimary healthcare services are playing a critical role in meeting increased need for end-of-life care in the community during the COVID-19 pandemic. They have adapted rapidly, but the significant emotional impact, especially for community nurses, needs addressing alongside rebuilding trusting and supportive team dynamics.

AimsTo assess the ‘Okay to Stay’ plan to investigate if this reduces visits to emergency departments, unplanned admissions and elective admission to hospital in elderly patients with long-term health conditions.BackgroundThe incidence of long-term conditions is rising as the elderly population increases, resulting in more people from this group attending emergency departments and being admitted to hospital. Okay to Stay is a simple plan for people with long-term conditions to help them remain in their own home if they suffer an acute exacerbation in their health. It was co-designed with professional and patient representatives with the aim of empowering patients and their carers to more effectively manage their long-term conditions.MethodsData from 50 patients (20 males, 30 females, mean baseline age 77.5 years) were compared 12 months before implementation of the plan and in the subsequent 12 months, with the significance of effects assessed at the 5 per cent significance level using t-tests.FindingsVisits to emergency departments were reduced by 1.86; unplanned emergency admissions were reduced by 1.28 and planned elective admissions were raised by 0.22 admissions per annum. The reduction in visits to the emergency department was significant (p = 0.009) and the reduction in emergency admissions was significant (p = 0.015). The change in elective admissions was not significant (p = 0.855). The Okay to Stay plan is effective in reducing visits to the emergency department and unplanned hospital admissions in people with long-term conditions. This is a positive step to supporting vulnerable and complex patients who are cared for at home, and facilitates the recognition by the individual of the possibility to stay at home with the support of health professionals. There are potential cost benefits to the investment of initiating an Okay to Stay plan through the avoidance of visits to the emergency department and non-elective admissions to hospital.

Background In November 2016 the in-patient unit (IPU) was temporarily closed and relocated to a nursing home to allow essential demolition work. This meant a reduction from 12 to 5 IPU beds. An Enhanced Hospice at Home (EHAH) service was developed to mirror the care we deliver in IPU and support the reduction in beds. Aim Our organisation wanted to ensure that patients’ needs and wishes continued to be met. To enable this, the service supports four patients in their own home environment for end of life care or complex symptom control issues. It is enabling us to bring our in-patient care out into the community. Methods A team of experienced registered nurses and health care assistants offer up to four visits a day to provide personal care, symptom management and emotional support. Specialist hospice doctors provide daily visits depending on the patient’s clinical needs. Care in the community still involves our wider multidisciplinary team including therapists, family support and benefit advice. Results During the project data has shown 93% of patients’ PPDs that have been home have been met. Combined IPU and EHAH admissions are higher than previous IPU admissions alone. Staff costs have been unchanged by splitting the service. Feedback Includes ‘I felt the team were excellent and it was obvious they were very experienced as they knew exactly how to advise myself and my brother with all aspect of our mother’s care.’ ‘My family felt the care we received was invaluable, it enabled my husband to pass from this world with dignity. It would be wonderful to think that all people could receive this special care in the last days of their lives.’ Conclusion This EHAH has not only helped us provide holistic specialist care to our patients and families but it has also given us the opportunity to build working relationships with GPs and district nurses and be able to share our knowledge and skills.

Acuity and dependency in the community nursing caseload in combination with safe staffing levels are a national issue of concern. Current evidence suggests that there are no clear approaches to determining staff capacity and skill mix in these community settings. As community nursing caseloads are large with differing complexities, there is a need to allocate community nursing with the best skill mix to achieve the best patient outcomes. A city-wide service improvement initiative developed a tool to classify and categorise patient demand and this was linked to an electronic patient record system. The aim was to formulate an effective management response to different levels of acuity and dependency within community nursing teams and a consensus approach was used to allow the definition of complexity for twelve packages of care. The tool was piloted by a group of community nurses to assess the validity as a method to achieve a caseload classification. Seventy nurses were trained and applied the tool to 3000 patient referrals. Based on this, standards of care were agreed including expectations of assessment, intervention, visit length and frequency. Community nursing caseloads can now be organised according to acuity and complexity of patient need, which determines allocation of staff and skill mix.

Background and purpose: The peroxisome proliferator-activated receptor-g (PPARg) agonist pioglitazone has previously been shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease, an effect attributed to its anti-inflammatory properties. In the present investigation, we provide evidence that pioglitazone is effective in the MPTP mouse model, not via an anti-inflammatory action, but through inhibition of MAO-B, the enzyme required to biotransform MPTP to its active neurotoxic metabolite 1-methyl-4-phenylpyridinium (MPP þ ). Experimental approach: Mice were treated with pioglitazone (20 mg kg � 1 b.i.d. (twice a day), p.o., for 7 days), prior and post or post-MPTP (30 mg kg � 1 s.c.) treatment. Mice were then assessed for motor impairments on a beam-walking apparatus and for reductions in TH immunoreactivity in the substantia nigra and depletions in striatal dopamine. The effects of pioglitazone on striatal MPP þ levels and MAO-B activity were also assessed. Key results: Mice treated with MPTP showed deficits in motor performance, marked depletions in striatal dopamine levels and a concomitant reduction in TH immunoreactivity in the substantia nigra. Pretreatment with pioglitazone completely prevented these effects of MPTP. However, pretreatment with pioglitazone also significantly inhibited the MPTP-induced production of striatal MPP þ and the activity of MAO-B in the striatum. Conclusions and implications: The neuroprotection observed with pioglitazone pretreatment in the MPTP mouse model was due to the blockade of the conversion of MPTP to its active toxic metabolite MPP þ , via inhibition of MAO-B. British Journal of Pharmacology (2008) 154, 226–233; doi:10.1038/bjp.2008.78; published online 10 March 2008

A beam-walking apparatus has been evaluated for its ability to detect motor impairments in mice acutely treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg, s.c., single or double administration). Mice subjected to MPTP lesioning showed deficits in motor performance on the beam-walking task, for up to 6 days post-MPTP administration, as compared to saline-treated controls. In addition, MPTP-treated mice were detected to have a marked depletion in striatal dopamine levels and a concomitant reduction in substantia nigra (SN) tyrosine hydroxylase (TH) immunoreactivity, at 7 days post-MPTP administration, indicative of dopaminergic neuronal loss. Pre-administration of the potent MAO-B inhibitor R-(-)-deprenyl at 3 or 10 mg/kg, 30 min, s.c, significantly inhibited the MPTP-induced reduction in SN TH-immunoreactivity, striatal dopamine depletions and impairments in mouse motor function. The data described in the present study provides further evidence that functional deficits following an acute MPTP dosing schedule in mice can be quantified and are related to nigro-striatal dopamine function.

This narrative illustrates how easy it is to be thoughtless when treating patients, resulting in the patient feeling dehumanized and belittled. This has the potential to trigger dental fear in vulnerable individuals.

A single dose of the orexin-1 (OX1) receptor antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5] naphthyridin-4-yl urea hydrochloride (SB-334867-A) reduces orexin-A-induced feeding and natural feeding in Sprague Dawley rats. In this study, the anti-obesity effects of SB-334867-A were determined in genetically obese (ob/ob) mice dosed with SB-334867-A (30 mg/kg, i.p.) once daily for 7 days, and then twice daily for a further 7 days. SB-334867-A reduced cumulative food intake and body weight gain over 14 days. Total fat mass gain, determined by Dual Emission X-ray Absorptiometry, was reduced, while gain in fat-free mass was unchanged. Fasting (5 h) blood glucose was also reduced at the end of the study, with a trend to reduced plasma insulin. Interscapular brown adipose tissue (BAT) weight was reduced, the tissue was noticeably darker in colour and quantitative PCR (TaqMan) analysis of this tissue showed a trend to an increase in uncoupling protein-1 mRNA expression, suggesting that SB-334867-A might stimulate thermogenesis. This was confirmed in a separate study in which a single dose of SB-334867-A (30 mg/kg, i.p.) increased metabolic rate over 4 h in ob/ob mice. OX1 receptor mRNA was detected in BAT, and its expression was increased by 58% by treatment with SB-334867-A. This is the first demonstration that OX1 receptor antagonists have potential as both anti-obesity and anti-diabetic agents.

The ability of native uncoupling protein-3 (UCP3) to uncouple mitochondrial oxidative phosphorylation is controversial. We measured the expression level of UCP3 and the proton conductance of skeletal muscle mitochondria isolated from transgenic mice overexpressing human UCP3 (UCP3-tg) and from UCP3 knockout (UCP3-KO) mice. The concentration of UCP3 in UCP3-tg mitochondria was approximately 3 microg/mg protein, approximately 20-fold higher than the wild type value. UCP3-tg mitochondria had increased nonphosphorylating respiration rates, decreased respiratory control, and approximately 4-fold increased proton conductance compared with the wild type. However, this increased uncoupling in UCP3-tg mitochondria was not caused by native function of UCP3 because it was not proportional to the increase in UCP3 concentration and was neither activated by superoxide nor inhibited by GDP. UCP3 was undetectable in mitochondria from UCP3-KO mice. Nevertheless, UCP3-KO mitochondria had unchanged respiration rates, respiratory control ratios, and proton conductance compared with the wild type under a variety of assay conditions. We conclude that uncoupling in UCP3-tg mice is an artifact of transgenic expression, and that UCP3 does not catalyze the basal proton conductance of skeletal muscle mitochondria in the absence of activators such as superoxide.

A variety of evidence implicates the orexins, especially orexin-A, in the regulation of food intake, but it has not been established whether this effect is mediated by the orexin-1 or orexin-2 receptor. In the present study, a selective orexin-1 receptor antagonist, 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea hydrochloride (SB-334867-A), was administered intraperitoneally to rats under various conditions, and food consumption was subsequently measured over 24 h. In male rats, a single dose of SB-334867-A (30 mg/kg, i.p.) given during the light phase reduced both orexin-A-induced food intake (7 nmol, i.c.v.) and feeding stimulated by an overnight fast for 4 h. When given at the start of the dark phase, food consumption was reduced in both male and female rats over 24 h. Daily injections at the start of the dark phase for 3 days reduced natural feeding in male rats over 24 h on days one and three. These findings demonstrate direct inhibition of orexin-A induced food intake with a selective orexin-1 receptor antagonist. Furthermore, the suppression of nocturnal feeding and food intake stimulated by an overnight fast supports other evidence that orexin-A is involved in the regulation of natural feeding and suggests that orexin-1 receptor antagonists could be useful in the treatment of obesity.

Uncoupling protein-3 (UCP-3) is a recently identified member of the mitochondrial transporter superfamily that is expressed predominantly in skeletal muscle. However, its close relative UCP-1 is expressed exclusively in brown adipose tissue, a tissue whose main function is fat combustion and thermogenesis. Studies on the expression of UCP-3 in animals and humans in different physiological situations support a role for UCP-3 in energy balance and lipid metabolism. However, direct evidence for these roles is lacking. Here we describe the creation of transgenic mice that overexpress human UCP-3 in skeletal muscle. These mice are hyperphagic but weigh less than their wild-type littermates. Magnetic resonance imaging shows a striking reduction in adipose tissue mass. The mice also exhibit lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. This provides evidence that skeletal muscle UCP-3 has the potential to influence metabolic rate and glucose homeostasis in the whole animal.

In order to better understand the practice of dispersant use, a review has been undertaken of marine oil spills over a 10 year period (1995-2005), looking in particular at variations between different regions and oil-types. This viewpoint presents and analyses the review data and examines a range of dispersant use policies. The paper also discusses the need for a reasoned approach to dispersant use and introduces past cases and studies to highlight lessons learned over the past ten years, focussing on dispersant effectiveness and monitoring; toxicity and environmental effects; the use of dispersants in low salinity waters; response planning and future research needs.

The automated behavioural apparatus, LABORAS™ (Laboratory Animal Behaviour Observation, Registration and Analysis System), has been further validated with respect to the ability of the system to detect behavioural impairments in mice, following various dopaminergic manipulations. Initially data were obtained from mice administered with amphetamine, haloperidol, SCH23390, apomorphine and l -DOPA, with the focus on locomotor and grooming activities. The data recorded by LABORAS™ on administration of these pharmacological tool compounds, is comparable with published findings using standard LMA systems and conventional observer methods. In addition the home cage behaviour of mice administered with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using an acute dosing regimen was also investigated. In LABORAS™, mice subjected to MPTP lesioning showed deficits in spontaneous motor activity at day 6–7 post-MPTP administration, over a 24 h test period, as compared to saline treated controls. The data captured and analysed using LABORAS™, suggests that the automated system is able to detect both pharmacologically and lesion-induced changes in behaviour of mice, reliably and efficiently.

This article is based on the premise that mental wellness for older adults can be promoted through communication and presents a model drawing on the constructs of contemplating, caring, coping, and conversing. The importance of interpersonal communication processes in the care of older adults and some barriers to communication and mental wellness are briefly reviewed. This article challenges nurses to develop awareness of their own caregiving styles and communication processes, and to assist others (e.g., family caregivers, care receivers) to communicate and interact more effectively to advance mental wellness for older adults.

The precise mechanism by which PPARgamma activation by thiazolidinediones (TZDs) improves insulin sensitivity is still unclear. Recent studies have focused on the role of adipocytokines in metabolic control and their regulation by TZDs. In this study, we compared the chronic effects of antihyperglycemic doses of the TZD rosiglitazone, the beta3-adrenoceptor agonist BRL-35135, and the PPARalpha agonist Wy-14,643 on the mRNA expression of adipocytokines in WAT of db/db mice. Rosiglitazone treatment decreased adiponectin and resistin mRNA levels by 57 and 72%, respectively (P0.001), with no effect on the level of TNFalpha or RELMalpha transcripts. In comparison, Wy-14,643 reduced adiponectin transcript levels by 31% (P = 0.015) while BRL-35135 increased RELMalpha mRNA expression by 245% (P0.001) without effect on the other transcripts. Our results indicate that although a reduction in adiponectin and resistin mRNA levels in WAT by rosiglitazone treatment of diabetic mice may contribute to the antidiabetic effects, an alteration in TNFalpha, adiponectin, resistin, or RELMalpha mRNA expression is not absolutely required for the regulation of blood glucose concentration in the db/db mouse.

Insulin stimulation of adipose and muscle cells results in the translocation of GLUT4 from an intracellular location to the plasma membrane; this translocation is defective in insulin resistance. Studies have suggested an important role for synaptobrevin and syntaxin homologues in this event, particularly the v-soluble N-ethylmaleimide attachment protein receptors (SNAREs) cellubrevin and vesicle-associated membrane protein-2 (VAMP-2) and the t-SNARE syntaxin 4, but the expression of these proteins has not been studied in insulin-resistant tissues. Therefore, we examined SNARE protein content in skeletal muscle from Zucker diabetic fatty (ZDF) rats compared with lean controls and determined the effect of the thiazolidinedione insulin sensitizer rosiglitazone on these proteins. GLUT4 levels in skeletal muscle from ZDF rats were similar to those in lean control animals. In contrast, cellubrevin, VAMP-2, and syntaxin 4 protein levels were elevated (2.8-fold, P = 0.02; 3.7-fold, P = 0.01; and 2.2-fold, P < 0.05, respectively) in skeletal muscle from ZDF rats compared with lean controls. Restoration of normoglycemia and normoinsulinemia in ZDF rats with rosiglitazone (30 micromol/kg) normalized cellubrevin, VAMP-2, and syntaxin 4 protein to levels approaching those observed in lean control animals. These data show that elevated v- and t-SNARE protein levels are associated with insulin resistance in skeletal muscle and that these increases may be reversed by rosiglitazone treatment concomitant with a restoration of glycemic control. Such increases in SNARE protein levels were not observed in streptozotocin-induced diabetic rats, which suggests that hyperinsulinemia rather than hyperglycemia may be more important in modulating SNARE protein expression in rodent models of insulin resistance. Consistent with this hypothesis, elevated levels of SNARE proteins were also observed in 3T3-L1 adipocytes chronically treated with insulin (500 nmol/l for 24 h). These data argue that SNARE protein levels may be altered in insulin-resistant states and that the levels of these proteins are modulated by agents that increase insulin sensitivity. Moreover, these data demonstrate for the first time altered expression of proteins known to regulate GLUT4 translocation in a model of diabetes.

The chiral synthesis of the potent and selective alpha-2A antagonist, BRL 48962, is described. Evaluation of BRL 48962 at cloned human alpha-adrenoceptors indicates that this antagonist has a selectivity in the order of 30-fold for the alpha-2A subtype.