Study protocol: older people in retirement villages. A survey and randomised trial of a multi-disciplinary invention designed to avoid adverse outcomes.

BACKGROUND: There is increasing interest among older people in moving into retirement villages (RVs), an attractive option for those seeking a supportive community as they age, while still maintaining independence. Currently in New Zealand there is limited knowledge of the medical, service supports, social status and needs of RV residents. The objective of this study is to explore RV facilities and services, the health and functional status of RV residents, prospectively study their healthcare trajectories and to implement a multidisciplinary team intervention to potentially decrease dependency and impact healthcare utilization. METHODS: All RVs located in two large district health boards in Auckland, New Zealand were eligible to participate. This three-year project comprised three phases: The survey phase provided a description of RVs, residents' characteristics and health and functional status. RV managers completed a survey of size, facilities and recreational and healthcare services provided in the village. Residents were surveyed to establish reasons for entry to the village and underwent a Gerontology Nurse Specialist (GNS) assessment providing details of demographics, social engagement, health and functional status. The cohort study phase examines residents' healthcare trajectories and adverse outcomes, over three years. The final phase is a randomised controlled trial of a multidisciplinary team intervention aimed to improve health outcomes for more vulnerable residents. Residents who triggered potential unmet health needs during the assessment in the survey phase were randomised to intervention or usual care groups. Multidisciplinary team meetings included the resident and support person, a geriatrician or gerontology nurse practitioner, GNS, pharmacist and General Practitioner. The primary outcome of the randomised controlled trial will be first acute hospitalization. Secondary outcomes include all acute hospitalizations, long-term care admissions, and all-cause mortality. DISCUSSION: This paper describes the study protocol of this complex study. The study aims to inform policies and practices around health care services for residents in retirement villages. The results of this trial are expected early 2020 with publication subsequently. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry: ACTRN12616000685415 . Registered 25.5.2016. Universal Trial Number (UTN): U111-1173-6083.

Diverticular disease epidemiology: acute hospitalisations are growing fastest in young men.

BACKGROUND: Older age has long been linked to risk of diverticulitis, but the epidemiology is seldom described for a national population. The aim of this study was to investigate age- and gender differences in incidence, temporal trends, lifetime risk and prevalence related to acute diverticulitis hospitalisations in New Zealand. METHODS: Records of all hospitalisations with diverticulitis the primary diagnosis were obtained from the Ministry of Health for the period 2000-2015. The first acute diverticulitis admission recorded for an individual was taken as an incident event; all others were classified as recurrent. Trends in age- and sex-specific and age-standardised incidence rates are described, and lifetime risk and prevalence estimated. RESULTS: Over the 16 years from 2000 to 2015, 37,234 acute hospitalisations for diverticulitis were recorded in 28,329 people aged 30 + years (median = 66 years). Rates of incident hospitalisations rose with age, from 5/10,000 person-years at age 50-54 years to 19/10,000py by age 80-84 years. Rates for women were lower than men before age 55 years, but higher thereafter. Age-standardised rates rose 0.2/10,000py annually, but approximately doubled among men aged < 50 years. Lifetime risk was estimated at over 5%, with the prevalence pool rising to over 1.5% of the population aged 30+ in 2030. CONCLUSIONS: Rapid increases in diverticulitis admissions among young men since 2000 correspond with increases reported elsewhere but remain unexplained; notably young women follow similar trends 5-10 years later. Increasing incidence, combined with population ageing, adds urgency to explain diverticular formation, to understand factors that trigger or provoke their inflammation/infection, and to clarify treatment and (self-)management pathways.

Vinblastine/Methotrexate for Debilitating and Progressive Plexiform Neurofibroma in Children and Young Adults with Neurofibromatosis Type 1: A Phase 2 Study.

Limited therapies exist for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN). For this reason, the activity of vinblastine (VBL) and methotrexate (MTX) was evaluated in children and young adults with NF1 and PN. Patients ≤ 25 years of age with progressive and/or inoperable NF1-PN received VBL 6 mg/m2 and MTX 30 mg/m2 weekly for 26 weeks, followed by every 2 weeks for 26 weeks. Objective response rate was the primary endpoint. Of 25 participants enrolled, 23 were evaluable. The median age of participants was 6.6 years (range 0.3-20.7). The most frequent toxicities were neutropenia and elevation of transaminases. On two-dimensional (2D) imaging, 20 participants (87%) had stable tumor, with a median time to progression of 41.5 months (95% confidence interval 16.9, 64.9). Two of eight participants (25%) with airway involvement demonstrated functional improvements including decreased positive pressure requirements and apnea-hypopnea index. A post hoc three-dimensional (3D) analysis of PN volumes was completed on 15 participants with amenable imaging; 7 participants (46%) had progressive disease on or by the end of therapy. VBL/MTX was well-tolerated but did not result in objective volumetric response. Furthermore, 3D volumetric analysis highlighted the lack of sensitivity of 2D imaging for PN response evaluation.

Hip fracture in Auckland: contrasting models of care in two major hospitals.

BACKGROUND: The optimal setting and design of care for elderly patients with hip fracture is unknown. North Shore Hospital (NSH) and Middlemore Hospital (MMH) are two major hospitals in the Auckland region operating different models of orthogeriatric care. The aim of the study was to compare hip fracture care between NSH and MMH. METHODS: A retrospective case record audit of patients aged 65 years and older with hip fracture from July to December 2004 at MMH and NSH was carried out. RESULTS: Charts for 203 patients (101 MMH and 102 NSH) were reviewed. The two groups were similar in age (mean age 83.2 years), sex (80% women) and other casemix factors. Median time from admission to theatre was shorter in NSH (21 vs 44 h, P < 0.0001). Length of stay was significantly shorter at NSH (mean difference 4.4 days, 95% confidence interval 1.1-7.6 when adjusted for casemix factors). Significantly more NSH patients were transferred for rehabilitation than MMH patients (75 vs 51%). At discharge, significantly more MMH patients (34 vs 14%) were treated with alendronate. Of 126 patients admitted from home, 81% returned home, 4% went to rest homes, 13% to private hospitals and 2% died; differences between centres were not significant. Overall inpatient mortality was 3.9%. CONCLUSION: The orthogeriatric model of care at NSH was associated with a shorter overall length of stay, earlier transfer to the Assessment, Treatment and Rehabilitation setting, and a higher proportion rehabilitated in Assessment, Treatment and Rehabilitation. Outcomes in terms of discharge destination and 6-month mortality were similar at both centres.

Reducing emergency presentations from long-term care: A before-and-after study of a multidisciplinary team intervention.

INTRODUCTION: The complexity of care required by many older people living in long-term care (LTC) facilities poses challenges that can lead to potentially avoidable referrals to a hospital emergency department (ED). The Aged Residential Care Intervention Project (ARCHIP) ran an implementation study to evaluate a multidisciplinary team (MDT) intervention supporting LTC facility staff to decrease potentially avoidable ED presentations by residents. METHODS: ARCHIP (conducted in 21 facilities [1,296 beds] with previously noted high ED referral rates) comprised clinical coaching for LTC facility staff by a gerontology nurse specialist (GNS) and an MDT (facility senior nurse, resident's general practitioner, GNS, geriatrician, pharmacist) review of selected high-risk residents' care-plans. A before-after repeated measures analysis was conducted for 9 months before and 9 months after intervention commencement (a 29-month period because of staggered facility enrolment). Modelling was adjusted for time trend, seasonality, facility size, and cluster effect. RESULTS: ED admission rate ratio post- versus pre-intervention was 0.75 (95% C.I. 0.63, 0.89, p-value = 0.0008), a 25% reduction in ED presentations post-intervention. A sensitivity model used a shorter, staggered time period centred on intervention start (9 months pre-intervention and 9 months post-intervention) for each facility, and a four-level categorical intervention variable testing intervention effect over time. The sensitivity test showed a 24% reduction in ED presentations in months 1-3 post-intervention (p-value = 0.07), a 34% reduction in months 4-6 (p-value = 0.01), and a 32% reduction in ED presentations in months 7-9 (p-value = 0.03). However, when the higher ED referral rates for 3 months immediately pre-intervention were modelled, the impact of the intervention on ED presentation rates reverted almost to previous levels. KEY CONCLUSIONS: A GNS-led MDT outreach intervention, targeted at selected conditions, decreases avoidable ED admissions of high-risk residents from selected facilities.

Global changes in the hippocampal proteome following exposure to an enriched environment.

Exposure to an enriched environment promotes neurochemical, structural and neurophysiological changes in the brain and is associated with enhanced synaptic plasticity and improved hippocampal-dependent learning. Using a global proteomics-based approach we have now been able to reveal the altered expression of a diverse range of hippocampal proteins following exposure to an enriched environment. Male Hooded Lister rats (8 weeks) were subjected to a 6-week regimen in which they were housed in either non-enriched (open field) or enriched conditions (toys, wheels etc.). Whole protein extracts from stratum pyramidale and stratum radiatum of area CA1 were then isolated and subjected to differential gel electrophoresis [McNair K, Davies CH, Cobb SR (2006) Plasticity-related regulation of the hippocampal proteome. Eur J Neurosci 23(2):575-580]. Of the 2469 resolvable protein spots detected in this study, 42 spots (1.7% of the detectable proteome) derived from predominantly somatic fractions and 32 proteins spots from dendritic fractions (1.3% of detectable proteome) were significantly altered in abundance following exposure to an enriched environment (somatic: 14 increased/28 decreased abundance, range -1.5 to +1.4-fold change; dendritic: 16 increased, 16 decreased abundance, range -1.6 to +3.0-fold change). Following in-gel tryptic digestion and Maldi-Tof/Q-star mass spectrometry, database searching revealed the identity of 50 protein spots displaying environmental enrichment-related modulation of expression. Identified proteins belonged to a variety of functional classes with gene ontology analysis revealing the majority (>70%) of regulated proteins to be part of the energy metabolism, cytoplasmic organization/biogenesis and signal transduction processes.

Is there a temporal pattern in the occurrence of subarachnoid hemorrhage in the southern hemisphere? Pooled data from 3 large, population-based incidence studies in Australasia, 1981 to 1997.

BACKGROUND AND PURPOSE: Publications on the temporal pattern of the occurrence of subarachnoid hemorrhage (SAH) have produced conflicting results. Variations between studies may relate to the relatively small numbers of SAH cases analyzed, including those in meta-analyses. METHODS: We identified all cases of SAH from 3 well-designed population-based studies in Australia (Adelaide, Hobart, and Perth) and New Zealand (Auckland) during 3 periods between 1981 and 1997. The diagnosis of SAH was confirmed with CT, cerebral angiography, cerebrospinal fluid analysis, or autopsy in all cases. Information on the time of occurrence of each event was obtained. Risk ratios (RRs) and 95% CIs were calculated using Poisson regression, with age, sex, smoking status, and history of hypertension entered in the model as covariates. RESULTS: A total of 783 cases of SAH were registered. Age- and sex-adjusted RRs of SAH occurrence were highest in the period between 6 AM and 12 MIDNIGHT (RR 3.2, 95% CI 2.4-4.3) and in winter and spring (RR 1.3, 95% CI 1.1-1.5; RR 1.3, 95% CI 1.1-1.5; respectively). No particular pattern of SAH occurrence was observed according to the day of the week. Restriction of the analyses to proved aneurysmal SAH did not substantially change the point estimates. CONCLUSIONS: Circadian and circaseptan (weekly) fluctuations of SAH occurrence in the southern hemisphere are similar to those in the northern hemisphere, but the occurrence of SAH in Australasia exhibits clear seasonal (winter and spring) peaks.

Melatonin in older people with age-related sleep maintenance problems: a comparison with age matched normal sleepers.

STUDY OBJECTIVES: To determine whether older people with age-related sleep maintenance problems have significantly lower melatonin levels than comparable normal sleepers. DESIGN: Case-control study. SETTING: A largely urban population, Auckland, New Zealand. PARTICIPANTS: People over the age of 65 years, who either slept normally, or had age-related sleep maintenance problems. Participants were recruited through media advertising, and local interest groups. Initial screening was by mail (Pittsburgh Sleep Quality Index), followed by interviews at a hospital day clinic. Exclusions included those with depression, cognitive impairment, medical and/or environmental problems which might impair sleep. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: A metabolite of plasma melatonin, 6-sulphatoxymelatonin (aMT6s) was measured in the urine of 57 normal sleepers, and 53 people with age-related problems over 24 hours in three aliquots: 12:00-19:00h, 19:00-07:00h, 07:00-12:00h. There were clear differences in self reported quality of sleep but no difference in mean aMT6s 24 hour or total night excretory levels, or night/day ratios. CONCLUSIONS: Older people with age-related sleep maintenance problems do not have lower melatonin levels than older people reporting normal sleep.

Approaches to the problems of measuring the incidence of stroke: the Auckland Stroke Study, 1991-1992.

BACKGROUND: Stroke registers are the preferred choice for determining incidence, case-fatality and severity of acute stroke in defined populations. This paper highlights some of the problems likely to be encountered in this endeavour by describing the experience of measuring acute stroke prospectively. METHODS: The Auckland Stroke Study is a community-based study among 945,000 residents of the Auckland region, New Zealand. Standard definitions and overlapping case-finding methods were used to identify all new acute stroke events occurring during the 12-month period ending 1 March 1992. Particular attention was directed at including non-fatal strokes managed outside hospital. The latter were identified by use of a cluster sample, a technique suitable for populations where residents have a personal primary health care physician. RESULTS: The comprehensive sources of referral to the study involved the review of 5736 records, less than one-third of which met the criteria for inclusion. The majority of included acute stroke events (n = 1803) were found through routinely available sources such as hospital admission records (63%) and death registrations (10%). The remainder (27%) were identified through intensive efforts at case-finding of stroke events managed outside hospital. The 1803 events were registered in 1761 people, 817 men and 944 women; for 587 (72%) men and 718 (76%) women, the stroke was the first ever experienced. CONCLUSIONS: While time-consuming, costly and demanding, there appears to be no easier alternative to a register to estimate incidence. This study demonstrates the importance of the use of comprehensive case-finding sources and suggests approaches to overcoming the difficulties in monitoring stroke incidence in large populations.

Older adults and healthy lifestyle issues: results of a community study.

AIM: To discover sources of information about, levels of understanding of, and degrees of commitment to a healthy lifestyle on the part of elderly people in the community as a preliminary to mounting health promotion and education initiatives. METHOD: In 1992 500 people aged 60 and over were surveyed anonymously using a 33 item questionnaire. This sought information on a wide range of health and lifestyle issues in older age. The material in this paper refers to only four of the questions asked, namely those relating to sources of, knowledge of, and interest in information on health and ageing. RESULTS: Doctors were perceived to be the most important sources of health information (89% of respondents rating them as "very" or "moderately" important). Relatives/friends and books/magazines were the next most important sources (56 and 55% respectively). High levels of misinformation about lifestyle issues were revealed. Whilst 85+% of respondents answered correctly that smoking was deleterious and strong social ties advantageous to good health in old age there was confusion about causes of osteoporosis, use of vitamins, likelihood of developing dementia and even the importance of exercise. This has implications for the content of health promotion programmes. Contrary to previously published research, we found no correlation between educational or socioeconomic status or gender, and knowledge about health issues and healthy lifestyles. CONCLUSION: Studies of this type clearly have the ability to provide a range of information which ought to be available to those responsible for the planning of health promotion and education initiatives for older adults.

A profile of the 7500 people in aged-care institutions in Auckland.

A study was carried out in 1988 to describe the residents and patients of aged-care institutions in Auckland against which future measures, including planned changes in licensing and funding, could be made. Information was collected for each patient in every hospital (public and private) and each resident in all old people's homes in the Auckland region between January and June 1988. Of the 7516 people surveyed (99.4% response rate), 70% were residents in old people's homes, 25% were patients in private hospitals and 6% were cared for in the public hospital sector. Of the people surveyed, 71% were women. The average age of women, 82 years, was 6.5 years older than that of men. Three-quarters of all women and 44% of men in care were widowed. Women had a higher rate of admission to institutions than did men with almost one in two women and one in four men in the age group 85 years and over being in long term care. Rates of institutionalisation for Maoris and Pacific Islanders were the same as for Europeans. The majority of elderly people received regular contact and concern from family members. This study has demonstrated that Auckland has a higher proportion of the elderly population (7.6% of the population 65 years and over) in long term care compared with other areas of New Zealand.

Dependency levels of people in aged care institutions in Auckland.

Between January and June 1988, a survey of 7516 people in aged care facilities in the Auckland region (99.4% response rate) was undertaken to ascertain the extent and provision of care for elderly people requiring ongoing care in order to make comparisons with other centres in New Zealand. Information was gathered about their ability to perform various activities of daily living by staff members who completed a structured precoded and pretested questionnaire for each resident or patient. Overall levels of dependency were also assessed as part of the questionnaire: 13% were assessed as requiring long stay hospital care, 48% had moderate or appreciable dependency, and the remainder had some dependency (23%) or none at all (16%). Almost one quarter (23%) of the 5213 residents in old people's homes were rated as apparently independent. Of people in religious and welfare residential homes, 38% were rated as independent whereas in commercial rest homes 12% of people were classified in this way. This high level of apparent independence in religious and welfare homes is the main aspect in which the Auckland long term care scene is distinct from other regions in the country.

Assessment for rest home subsidy: are the elderly getting a fair deal?

AIM: To describe the role of a geriatric service in assessing the needs of elderly people at home or in rest homes referred for a subsidy for rest home care, and to compare this assessment with the composite dependency scale (CDS), a Department of Social Welfare assessment instrument. METHODS: A 47 item questionnaire was completed by the geriatric service at the time of assessment of elderly people in the community or in rest homes. RESULTS: Of 280 assessments, 100 were from private homes, 180 from rest homes. Sixty-three per cent in rest homes were referred only because private funds were exhausted, 33% for a change in dependency category. These two groups plus those at home were used as a basis for comparison in subsequent analysis. Of those at home: 30% already had a rest home bed arranged; 77% remembered being consulted about rest home care, but only 38% were sure they wanted to go into such care. The proportion of those too independent or too sick for rest home care was: private homes 14%, rest home resident requiring subsidy 6%, rest home requiring change in category status 11%. Twenty three percent of those at home could continue there with or without additional support. No significant difference was found in dependency between those in rest homes only seeking funding, and those at home, but both of these groups were significantly less dependent than those seeking an increase in subsidy. There was only a moderate correlation (rs = 0.778) between the geriatric service assessment of dependency and the composite dependency score. CONCLUSIONS: Many elderly people do not feel properly consulted about rest home placement, and some could be supported at home for longer. It is likely that many who can afford rest home fees are entering too early and then asking for a subsidy when their funds are exhausted. By then it is almost impossible to insist on alternatives in the community. A policy of geriatric service assessment for all seeking entry into rest home care should ensure independent consultation and consideration of alternative strategies. More research is required to examine cost implications of unrestricted movement into rest homes.

Geographical variations in the organisation of general practice.

AIMS: To describe organisational characteristics of New Zealand general practice and to investigate inter-regional variations in these characteristics. METHODS: Data were collected by standardised questionnaires from general practitioners in Auckland, Waikato and Taranaki. The Waikato data were collected in July-August 1991 by postal survey, the Taranaki data were collected May-June 1992 by postal survey and the Auckland data were collected December 1990 to January 1991 by face-to-face interview. RESULTS: The response rates were Auckland 98% (167/171), Waikato 84% (185/220) and Taranaki 79% (79/100). There were significantly more overseas trained graduates in rural areas than in urban areas. Average practice size was 2.3 full time equivalent doctors, with each 100 doctors employing 71 nurses and 77 receptionists. The number of patients seen per week ranged from 109-141. Almost all (95%) general practitioners operated appointment systems. One in five general practitioners had patients in private hospitals, and more than half (58%) had patients in rest homes. At the time of interview, 29% of Auckland general practitioners used computers in their practices compared with over 50% in Waikato and Taranaki (p < 0.05). A smaller proportion of Auckland general practitioners had access to age/sex registers and fewer Auckland general practitioners had a recall system. Of Auckland general practitioners with recall systems, a greater proportion used them for mammograms, blood pressure and lipid measurements compared with elsewhere. CONCLUSIONS: There are some significant regional variations in the functional characteristics of general practice in New Zealand which should be taken into account when planning primary care services in different regions. Should budget holding and managed care be introduced, computerised practices will be required. This will have significant resource implications.

Functional disability in residents of Auckland rest homes.

OBJECT: to measure the extent of disability in residents of Auckland rest homes and to document any differences between religious and welfare homes and commercial homes. METHODS: analysis of a 36 item questionnaire on 2087 residents in 32 religious and welfare homes and 3126 residents in 191 commercial homes (98.7% response rate). RESULTS: residents in commercial homes were significantly more disabled than those in religious and welfare homes: 24% compared with 12% were incontinent, 62% and 31% confused, and 78% and 49% respectively needed assistance with mobility and selfcare. Of special concern were 7% and 3% who were doubly incontinent, 7% and 2% confused to the point of disturbing other residents, and 4% and 2% who met the criteria for hospital care. CONCLUSIONS: a significant number of residents were disabled and required help in important aspects of simple self care. Informed advice, variety, and choice in type of care are mandatory before entering a rest home. Homes must employ trained staff who can identify and minimise problems so as to ensure optimal quality of life for residents.

Young disabled residents in old people's homes.

A survey of the status of residents in aged care facilities in the Auckland region conducted in 1988 indicated that almost 9% (645) of the 7516 people studied were under 65 years of age. Rates were markedly higher for people of Maori descent than for those of European descent in this age group. For nonMaori, the rate for men was higher than that for women, but for Maori the opposite was the case. The majority of these young residents (94%) were being cared for in commercial old people's homes. One half were cared for in just 29 of the 223 homes in the region. While most (59%) were admitted after the age of 50, 15% were admitted before they were 40 and must expect to liver their lives out in institutions primarily housing elderly residents. Almost half of those in old people's homes had been admitted from a psychiatric hospital. The authors are concerned that so many young people appear to be in old people's homes because of a lack of alternative accommodation which is more suited to their care.

The response of evidential breath alcohol testing instruments with subjects exposed to organic solvents and gases. III. White spirit exposure during domestic painting.

The concentration of white spirit vapour in the breathing zone of a volunteer engaged in domestic painting activities has been investigated. Air was continuously sampled and analysed using an infra-red gas analyser (Miran) during painting experiments. Both indoor and outdoor painting tasks were undertaken using commercial paints in a wide variety of situations. For each task the time weighted average (TWA) exposure has been determined. In no case did the TWA exposure exceed the Occupational Exposure Limit-Long Term Exposure Limit (OEL-LTEL) of 100 ppm. The results have been used to discuss the significance of previous studies in which volunteers were exposed to white spirit vapour in an exposure chamber to test for possible interference in breath alcohol testing.

Increasing self-efficacy through empowerment: preoperative education for orthopaedic patients.

PURPOSE: To examine whether patients who received an empowerment model of education for preoperative orthopaedic teaching had improved outcomes compared to patients who received the traditional education. DESIGN: An experimental (empowerment teaching method) group vs. comparison (traditional teaching method) group posttest design. SAMPLE: Seventy-four patients undergoing elective orthopaedic surgery. METHODS: Following the preoperative teaching session, patients in both groups completed a questionnaire designed to measure their perceptions of the teaching (empowerment) and self-efficacy (belief in their ability to carry out perioperative tasks). A chart audit and phone interview was done after discharge to assess length of stay, pain management, complications, and patient perceptions of the ability to complete perioperative tasks. FINDINGS: Patients in the empowerment group felt the educational approach was more empowering and had significantly higher self-efficacy scores than those in the traditional teaching group. There was much less variation in empowerment and self-efficacy scores in the empowerment group. The empowerment group reported feeling greater confidence in performing perioperative tasks. There were no differences in length of stay, complications or pain control. CONCLUSION: Use of an empowerment teaching approach enabled patients to become more confident in their ability to carry out perioperative tasks and become a more integral part of the preoperative teaching process. IMPLICATIONS FOR NURSING RESEARCH: The theoretical model will be used to structure other educational programs and guide research. More sensitive measures of complications and pain control should be considered for future studies.

Drugs acting at 5-HT4 , D2 , motilin, and ghrelin receptors differ markedly in how they affect neuromuscular functions in human isolated stomach.

BACKGROUND: Progress in identifying safer, effective drugs to increase gastric emptying is impeded by failed clinical trials. One potential reason for failure is lack of translation from animal models to the human condition. To make progress, the actions of existing drugs and new therapeutic candidates need to be understood in human isolated stomach. METHODS: Neuromuscular activities were evoked in human gastric antrum circular muscle by electrical field stimulation (EFS), defined phenotypically using pharmacological tools. KEY RESULTS: EFS evoked cholinergically mediated contractions, attenuated by simultaneous nitrergic activation. The 5-HT4 receptor agonist/D2 antagonist metoclopramide and the selective 5-HT4 agonist prucalopride, facilitated contractions in the absence (respectively, Emax 95 ± 29% and 42 ± 9%, n = 3-6 each concentration) and presence (139 ± 38%, 55 ± 13%, n = 3-5) of the NO synthase inhibitor L-NAME, without affecting submaximal contractions to carbachol; the 5-HT4 antagonist SB204070 prevented facilitation by metoclopramide 100 µM (respectively, -5 (range -26 to 34) and 167 (12-1327)% in presence and absence; n = 5-6). The selective motilin receptor agonist camicinal provided considerably greater facilitation (478 (12-2080)% at 30 µM, n = 8). Domperidone (0.001-100 µM; n = 3-6) and acylated or des-acylated ghrelin (1-300 nM; n = 2-4) had no consistent activity, even with protease inhibitors. CONCLUSIONS & INFERENCES: 5-HT4 receptor agonists show different efficacies. Motilin receptor activation has greater potential to increase gastric emptying, whereas ghrelin and D2 receptor antagonism have no direct activity. Drugs stimulating human gastric motility directly can act regardless of disease mechanisms, whereas drugs without direct activity but an ability to block nausea/vomiting may be effective only if these symptoms exist.

Regionally dependent neuromuscular functions of motilin and 5-HT4 receptors in human isolated esophageal body and gastric fundus.

BACKGROUND: Motilin agonists promote human gastric motility and cholinergic activity, but excitatory and inhibitory actions are reported in the esophagus. The effect of 5-HT4 agonists in esophagus is also unclear. Perhaps the use of drugs with additional actions explains the variation. The aim, therefore, was to examine how motilin and prucalopride, selective motilin and 5-HT4 receptor agonists, modulate neuromuscular functions in human esophagus and gastric fundus. METHODS: Electrical field stimulation (EFS) evoked nerve-mediated contractions of circular and longitudinal muscle from human esophageal body and circular muscle from gastric fundus. KEY RESULTS: In esophageal circular muscle EFS evoked brief contraction, followed by another contraction on termination of EFS, each prevented by atropine. Nitric oxide synthase inhibition facilitated contraction during EFS and the overall contraction became monophasic. In esophagus longitudinal muscle and gastric fundus, EFS evoked cholinergically mediated, monophasic contractions, attenuated by simultaneous nitrergic activation. Motilin (100-300 nM) reduced esophagus circular muscle contractions during EFS, unaffected by L-NAME or apamin. Motilin 300 nM also reduced EFS-evoked contractions of longitudinal muscle. Similar concentrations of motilin facilitated cholinergic activity in the fundus and increased baseline muscle tension. Prucalopride facilitated EFS-evoked contractions in esophagus (tested at 30 µM) and fundus (0.1-30 µM). CONCLUSIONS & INFERENCES: Selective motilin and 5-HT4 agonists have different, region-dependent abilities to modulate human esophageal and stomach neuromuscular activity, exemplified by weak inhibition (motilin) or excitation (5-HT4) in esophageal body and excitation for both in stomach. In different patients with motility dysfunctions, motilin and 5-HT4 agonists may reduce gastro-esophageal reflux in different ways.