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.

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.

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.

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.

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.

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility.

BACKGROUND AND PURPOSE: Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimize side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the AChE inhibitor donepezil (used for Alzheimer's disease, with reduced cardio-bronchial liability) and prucalopride, the first selective, clinically available 5-HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon. EXPERIMENTAL APPROACH: Neuronally mediated muscle contractions and relaxations of human colon were evoked by electrical field stimulation (EFS) and defined phenotypically as cholinergic, nitrergic or tachykinergic using pharmacological tools; the effects of drugs were determined as changes in 'area under the curve'. KEY RESULTS: Prucalopride increased cholinergically mediated contractions (EC50 855 nM; 33% maximum increase), consistent with its ability to stimulate intestinal motility; donepezil (477%) and neostigmine (2326%) had greater efficacy. Concentrations of donepezil (30-100 nM) found in venous plasma after therapeutic doses had minimal ability to enhance cholinergic activity. However, donepezil (30 nM) together with prucalopride (3, 10 µM) markedly increased EFS-evoked contractions compared with prucalopride alone (P = 0.04). For example, the increases observed with donepezil and prucalopride 10 µM together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n = 3-7, each concentration). CONCLUSIONS AND IMPLICATIONS: Potential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction.

Translational neuropharmacology: the use of human isolated gastrointestinal tissues.

Translational sciences increasingly emphasize the measurement of functions in native human tissues. However, such studies must confront variations in patient age, gender, genetic background and disease. Here, these are discussed with reference to neuromuscular and neurosecretory functions of the human gastrointestinal (GI) tract. Tissues are obtained after informed consent, in collaboration with surgeons (surgical techniques help minimize variables) and pathologists. Given the difficulties of directly recording from human myenteric neurones (embedded between muscle layers), enteric motor nerve functions are studied by measuring muscle contractions/relaxations evoked by electrical stimulation of intrinsic nerves; responses are regionally dependent, often involving cholinergic and nitrergic phenotypes. Enteric sensory functions can be studied by evoking the peristaltic reflex, involving enteric sensory and motor nerves, but this has rarely been achieved. As submucosal neurones are more accessible (after removing the mucosa), direct neuronal recordings are possible. Neurosecretory functions are studied by measuring changes in short-circuit current across the mucosa. For all experiments, basic questions must be addressed. Because tissues are from patients, what are the controls and the influence of disease? How long does it take before function fully recovers? What is the impact of age- and gender-related differences? What is the optimal sample size? Addressing these and other questions minimizes variability and raises the scientific credibility of human tissue research. Such studies also reduce animal use. Further, the many differences between animal and human GI functions also means that human tissue research must question the ethical validity of using strains of animals with unproved translational significance.

Motilin: towards a new understanding of the gastrointestinal neuropharmacology and therapeutic use of motilin receptor agonists.

UNLABELLED: The gastrointestinal hormone motilin has been known about for >40 years, but after identification of its receptor and subsequent development of new tools and methods, a reappraisal of its actions is required. Firstly, it is important to note that motilin and ghrelin receptors are members of the same family (similar genomic organization, gastrointestinal distribution and abilities to stimulate gastrointestinal motility), yet each fails to recognize the ligand of the other; and whereas ghrelin and ghrelin receptors are widespread outside the gastrointestinal tract, motilin and its receptors are largely restricted to the gastrointestinal tract. Secondly, although some studies suggest motilin has activity in rodents, most do not, and receptor pseudogenes exist in rodents. Thirdly, motilin preferentially operates by facilitating enteric cholinergic activity rather than directly contracting the muscle, despite the relatively high expression of receptor immunoreactivity in muscle. This activity is ligand-dependent, with short-lasting actions of motilin contrasting with longer-lasting actions of the non-selective and selective motilin receptor agonists erythromycin and GSK962040. Finally, the use of erythromycin (also an antibiotic drug) to treat patients requiring acceleration of gastric emptying has led to concerns over safety and potential exacerbation of antibiotic resistance. Replacement motilin receptor agonists derived from erythromycin (motilides) have been unsuccessful. New, non-motilide, small molecule receptor agonists, designed to minimize self-desensitization, are now entering clinical trials for treating patients undergoing enteral feeding or with diabetic gastroparesis. Thus, for the translational pharmacologist, the study of motilin illustrates the need to avoid overreliance on artificial systems, on structural information and on animal studies. LINKED ARTICLES: This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7.

Regional- and agonist-dependent facilitation of human neurogastrointestinal functions by motilin receptor agonists.

BACKGROUND AND PURPOSE: Delayed gastric emptying is poorly managed. Motilin agonists are potential treatments but inadequate understanding into how enteric nerve functions are stimulated compromises drug/dose selection. Resolution is hampered by extreme species dependency so methods were developed to study human gastrointestinal neuromuscular activities and the neurobiology of motilin. EXPERIMENTAL APPROACH: Protocols to study neuromuscular activities were developed for different regions of human stomach and intestine (71 patients) using circular muscle preparations and electrical field stimulation (EFS) of intrinsic nerves. Other tissues were fixed for immunohistochemistry. KEY RESULTS: EFS evoked contractions and/or relaxations via cholinergic and nitrergic neurons, with additional tachykinergic activity in colon; these were consistent after 154 min (longer if stored overnight). Motilin 1-300 nM and the selective motilin agonist GSK962040 0.1-30 µM acted pre-junctionally to strongly facilitate cholinergic contractions of the antrum (E(max) ≈ 1000% for motilin), with smaller increases in fundus, duodenum and ileum; high concentrations increased baseline muscle tension in fundus and small intestine. There were minimal effects in the colon. In the antrum, cholinergic facilitation by motilin faded irregularly, even with peptidase inhibitors, whereas facilitation by GSK962040 was long lasting. Motilin receptor immunoreactivity was identified in muscle and myenteric plexus predominantly in the upper gut, co-expressed with choline acetyltransferase in neurons. CONCLUSIONS AND IMPLICATIONS: Motilin and GSK962040 strongly facilitated cholinergic activity in the antrum, with lower activity in fundus and small intestine only. Facilitation by motilin was short lived, consistent with participation in migrating motor complexes. Long-lasting facilitation by GSK962040 suggests different receptor interactions and potential for clinical evaluation.

GSK962040: a small molecule motilin receptor agonist which increases gastrointestinal motility in conscious dogs.

BACKGROUND: GSK962040, a small molecule motilin receptor agonist, was identified to address the need for a safe, efficacious gastric prokinetic agent. However, as laboratory rodents lack a functional motilin system, studies in vivo have been limited to a single dose, which increased defecation in rabbits. Motilin agonists do not usually increase human colonic motility, so gastric prokinetic activity needs to be demonstrated. METHODS: The effect of intravenous GSK962040 on gastro-duodenal motility was assessed in fasted dogs implanted with strain gauges. Activity was correlated with blood plasma concentrations of GSK962040 (measured by HPLC-MS/MS) and potency of GSK962040 at the dog recombinant receptor [using a Fluorometric Imaging Plate Reader (Molecular Devices, Wokingham, UK) after expression in HEK293 cells]. KEY RESULTS: GSK962040 activated the dog motilin receptor (pEC(50) 5.79; intrinsic activity 0.72, compared with [Nle(13) ]-motilin). In vivo, GSK962040 induced phasic contractions, the duration of which was dose-related (48 and 173 min for 3 and 6 mg kg(-1) ), driven by mean plasma concentrations >1.14 µmol L(-1) . After the effects of GSK962040 faded, migrating motor complex (MMC) activity returned. Migrating motor complex restoration was unaffected by 3 mg kg(-1) GSK962040 but at 6 mg kg(-1) , MMCs returned 253 min after dosing, compared with 101 min after saline (n=5 each). CONCLUSIONS & INFERENCES: The results are consistent with lower potency for agonists at the dog motilin receptor, compared with humans. They also define the doses of GSK962040 which stimulate gastric motility. Correlation of in vivo and in vitro data in the same species, together with plasma concentrations, guides further studies and translation to other species.

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.

Should the first priority in cardiovascular risk management be those with prior cardiovascular disease?

BACKGROUND: Cardiovascular disease (CVD) prevention guidelines typically dichotomise patients by history of CVD, as patients with prior CVD are assumed to be at high CVD risk, whatever their CVD risk profiles. OBJECTIVE: To assess the appropriateness of this practice by comparing CVD event rates of patients with and without prior CVD, over and above risk predicted by standard CVD risk factors. METHODS: Between 2002 and 2007 CVD risk assessments were generated using a web-based Framingham risk prediction algorithm in routine primary care. Individual risk profiles were subsequently linked to national hospitalisation and death records. Observed and predicted (Framingham) CVD risk were compared in patients with and without prior CVD. RESULTS: 35 760 patients were assessed including 10.4% with prior CVD. Of 1216 first CVD events during an average follow-up of 2.05 years, 42% occurred in those with prior CVD. Among those without prior CVD, the predicted Framingham five-year CVD risk was similar to the observed risk extrapolated to five years; in the highest Framingham risk band (>20% five-year risk), observed risk was 25.3%. Among those with prior CVD the observed risk extrapolated to five years rose from 21.7% in the lowest Framingham risk band (<5%) to 49% in the highest (>20%). CONCLUSIONS: Patients with prior CVD have five-year CVD risks approximately 20% higher, in absolute terms than patients without prior CVD, after accounting for standard risk factors. Almost half the CVD events occurred in those with prior CVD. These patients should be the highest priority for intensive preventive management in primary care.

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.

Tillering in grain sorghum over a wide range of population densities: identification of a common hierarchy for tiller emergence, leaf area development and fertility.

Most studies of tiller development have not related the physiological and morphological features of each culm to its subsequent fertility. This introduces problems when trying to account for the effects of tillering on yield in crop models. The objective of this study was to detect the most likely early determinants of tiller fertility in sorghum by identifying hierarchies for emergence, fertility and grain number of tillers over a wide range of assimilate availabilities. Emergence, phenology, leaf area development and dry weight partitioning were quantified weekly for individual tillers and main culms of tillering and uniculm plants grown at one of four densities, from two to 16 plants m(-2). For a given plant in any given density, the same tiller hierarchy applied for emergence of tillers, fertility of the emerged tillers and their subsequent grain number. These results were observed over a range of tiller fertility rates (from 7 to 91%), fertile tiller number per plant at maturity (from 0.2 to 4.7), and tiller contribution to grain yield (from 5 to 78 %). Tiller emergence was most probably related to assimilate supply and light quality. Development, fertility and contribution to yield of a specific tiller were highly dependent on growing conditions at the time of tiller emergence, particularly via early leaf area development of the tiller, which affected its subsequent leaf area accumulation. Assimilate availability in the main culm at the time of tiller emergence was the most likely early determinant of subsequent tiller fertility in this study.

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.

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.

A capillary whole blood method for measuring the INR.

This study describes a method of measuring the INR on native whole blood capillary samples using Innovin recombinant thromboplastin. Modification of the reagent was necessary to compensate for the nonoptimal level of calcium in the sample/reagent mixture. Ninety-five percent of results obtained by the capillary blood method were no more than 0.42 INR higher or 0.38 INR lower than the venous blood method. The effect of changes in haematocrit was minimal. Significant differences in results were found between the Innovin and Thrombotest capillary blood methods. Provided the reagent was properly stored, there was no reagent drift and satisfactory results were obtained on samples supplied by UKNEQAS (coagulation) from previous trials. The method described is a convenient, simple and accurate method of measuring the INR using native capillary whole blood and Innovin recombinant thromboplastin.

Health-related quality of life among long-term survivors of stroke : results from the Auckland Stroke Study, 1991-1992.

BACKGROUND AND PURPOSE: The consequences of stroke are a major health concern. This study was conducted to compare the health-related quality of life among long-term survivors of stroke with that of the general population. METHODS: Our data are taken from a population-based case-control study of all 6-year survivors of stroke with an age- and sex-matched control population. SF-36 mean scores for cases were compared with raw and standardized control and New Zealand norm mean scores. RESULTS: Of the original 1761 registered cases, 639 were still alive at 6-year follow-up, and all of these participated in the study. Case patients were more likely than control subjects to be dependent in all basic activities of daily living. Crude mean scores were lower for women; as age increased; for those living in institutions; when the SF-36 was completed by proxy; and when help was required with the activities of daily living. Cases had statistically lower mean scores than both the control group and New Zealand norms for physical functioning and general health. After standardization for age and sex, no differences were found between cases and controls in mental health and bodily pain. CONCLUSIONS: Health-related quality of life appears to be relatively good for the majority of patients 6 years after stroke. Despite significant ongoing physical disability, survivors of stroke appear to adjust well psychologically to their illness.

Sensitivity of Shah, Vanclay and Cooper's modified Barthel Index.

OBJECTIVE: To investigate whether Shah, Vanclay and Cooper's modification of the Barthel Index improved its sensitivity to change. DESIGN: Correlational study. SETTING: School of Occupational Therapy at Auckland Institute of Technology, Auckland, New Zealand. SUBJECTS: One hundred subjects requiring rehabilitation following a stroke. MAIN OUTCOME MEASURES: Change in function which was measured using Shah, Vanclay and Cooper's (1989) modified Barthel Index and walking speed over 10 metres. RESULTS: Five statistical analyses were undertaken, none of which demonstrated clear superiority of one measure over the other. CONCLUSIONS: The study did not indicate the modified Barthel Index to be more sensitive to change than the 20-point Barthel Index for this population. The statistical analysis strategies utilized are recommended for similar studies.