A pilot randomized controlled trial comparing effectiveness of prism glasses, visual search training and standard care in hemianopia.

OBJECTIVE: Pilot trial to compare prism therapy and visual search training, for homonymous hemianopia, to standard care (information only). METHODS: Prospective, multicentre, parallel, single-blind, three-arm RCT across fifteen UK acute stroke units. PARTICIPANTS: Stroke survivors with homonymous hemianopia. INTERVENTIONS: Arm a (Fresnel prisms) for minimum 2 hours, 5 days per week over 6 weeks. Arm b (visual search training) for minimum 30 minutes, 5 days per week over 6 weeks. Arm c (standard care-information only). INCLUSION CRITERIA: Adult stroke survivors (>18 years), stable hemianopia, visual acuity better than 0.5 logMAR, refractive error within ±5 dioptres, ability to read/understand English and provide consent. OUTCOMES: Primary outcomes were change in visual field area from baseline to 26 weeks and calculation of sample size for a definitive trial. Secondary measures included Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual, Short Form-12 questionnaires and Radner reading ability. Measures were post-randomization at baseline and 6, 12 and 26 weeks. RANDOMIZATION: Randomization block lists stratified by site and partial/complete hemianopia. BLINDING: Allocations disclosed to patients. Primary outcome assessor blind to treatment allocation. RESULTS: Eighty-seven patients were recruited: 27-Fresnel prisms, 30-visual search training and 30-standard care; 69% male; mean age 69 years (SD 12). At 26 weeks, full results for 24, 24 and 22 patients, respectively, were compared to baseline. Sample size calculation for a definitive trial determined as 269 participants per arm for a 200 degree2 visual field area change at 90% power. Non-significant relative change in area of visual field was 5%, 8% and 3.5%, respectively, for the three groups. Visual Function Questionnaire responses improved significantly from baseline to 26 weeks with visual search training (60 [SD 19] to 68.4 [SD 20]) compared to Fresnel prisms (68.5 [SD 16.4] to 68.2 [18.4]: 7% difference) and standard care (63.7 [SD 19.4] to 59.8 [SD 22.7]: 10% difference), P=.05. Related adverse events were common with Fresnel prisms (69.2%; typically headaches). CONCLUSIONS: No significant change occurred for area of visual field area across arms over follow-up. Visual search training had significant improvement in vision-related quality of life. Prism therapy produced adverse events in 69%. Visual search training results warrant further investigation.

Uncertainties in Steric Sea Level Change Estimation During the Satellite Altimeter Era: Concepts and Practices.

This article presents a review of current practice in estimating steric sea level change, focussed on the treatment of uncertainty. Steric sea level change is the contribution to the change in sea level arising from the dependence of density on temperature and salinity. It is a significant component of sea level rise and a reflection of changing ocean heat content. However, tracking these steric changes still remains a significant challenge for the scientific community. We review the importance of understanding the uncertainty in estimates of steric sea level change. Relevant concepts of uncertainty are discussed and illustrated with the example of observational uncertainty propagation from a single profile of temperature and salinity measurements to steric height. We summarise and discuss the recent literature on methodologies and techniques used to estimate steric sea level in the context of the treatment of uncertainty. Our conclusions are that progress in quantifying steric sea level uncertainty will benefit from: greater clarity and transparency in published discussions of uncertainty, including exploitation of international standards for quantifying and expressing uncertainty in measurement; and the development of community "recipes" for quantifying the error covariances in observations and from sparse sampling and for estimating and propagating uncertainty across spatio-temporal scales.

Precise microdissection of human prostate cancers reveals genotypic heterogeneity.

To determine the incidence of genetic heterogeneity in primary prostate cancer, we have microdissected 125 tumor and mesenchymal foci from 18 patient biopsies and analyzed the DNA for loss of heterozygosity using PCR microsatellite markers. In 100% of patients with genetic lesions on chromosome 8p, there was evidence for intratumoral genetic heterogeneity. There was also a low but significant incidence of loss of heterozygosity in mesenchymal tissue. Our results show that phenotypically similar tumor foci can have different genotypes and provide evidence for the multifocality of tumor development in the prostate.

Effect of exogenous cholecystokinin (CCK)-8 on food intake and plasma CCK, leptin, and insulin concentrations in older and young adults: evidence for increased CCK activity as a cause of the anorexia of aging.

Healthy aging is associated with reductions in appetite and food intake--the so-called anorexia of aging, which may predispose to protein-energy malnutrition. One possible cause of the anorexia of aging is an increased satiating effect of cholecystokinin (CCK). To investigate the impact of aging on the satiating effects of CCK, 12 young and 12 older healthy subjects received 25-min iv infusions of saline (control) and CCK-8, 1 ng/kg per min or 3 ng/k per min, on 3 separate days before a test meal. Older subjects ate less than young subjects, and food intake was suppressed 21.6% by CCK-8, compared with the control day (P < 0.05). The suppression of energy intake by CCK-8 in older subjects was twice that in young subjects (32 +/- 6% vs. 16 +/- 6% SEM, P < 0.05) and was related to plasma CCK-8 concentrations, which were higher at baseline (P < 0.05) and increased more during CCK-8 infusions in older than young subjects (P < 0.01). The extent of suppression of food intake per given rise in plasma CCK-8 concentrations did not differ between the two age groups (P = 0.35). Endogenous CCK concentrations were higher at baseline in older subjects (P < 0.001) and decreased during the CCK-8 but not control infusions (P < 0.01), suggesting that CCK suppresses its own release. Plasma leptin concentrations were not affected by CCK infusion, whereas postprandial insulin concentrations were lowered and the peak postprandial glucose concentration was delayed but not affected by CCK-8 infusion. Because older people retain their sensitivity to the satiating effects of exogenous CCK and plasma endogenous CCK concentrations are higher in older people, increased CCK activity may contribute to the anorexia of aging.

Effects of age on concentrations of plasma cholecystokinin, glucagon-like peptide 1, and peptide YY and their relation to appetite and pyloric motility.

BACKGROUND: Aging is associated with a decrease in appetite and a slowing of gastric emptying. The gastrointestinal hormones cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) may mediate these changes. OBJECTIVE: We investigated whether aging influenced the secretion of CCK, GLP-1, and PYY and their effects on appetite and pyloric motility. DESIGN: Eight healthy older (65-80 y) and 7 younger (20-34 y) men received isoenergetic (12.1 kJ/min) intraduodenal infusions of lipid and glucose for 120 min on separate days. Plasma CCK, GLP-1, and PYY concentrations were measured. RESULTS: Plasma CCK concentrations were higher in older than in younger subjects (P = 0.004) as a result of higher baseline values (4.7+/-0.2 compared with 3.2+/-0.2 pmol/L; P < 0.0001) and a greater rise during lipid infusion (increase from baseline: 7.1+/-0.5 compared with 5.3+/-0.6 pmol/L; P = 0.048). Plasma GLP-1 and PYY concentrations were not significantly different between groups. The decrease in hunger during intraduodenal lipid infusion was inversely related to the increase in CCK, GLP-1, and PYY in younger but not older subjects. During intraduodenal lipid infusion, the increase in isolated pyloric pressure wave (IPPW) frequency was positively related to GLP-1 and PYY and the increase in IPPW amplitude was positively related to CCK in older but not younger subjects, whereas the increase in IPPW amplitude and pyloric tone was negatively related to GLP-1 and PYY in younger subjects. CONCLUSIONS: Human aging is associated with increased CCK concentrations, which may contribute to the slowing of gastric emptying, mediated by increased pyloric motility. The role of increased plasma CCK concentrations in mediating the age-related decrease in appetite remains to be established.

Effects of aging on the opioid modulation of feeding in humans.

OBJECTIVES: To determine whether aging is associated with a reduction in the opioid modulation of feeding, which may be important in the pathogenesis of the "anorexia of aging." DESIGN: Three studies on separate days, in randomized order and double-blind fashion. SETTING: Clinical Human Research Laboratory, Department of Medicine, RAH, Adelaide, Australia. PARTICIPANTS: Twelve older (5 male/7 female) (age 65-84) and 12 young (5 male/7 female) (age 20-26) healthy subjects. INTERVENTION: Subjects received in double-blinded random order, intravenous bolus (10 minutes) and then continuous (140 minutes) infusions of saline (control), naloxone low dose (LD) (bolus 27 microg/kg; continuous 50 microg/kg/hr), or naloxone high dose (HD) (bolus 54.5 microg/kg; continuous 100 microg/kg/hr). MEASUREMENTS: After 120 minutes, subjects were offered a buffet meal, and their energy intake was quantified. Hunger, fullness, nausea, and drowsiness were assessed using visual analogue scales. RESULTS: The naloxone LD and HD infusions had no significant effect on ratings of hunger, fullness, or nausea, but increased drowsiness (P < .01) compared with the control infusion in both age groups. Older subjects ate less (P < .001) at the buffet meal than young subjects during all three infusions. Naloxone infusions reduced energy intake compared with control (P < .001), LD by 13.2 +/- 5.0% and HD by 10.7 +/- 5.0%, with no difference between the doses (P = .71). Overall, naloxone suppressed energy intake in both young and older subjects (P < .01). This suppression was slightly, but not significantly, greater in young than in older subjects (mean of LD and HD 16.4 +/- 4.9% vs 7.5 +/- 4.9%, P = .42), because of a trend to reduced suppression in older women. CONCLUSIONS: We conclude that healthy older adults retain their sensitivity to the suppressive effects of naloxone on food intake. Possible gender differences in this sensitivity warrant further investigation. A decline in opioid activity is unlikely to contribute substantially to the physiological anorexia of aging observed in older people.

Guar gum reduces postprandial hypotension in older people.

OBJECTIVE: To determine whether slowing of gastric emptying and glucose absorption with guar gum would reduce the fall in blood pressure after an oral glucose load in older subjects. DESIGN: A randomized, experimental, cross-over study. SETTING: Department of Nuclear Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia. PARTICIPANTS: Ten healthy subjects, age 67 to 78. MEASUREMENTS: Simultaneous measurements of gastric emptying, blood pressure, blood glucose, serum insulin, and oral glucose absorption (3-O-methyl-D-glucose [3-OMG]) on two occasions after ingestion of 300 mL water containing 50 g glucose and 30 mL lemon juice, 3 g 3-OMG labeled with 99mTc-sulphur colloid; with or without 9 g guar gum. Blood pressure and gastric emptying were monitored for 180 minutes. RESULTS: The magnitude of the falls in systolic (P = .02), diastolic (P < .05), and mean arterial (P = .05) blood pressure were less, and gastric emptying slower (P < .05), after guar. Blood glucose, insulin, and 3-OMG concentrations were reduced (P < .001 for all) by guar. 3-OMG concentrations were inversely related to the intragastric retention of glucose (r = -0.72, P = .02) and blood pressure was inversely related to 3-OMG (r = -0.64, P < .05) after the drink without guar. The blood glucose concentration was related to 3-OMG (r > 0.64, P < .05). CONCLUSION: Guar gum reduces the magnitude of the fall in blood pressure after oral glucose. Slowing of gastric emptying and glucose absorption may represent a novel approach to the treatment of postprandial hypotension.

In vitro models to study cellular differentiation and function in human prostate cancers.

In Vitro Models to Study Cellular Differentiation and Function in Human Prostate Cancers. To augment the currently available models of human prostate cancer in vitro, we have established extended life-span epithelial cultures from biopsies of well-differentiated prostate cancers. The genetic identity of the target cells was assessed by allelotyping, using microsatellites located on chromosome 8p, and microdissection of tissues and primary cell cultures. Cells with an extended life span (PxE6) were derived by recombinant retrovirus infection to introduce the human papilloma virus E6 gene (epithelial cells). Immunophenotyping of the resultant cell strains confirmed retention of differentiated cell functions, and the genotype of the E6-expressing epithelial cells was stable, while SV40-immortalized cultures were more unstable, leading to tetraploidy. All PxE6 cells eventually senesced, but an immortalized epithelial culture, P4E6, was derived from one of the epithelial cultures. The properties of this cell line, which remains close to diploid, are similar to those of early prostate cancer cells, and it retains expression of many prostate-associated antigens, such as prostate-specific antigen (PSA).

Relation between food intake and visual analogue scale ratings of appetite and other sensations in healthy older and young subjects.

OBJECTIVE: Visual analogue scales are widely used in appetite research, yet the validity of these scales to evaluate appetite and mood has not been assessed in older subjects. The aim of this study was to determine the relations between food intake and visual analogue scale (VAS) ratings of appetite and nonappetite sensations in healthy older and young subjects. DESIGN: Retrospective combined analysis of four single-blind, randomised, controlled appetite studies. SETTING: All studies were conducted in the University of Adelaide, Department of Medicine, Adelaide, Australia. SUBJECTS: A total of 45 healthy young men (n=24) and women (n=21) aged 18-35 y and 45 healthy older men (n=24) and women (n=21) aged 65-85 y were recruited by advertisement. INTERVENTIONS: Oral, intraduodenal or intravenous administration of treatments which suppressed food intake were compared to control. Up to 90 min after treatment, a test meal was offered and subjects ate freely for between 30 and 60 min. Perceptions were assessed by 100-mm visual analogue scales administered at regular intervals. RESULTS: Food intake at the test meal was positively related to perceptions of hunger, drowsiness, and calmness at both baseline and premeal (r>0.16, P<0.05), and inversely related to premeal ratings of fullness (r> 0.2, P<0.05) in both older and young subjects. Food intake was related to VAS ratings at least as strongly, if not more so, in older as in young subjects. CONCLUSIONS: These observations (i) confirm that food intake is related to perceptions of hunger and fullness as assessed by VAS in healthy older and young subjects, and (ii) suggest that sensations, not obviously associated with appetite, including 'drowsiness' and 'calmness', are also associated with food intake.

Risk of neoplasia and malignancy in "dominant" thyroid swellings.

OBJECTIVE: To determine the risk of neoplasia and malignancy in "dominant" thyroid swellings. DESIGN: Prospective analysis during six years. SETTING: Thyroid clinic serving the Grampian region. PATIENTS: 574 consecutive patients presenting with a discrete thyroid swelling, of whom 179 (31%) were classified clinically as having a dominant area of enlargement within a multinodular gland. RESULTS: After clinical and cytological assessment 77 dominant swellings were excised. Of the excised swellings, 45 were non-neoplastic and 32 neoplastic, including 11 malignant lesions. The minimum incidence of neoplasia and malignancy in all 179 dominant swellings was therefore 18% and 6% respectively. CONCLUSION: Dominant thyroid swellings should be regarded with greater clinical suspicion than has been traditional.

Evaluation of computer based clinical decision support system and risk chart for management of hypertension in primary care: randomised controlled trial.

OBJECTIVES: To investigate the effect of a computer based clinical decision support system and a risk chart on absolute cardiovascular risk, blood pressure, and prescribing of cardiovascular drugs in hypertensive patients. DESIGN: Cluster randomised controlled trial. SETTING: 27 general practices in Avon. PARTICIPANTS: 614 patients aged between 60 and 79 years with high blood pressure. INTERVENTIONS: Patients were randomised to computer based clinical decision support system plus cardiovascular risk chart; cardiovascular risk chart alone; or usual care. MAIN OUTCOME MEASURES: Percentage of patients in each group with a five year cardiovascular risk >/=10%, systolic blood pressure, diastolic blood pressure, prescribing of cardiovascular drugs. RESULTS: Patients in the computer based clinical decision support system and chart only groups were no more likely to have cardiovascular risk reduced to below 10% than patients receiving usual care. Patients in the computer based clinical decision support group were more likely to have a cardiovascular risk >/=10% than chart only patients, odds ratio 2.3 (95% confidence interval 1.1 to 4.8). The chart only group had significantly lower systolic blood pressure compared with the usual care group (difference in means -4.6 mm Hg (95% confidence interval -8.4 to -0.8)). Reduction of diastolic blood pressure did not differ between the three groups. The chart only group were twice as likely to be prescribed two classes of cardiovascular drugs and over three times as likely to be prescribed three or more classes of drugs compared with the other groups. CONCLUSIONS: The computer based clinical decision support system did not confer any benefit in absolute risk reduction or blood pressure control and requires further development and evaluation before use in clinical care can be recommended. Use of chart guidelines are associated with a potentially important reduction in systolic blood pressure.

Management of isolated thyroid swellings: a prospective six year study of fine needle aspiration cytology in diagnosis.

OBJECTIVE: To audit the accuracy and impact on the frequency of operation of fine needle aspiration cytology of isolated thyroid swellings. DESIGN: Prospective analysis over six years of cytological predictions compared with histological findings. SETTING: Thyroid clinic serving the Grampian region. PATIENTS: 395 Consecutive patients presenting with an isolated thyroid swelling, 307 of whom underwent surgical excision. Analysis was confined to a subgroup of 283 patients with satisfactory aspirates who were operated on. RESULTS: The positive predictive value of aspiration cytology for detecting malignant disease was 100% and the sensitivity 83%. The sensitivity for the detection of neoplasia (frank malignancy together with follicular adenomas) was 76%. The specificity was 58% and the overall accuracy 69%. Recalculation of data in previous papers with strict criteria showed the accuracy of aspiration cytology to be variable and lower than is widely accepted. Since the introduction of aspiration cytology 21% fewer operations for isolated thyroid swellings have been performed. CONCLUSIONS: As a basis of selection for surgical excision of isolated thyroid swellings according to prediction of neoplasia fine needle aspiration cytology is less reliable than is widely accepted. It is an adjunct to management rather than a definitive test, and negative cytological results do not exclude neoplastic disease. Further study should take account of the implications of repeated clinic attendances for review and aspiration as these may culminate in delayed surgical treatment.

A randomised controlled trial to compare the clinical and cost-effectiveness of prism glasses, visual search training and standard care in patients with hemianopia following stroke: a protocol.

INTRODUCTION: Homonymous hemianopia is a common and disabling visual problem after stroke. Currently, prism glasses and visual scanning training are proposed to improve it. The aim of this trial is to determine the effectiveness of these interventions compared to standard care. METHODS AND ANALYSIS: The trial will be a multicentre three arm individually randomised controlled trial with independent assessment at 6 week, 12 week and 26 week post-randomisation. Recruitment will occur in hospital, outpatient and primary care settings in UK hospital trusts. A total of 105 patients with homonymous hemianopia and without ocular motility impairment, visual inattention or pre-existent visual field impairment will be randomised to one of three balanced groups. Randomisation lists will be stratified by site and hemianopia level (partial or complete) and created using simple block randomisation by an independent statistician. Allocations will be disclosed to patients by the treating clinician, maintaining blinding for outcome assessment. The primary outcome will be change in visual field assessment from baseline to 26 weeks. Secondary measures will include the Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual-5D and Short Form-12 questionnaires. Analysis will be by intention to treat. ETHICS AND DISSEMINATION: This study has been developed and supported by the UK Stroke Research Network Clinical Studies Group working with service users. Multicentre ethical approval was obtained through the North West 6 Research ethics committee (Reference 10/H1003/119). The trial is funded by the UK Stroke Association. Trial Registration: Current Controlled Trials ISRCTN05956042. Dissemination will consider usual scholarly options of conference presentation and journal publication in addition to patient and public dissemination with lay summaries and articles. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05956042.

Pharmacological characterization of histamine receptors in the mouse seminal vesicle: sensitivity to H1- and H2-receptor agonists and antagonists.

Neither histamine nor the more specific H1- or H2-receptor agonists (0.2-220 micrometers) produced a contraction of the mouse seminal vesicle. However, all these agonists decreased resting tone and caused a dose-related inhibition of the electrically evoked twitch responses in these concentrations. The slopes of the percentage response versus log molar concentration curves for all agonists did not differ significantly from that of histamine. The rank order and relative potency of the compounds tested were: histamine (100%) greater than dimaprit (65%) greater than 4-methylhistamine (36%) greater than 2-methylhistamine (4.5%) greater than 2-(2-thiazolyl) ethylamine (1.7%). Inhibition of the twitch response by histamine was antagonized by cimetidine (3.5-140 micrometers) but not by mepyramine (0.1-1.0 micrometer). The slopes of Schild plots for cimetidine against histamine and dimaprit did not differ from unity, and the calculated pA2 values of cimetidine were 5.70 and 5.55, respectively. Histamine (2.2 and 6.5 micrometers) inhibited the contraction elicited by a submaximal concentration of exogenous noradrenaline (1 micrometer); this inhibition could also be selectively antagonized by cimetidine. These results demonstrate that histamine and selective H1- and H2-receptor agonists have an inhibitory action on the mouse seminal vesicle, and that this action is mediated via a post-junctional H2-receptor. The calculated pA2 values of cimetidine against histamine and dimaprit also suggest that the receptor in the mouse seminal vesicle of the conventional H1-type. The results further indicate that an H1-receptor is absent in the mouse seminal vesicle.

Species differences in histamine receptors in the seminal vesicle.

Histamine and specific H1- and H2-receptor agonists and antagonists in conjunction with phentolamine and (or) reserpine pretreatment were used to characterize histamine receptor(s) in the seminal vesicle of rat and guinea pig. Stimulation of H1 receptors produced a contraction whereas that of H2 receptors inhibited the contraction evoked by electrical field stimulation. The rat seminal vesicle was relatively refractory to the action of histamine and selective H1- or H2-receptor agonists. The evidence, however, does not preclude the presence of a small population of H2 receptors in this preparation. The guinea pig seminal vesicle contained both H1 and H2 receptors but the H1 receptors were dominant. The presence of H2 receptors in the guinea pig seminal vesicle could be demonstrated either with histamine after blockade of the dominant H1 receptor (mepyramine) or with dimaprit, a selective H2-receptor agonist. In a previous study, we reported that the mouse seminal vesicle contained an inhibitory H2 receptor but was virtually devoid of an excitatory H1 receptor. Data from that study and the present one indicate that there are marked qualitative and quantitative differences in the distribution of the two types of histamine receptors in the seminal vesicles of different species.

Quality of life for patients in an end-stage renal disease programme.

A group of 128 patients in an end-stage renal disease programme in Natal was studied in order to assess the relative success of the different treatment modalities in achieving optimal patient rehabilitation in regard to employability and social, psychological and medical status. Confirmation that successful transplantation achieves the best quality of life was obtained.

The effect of acute hyperglycaemia on appetite and food intake in Type 1 diabetes mellitus.

AIMS: To determine the effects of acute hyperglycaemia on appetite and food intake in Type 1 diabetes mellitus. METHODS: Two separate studies, each involving eight adults with uncomplicated Type 1 diabetes, were performed: one in the fasted state (A) and the other after a nutrient preload (B). In both studies, perceptions of appetite (hunger and fullness) and food intake at a buffet meal were evaluated during euglycaemia (blood glucose, approximately 6 mmol/l) and hyperglycaemia (blood glucose, approximately 14 mmol/l). Both experiments were randomized and single-blind. In study A, appetite was assessed in the fasted state for 90 min before the buffet meal. In study B, a nutrient 'preload' of Ensure and milk containing 13C-octanoic acid was consumed 90 min before the meal. Gastric emptying of the preload was quantified with a radioisotopic breath test technique. RESULTS: There was no significant difference in plasma insulin concentrations between euglycaemia and hyperglycaemia in either study. In study A, there were no differences in hunger, fullness or energy intake between the two treatment days. In study B, subjects were slightly less hungry between the preload and buffet meal during hyperglycaemia than euglycaemia (P = 0.04), and tended to have slower gastric emptying during hyperglycaemia (emptying coefficient, 3.89 +/- 0.16 vs. 3.57 +/- 0.21; P = 0.052), but there was no difference in food intake between hyperglycaemia and euglycaemia. CONCLUSIONS: Acute hyperglycaemia suppresses hunger after a nutrient preload, but not in the fasted state, in patients with uncomplicated Type 1 diabetes. This effect is small and not associated with changes in food intake.