Predation risk drives long-term shifts in migratory behaviour and demography in a large herbivore population.

Migration is an adaptive life-history strategy across taxa that helps individuals maximise fitness by obtaining forage and avoiding predation risk. The mechanisms driving migratory changes are poorly understood, and links between migratory behaviour, space use, and demographic consequences are rare. Here, we use a nearly 20-year record of individual-based monitoring of a large herbivore, elk (Cervus canadensis) to test hypotheses for changing patterns of migration in and adjacent to a large protected area in Banff National Park (BNP), Canada. We test whether bottom-up (forage quality) or top-down (predation risk) factors explained trends in (i) the proportion of individuals using 5 different migratory tactics, (ii) differences in survival rates of migratory tactics during migration and whilst on summer ranges, (iii) cause-specific mortality by wolves and grizzly bears, and (iv) population abundance. We found dramatic shifts in migration consistent with behavioural plasticity in individual choice of annual migratory routes. Shifts were inconsistent with exposure to the bottom-up benefits of migration. Instead, exposure to landscape gradients in predation risk caused by exploitation outside the protected area drove migratory shifts. Carnivore exploitation outside the protected area led to higher survival rates for female elk remaining resident or migrating outside the protected area. Cause-specific mortality aligned with exposure to predation risk along migratory routes and summer ranges. Wolf predation risk was higher on migratory routes than summer ranges of montane-migrant tactics, but wolf predation risk traded-off with heightened risk from grizzly bears on summer ranges. A novel eastern migrant tactic emerged following a large forest fire that enhanced forage in an area with lower predation risk outside of the protected area. The changes in migratory behaviour translated to population abundance, where abundance of the montane-migratory tactics declined over time. The presence of diverse migratory life histories maintained a higher total population abundance than would have been the case with only one migratory tactic in the population. Our study demonstrates the complex ways in which migratory populations change over time through behavioural plasticity and associated demographic consequences because of individuals balancing predation risk and forage trade-offs.

Ageing in people with Prader-Willi syndrome: mortality in the UK population cohort and morbidity in an older sample of adults.

BACKGROUND: The past two decades have seen a great improvement in the care of people with Prader-Willi syndrome (PWS), particularly with regard to control of diet and behaviour management. Has this affected mortality rates or thrown up new issues regarding premature ageing or dementia? We investigated two aspects of ageing in people with PWS: (1) an estimate of mortality over 9 years in a cohort of people with PWS, originally recruited in 1998-2000; and (2) premature ageing or dementia in people aged ⩾40 years. METHOD: (1) A follow-up of the population-based 1998-2000 cohort to investigate the subsequent mortality rate; and (2) the recruitment and structured assessment of all members of the Prader-Willi Syndrome Association UK (PWSA-UK) aged ⩾40 years who agreed to participate. RESULTS: Follow-up of the population-based 1998-2000 cohort gave a mortality rate of at least 7/62 over 9 years (1.25% per annum; 20 untraced), age at death was between 13 and 59 years. Twenty-six members of the PWSA-UK aged ⩾40 years were recruited, 18 of whom had a genetic diagnosis (gd) of PWS. Twenty-two (14 gd) showed no evidence of dementia. Four, with possible symptoms, are described in more detail; all are female, of maternal uniparental disomy (mUPD) genetic subtype, or have a disomic region, and all have a long history of psychotic illness. CONCLUSIONS: The mortality rate in people with PWS seems to be declining. The subgroup of people with PWS due to UPD or disomic region with female gender and a history of psychosis may be at risk of early onset dementia.

A longitudinal follow-up study of people with Prader-Willi syndrome with psychosis and those at increased risk of developing psychosis due to genetic subtype.

BACKGROUND: People with Prader-Willi syndrome (PWS), a genetically defined developmental disorder, are at increased risk of developing psychotic illness. This is particularly the case for those with a genetic subtype of PWS called maternal uniparental disomy (mUPD), where rates of psychosis are more than 60% by early adult life. Little is known about the long-term course of their disorder. METHOD: Individuals who had had episodes of psychosis or were at increased risk of developing psychosis due to their genetic subtype and had taken part in a previous study were contacted. Ten people were untraceable or deceased, leaving a total of 38 potential participants. Of these, 28 agreed to take part in a follow-up interview or complete a questionnaire about their mental health and medication. This represented 20/35 (57.1%) people from the original study who had had psychosis and 8/13 (61.5%) people who were at risk due to their genetic subtype. They were thought to be representative of those groups as a whole based on IQ and number of episodes of psychosis. RESULTS: Two individuals had had recurrent episodes of psychosis while all others remained well. There were no new-onset cases of psychosis in those at risk. Individuals with PWS remained on high levels of psychiatric medication throughout the follow-up period. CONCLUSIONS: Recurrent episodes of psychosis may be rare in people with PWS once stability has been achieved in the management of their illness. We speculate that this may be due to the protective influence of medication.

Appetite hormones and the transition to hyperphagia in children with Prader-Willi syndrome.

OBJECTIVE: Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder with several nutritional phases during childhood proceeding from poor feeding, through normal eating without and with obesity, to hyperphagia and life-threatening obesity, with variable ages of onset. We investigated whether differences in appetite hormones may explain the development of abnormal eating behaviour in young children with PWS. SUBJECTS: In this cross-sectional study, children with PWS (n=42) and controls (n=9) aged 7 months-5 years were recruited. Mothers were interviewed regarding eating behaviour, and body mass index (BMI) was calculated. Fasting plasma samples were assayed for insulin, leptin, glucose, peptide YY (PYY), ghrelin and pancreatic polypeptide (PP). RESULTS: There was no significant relationship between eating behaviour in PWS subjects and the levels of any hormones or insulin resistance, independent of age. Fasting plasma leptin levels were significantly higher (mean ± s.d.: 22.6 ± 12.5 vs 1.97 ± 0.79 ng ml(-1), P=0.005), and PP levels were significantly lower (22.6 ± 12.5 vs 69.8 ± 43.8 pmol l(-1), P<0.001) in the PWS group compared with the controls, and this was independent of age, BMI, insulin resistance or IGF-1 levels. However, there was no significant difference in plasma insulin, insulin resistance or ghrelin levels between groups, though PYY declined more rapidly with age but not BMI in PWS subjects. CONCLUSION: Even under the age of 5 years, PWS is associated with low levels of anorexigenic PP, as in older children and adults. Hyperghrelinaemia or hypoinsulinaemia was not seen in these young children with PWS. Change in these appetite hormones was not associated with the timing of the transition to the characteristic hyperphagic phase. However, abnormal and/or delayed development or sensitivity of the effector pathways of these appetitive hormones (for example, parasympathetic and central nervous system) may interact with low PP levels, and later hyperghrelinaemia or hypoinsulinaemia, to contribute to hyperphagia in PWS.

The presentation, course and outcome of COVID-19 infection in people with Prader-Willi syndrome: unexpected findings from an international survey.

BACKGROUND: Prader-Willi syndrome (PWS), is a genetically determined neurodevelopmental disorder, associated with intellectual disabilities and a high incidence of obesity, diabetes mellitus, and respiratory disorders. We hypothesised that COVID-19, a viral infection which more severely affects people with these conditions, would, in people with PWS, present atypically and result in severe outcomes. METHOD: A structured on-line questionnaire was piloted with parents and professionals at the International Prader-Willi Syndrome Organization (IPWSO) and promoted internationally through their global network. Family members/other carers were asked to complete if someone they cared for with PWS was strongly suspected or confirmed as having COVID-19. RESULTS: Over 1 year of the pandemic 72 responses were received, 47 adults, 25 children. The following underlying conditions were present: 16 people with PWS were overweight and 18 obese, five had diabetes mellitus and 18 sleep apnoea. Main presenting symptoms were raised temperature, fatigue/daytime sleepiness, dry cough, headache/pain, and feeling unwell, with illnesses generally lasting less than a week. Length of illness was not significantly related to age, BMI, sex, or genetic subtype. No one was ventilated or in an intensive care unit or died, one person was in hospital for four days needing oxygen. CONCLUSIONS: Contrary to our hypothesis, the PWS cohort had asymptomatic infection or mild illness. A possible explanation, supported by anecdotal evidence from parents and professional carers, is that people with PWS have a degree of innate immunity to viral infections. However, likely selection effects and a relatively low number of responses means that further evidence is needed to test this hypothesis.

Development of the eating behaviour in Prader-Willi Syndrome: advances in our understanding.

Prader-Willi Syndrome (PWS) is a genetically determined neurodevelopmental disorder associated with mild to moderate intellectual disability, growth and sex-hormone deficiencies and a propensity to overeat that leads to severe obesity. The PWS phenotype changes from an early disinterest in food to an increasing pre-occupation with eating and a failure of the normal satiety response to food intake. The prevention of severe obesity is primarily through strict control of access to food and it is this aspect that most limits the independence of those with PWS. This review considers the eating disorder in PWS, specifically how the as yet uncertain genetics of the syndrome and the transition from the early to the later phenotype might account for the later hyperphagia. On the basis of behavioural and imaging studies, a failure of satiety and excessive activation of neural reward pathways have both been suggested. We speculate that the overeating behaviour, consequent upon one or other of the above, could either be due to a direct effect of the PWS genotype on the feeding pathways of the hypothalamus or a consequence of prenatal changes in the regulation of genes responsible for energy balance that sets a high satiation threshold. Understanding the overeating in PWS will lead to more focused and successful management and ultimately, treatment of this life-threatening behaviour.

Recognition of emotion in facial expression by people with Prader-Willi syndrome.

BACKGROUND: People with Prader-Willi syndrome (PWS) may have mild intellectual impairments but less is known about their social cognition. Most parents/carers report that people with PWS do not have normal peer relationships, although some have older or younger friends. Two specific aspects of social cognition are being able to recognise other people's emotion and to then respond appropriately. In a previous study, mothers/carers thought that 26% of children and 23% of adults with PWS would not respond to others' feelings. They also thought that 64% could recognise happiness, sadness, anger and fear and a further 30% could recognise happiness and sadness. However, reports of emotion recognition and response to emotion were partially dissociated. It was therefore decided to test facial emotion recognition directly. METHOD: The participants were 58 people of all ages with PWS. They were shown a total of 20 faces, each depicting one of the six basic emotions and asked to say what they thought that person was feeling. The faces were shown one at a time in random order and each was accompanied by a reminder of the six basic emotions. RESULTS: This cohort of people with PWS correctly identified 55% of the different facial emotions. These included 90% of happy faces, 55% each of sad and surprised faces, 43% of disgusted faces, 40% of angry faces and 37% of fearful faces. Genetic subtype differences were found only in the predictors of recognition scores, not in the scores themselves. Selective impairment was found in fear recognition for those with PWS who had had a depressive illness and in anger recognition for those with PWS who had had a psychotic illness. CONCLUSIONS: The inability to read facial expressions of emotion is a deficit in social cognition apparent in people with PWS. This may be a contributing factor in their difficulties with peer relationships.

Relationship between the IQ of people with Prader-Willi syndrome and that of their siblings: evidence for imprinted gene effects.

BACKGROUND: Genetic disorders occasionally provide the means to uncover potential mechanisms linking gene expression and physical or cognitive characteristics or behaviour. Prader-Willi syndrome (PWS) is one such genetic disorder in which differences between the two main genetic subtypes have been documented (e.g. higher verbal IQ in one vs. higher performance IQ in the other; slower than normal reaction time in one vs. normal in the other). In a population study of PWS, the IQ distribution of people with PWS was approximately normal. This raises the question of whether this distribution arose from a systematic effect of PWS on IQ (hypothesis 1) or whether it was the fortuitous result of random effects (hypothesis 2). METHOD: The correlation between PWS and sibling IQ was determined in order to discriminate between the two hypotheses. In the first case we would expect the correlation to be similar to that found in the general population (0.5); in the second case it would be zero. RESULTS: It was found that the overall PWS-sibling IQ correlation was 0.3 but that the two main genetic subtypes of PWS differed in their familial IQ relationships. As expected, the IQs of normal siblings correlated 0.5, and this was also the case with one genetic subtype of PWS (uniparental disomy) and their siblings, while the other subtype IQ correlated -0.07 with sibling IQ. CONCLUSIONS: This is a potentially powerful result that gives another clue to the role of genes on chromosome 15 in the determination of IQ. It is another systematic difference between the genetic subtypes of PWS, which needs an explanation in terms of the very small genetic differences between them.

The European Prader-Willi Syndrome Clinical Research Database: an aid in the investigation of a rare genetically determined neurodevelopmental disorder.

BACKGROUND: Prader-Willi Syndrome (PWS) is a rare genetically determined neurodevelopmental disorder with a complex phenotype that changes with age. The rarity of the syndrome and the need to control for different variables such as genetic sub-type, age and gender limits clinical studies of sufficient size in any one country. A clinical research database has been established to structure data collection and to enable multinational investigations into the development of children and adults with PWS. METHODS: As part of a joint basic science and clinical study of PWS funded through Framework 6 of the European Union (EU), an expert multidisciplinary group was established that included clinicians involved in PWS research and clinical practice, expert database software developers, and representatives from two national PWS Associations. This group identified the key issues that required resolution and the data fields necessary for a comprehensive database to support PWS research. RESULTS: The database consists of six 'index' entry points and branching panels and sub-panels and over 1200 data 'fields'. It is Internet-based and designed to support multi-site clinical research in PWS. An algorithm ensures that participant data are anonymous. Access to data is controlled in a manner that is compatible with EU and national laws. The database determines the assessments to be used to collect data thereby enabling the combining of data from different groups under specifically agreed conditions. The data collected at any one time will be determined by individual research groups, who retain control of the data. Over time the database will accumulate data on participants with PWS that will support future research by avoiding the need for repeat data collection of fixed data and it will also enable longitudinal studies and treatment trials. CONCLUSION: The development of the database has proved to be complex with various administrative and ethical issues to be addressed. At an early stage, it was important to clarify the exact function of the database. It was agreed that it was primarily to support grant-funded research rather than clinical practice. The most complex issues that had to be addressed were concerned with data ownership and establishing the rules for data entry, retrieval and sharing that are compatible with data protection laws, and which are likely to be acceptable to participants and their families and to individual research groups.

Bone mineral density and content of collegiate throwers: influence of maximum strength.

AIM: Bone changes in size and density in response to different levels of stress. Alterations to bone mineral density (BMD) appear to occur in a site specific manner. Even though BMD has been examined in many populations there is a paucity of data looking at strength-power athletes, such as throwers. Therefore, the purpose of this study was to examine the BMD of a group of USA Division I collegiate throwers (e.g. shot put, discus, etc.). METHODS: Seven throwers (4 males; 3 females) who were 19.0 + or - 0.9 years had their BMD compared to an age matched control group (n = 14; 8 women and 6 men) and normative data. BMD was measured with dual X-ray absorptometry. Potential right/left side and sex difference in BMD were also examined. Maximal isometric strength was assessed using a mid-thigh pull while standing on a forceplate which generated force-time curves. Peak force (PF) and normalized peak force (PFa) were then correlated with BMDs. RESULTS: Generally, throwers had denser bones with male throwers tending to have a greater total BMD (P < or = 0.05). The dominant arm BMD was slightly greater when compared to non-dominant arm (P < or = 0.05). Furthermore, total body BMD was related to PF (r = 0.68, r(2) = 0.46) and PFa (r = 0.56, r(2) = 0.31). CONCLUSIONS: Throwers have greater BMDs than non-athletes and most other athletes. However, throwers only showed a small indication of sidedness. It is likely that the BMDs observed in this study stem from the training intervention (e.g. whole body heavy lifting) undertaken by this population.

Pre-, peri- and postnatal complications in Prader-Willi syndrome in a UK sample.

BACKGROUND: Few studies describe in detail the pregnancy and early development of infants with Prader-Willi syndrome (PWS). However, variations at these early stages may partially account for differences in the later phenotype. A recent paper described an abnormally high number of problems in pregnancy and early infancy in a large sample of people with PWS but this sample was not homogeneous with respect to age and potentially liable to cohort effects. AIMS: To describe the early development of infants with PWS, younger and more homogeneous for age, and to investigate whether such high rates of perinatal problems are still present despite medical advances and whether there are differences according to the genetic subtypes. STUDY DESIGN: Using a structured interview, data were collected from mothers and from relevant GP and hospital records. SUBJECTS: Forty-six babies with PWS, born in a six-year period 2000-2006, and their mothers. OUTCOME MEASURES: Problems arising during pregnancy, the birth process and the neonatal period and the birth characteristics of the babies. RESULTS: An abnormally high number of problems associated with the early developmental period similar to those previously reported were observed. The only significant difference between the genetic subtypes was that mother's age was positively correlated with birth weight for UPD (and negatively correlated for deletion subtypes). CONCLUSIONS: High rates of, and variability in, the nature and severity of problems arising during early development have been confirmed. To establish whether variability in the later phenotype is influenced by such differences requires a longitudinal study.

Cross-cultural comparisons of obesity and growth in Prader-Willi syndrome.

Introduction The present study reports cross-cultural comparisons of body mass index (BMI) and growth in Prader-Willi syndrome, a neurodevelopmental disorder associated with obesity, growth restriction and mild learning disability. Our objectives were to: (1) compare rates of obesity in adults with Prader-Willi syndrome (PWS) in France, with data available from Belgium, the UK and the USA; (2) compare growth of French children with PWS with their counterparts in Germany and the USA; and (3) evaluate the contribution of genetic, medical and social parameters to obesity outcome in French children and adults with PWS. Method (1) Cross-sectional comparison of BMI of 40 French adults, 38 Belgian adults, 46 British adults and 292 North American adults; (2) Construction of growth curves for French children aged 2-20 years from longitudinal data for 150 individuals with PWS, and comparison with published growth curves from Germany and the USA; and (3) Longitudinal regression analysis of 141 French children and adults to determine the factors contributing to obesity outcome. Results A total of 82.5% French adults with PWS have BMI > 30 compared with 65.8% in Belgium (n.s.), 58.2% in the USA (P < 0.005), and 54.3% in the UK (P < 0.01). Higher rates of obesity in females vs. males were found in the USA sample (P < 0.001) but not in the other samples. In contrast to adults, growth curves for French children with PWS show similar rates of growth compared with children with PWS in Germany and the USA. The principal determining factors of BMI status in the French PWS population are age (P < 0.0001), cohort (born within the last 15 years vs. born over 15 years ago, P < 0.0002) and growth hormone replacement therapy (P < 0.0002). Significant subsidiary effects include domestic situation (P < 0.0001), genetic diagnosis (P < 0.0001) and age of diagnosis (P < 0.0001). Conclusions French adults with PWS have significantly higher rates of obesity than adults in the UK and the USA, but growth in French children with PWS is similar to the USA and Germany. Clinical management has a greater impact on obesity outcome in PWS than cultural factors.

Creation of genome-wide protein expression libraries using random activation of gene expression.

Here we report the use of random activation of gene expression (RAGE) to create genome-wide protein expression libraries. RAGE libraries containing only 5 x 10(6) individual clones were found to express every gene tested, including genes that are normally silent in the parent cell line. Furthermore, endogenous genes were activated at similar frequencies and expressed at similar levels within RAGE libraries created from multiple human cell lines, demonstrating that RAGE libraries are inherently normalized. Pools of RAGE clones were used to isolate 19,547 human gene clusters, approximately 53% of which were novel when tested against public databases of expressed sequence tag (EST) and complementary DNA (cDNA). Isolation of individual clones confirmed that the activated endogenous genes can be expressed at high levels to produce biologically active proteins. The properties of RAGE libraries and RAGE expression clones are well suited for a number of biotechnological applications including gene discovery, protein characterization, drug development, and protein manufacturing.

An effective conscious animal model of atrial fibrillation.

In 11 fully conscious dogs with chronically implanted spicardial electrodes, 50 Hz sine-wave electrical stimulation of the left atrium reliably and repeatedly produced an arrhythmia which was indistinguishable from atrial fibrillation in terms of its ECG appearance, the statistical properties of the ventricular response and responses to a number of pharmacological agents. In five of the 11 preparations this arrhythmia consistently persisted for periods in excess of 10 min following the cessation of stimulation, indicating an intrinsic cardiac basis for the arrhythmia and suggesting that it is true atrial fibrillation. A close correlation between the ventricular response to this arrhythmia and the degree of atrioventricular conductivity, together with the observation that dramatic changes can occur in ventricular responses without corresponding changes in atrial activity, suggest that the ventricular response is mainly a function of the atrio-ventricular conducting system. The experimental model described is useful for the study of both short and long term drug action no atrial fibrillation and for the evaluation of methods used therapeutically in attempts to terminate episodes of paroxysmal atrial fibrillation.

Matrix metalloproteinase (MMP)-9 type IV collagenase/gelatinase implicated in the pathogenesis of Sjögren's syndrome.

Type IV collagenases/gelatinases (matrix metalloproteinases MMP-2 and MMP-9) in labial salivary glands (LSG) and saliva in Sjögren's syndrome (SS) and healthy controls were studied. Zymograms and Western blots disclosed that SS saliva contained 92/82 kD MMP-9/type IV collagenase duplex. Specific activity measurement disclosed 53.1+/-9.8 U/mg protein MMP-9 in SS compared to 16.5+/-2.6 U/mg in healthy controls (p=0.01). MMP-2 did not differ between SS and controls. In SS salivary glands, MMP-2 and MMP-9 were also expressed, in addition to stromal fibroblasts and occasional infiltrating neutrophils, respectively, in acinar end piece cells. In addition, an effective proMMP-9 activator, human trypsin-2 (also known as tumor-associated trypsin-2 or TAT-2), was found in acinar end piece cells and in saliva. Interestingly, proteolytically processed MMP-9 was found in saliva (vide supra), and in vivo activated MMP-9 was significantly higher in SS than in controls (p=0.002). LSGs, particularly in SS, were characterized ultrastructurally by areas containing small cytoplasmic vesicles in the basal parts of the epithelial cells associated with areas of disordered and thickened basal lamina. Based on our results, we conclude here that SS saliva contains increased concentrations of MMP-9, which is of glandular origin in part. Pro MMP-9 is to a large extent proteolytically activated. This is probably mediated by the most potent pro MMP-9 activator found in vivo thus far, namely trypsin-2. Therefore, the MMP 9/trypsin-2 cascade may be responsible for the increased remodelling and/or structural destruction of the basement membrane scaffolding in salivary glands in SS. Due to the role of basal lamina as an important molecular sieve and extracellular matrix-cell signal, these pathological changes may contribute to the pathogenesis of the syndrome.

Mathematical ability and the right-shift theory of handedness.

A genetic theory of handedness, the right-shift theory, associates differential patterns of cerebral functioning with contrasting handedness groups and suggests that individuals with an rs + + genotype will be disadvantaged in mathematical performance. This hypothesis is investigated with contrasting handedness groups drawn from a national sample of over 11,000 children from the National Child Development Study. Some differentiation in cognitive performance between handedness groups is found in the direction predicted by the right-shift theory but the level of the findings is not statistically significant. The rs+ +/mathematical deficit hypothesis is not confirmed.

Once- and twice-daily bevantolol for systemic hypertension using 24-hour ambulatory intraarterial blood pressure recording.

The antihypertensive efficacy of bevantolol, a selective beta 1-adrenoreceptor antagonist, was evaluated in 17 patients with essential hypertension, using continuous ambulatory intraarterial blood pressure (BP) monitoring. The study compared a twice-daily regimen (titrated dose of 200 to 600 mg/day) with the same amount given in a single daily dose. Within-patient comparisons of mean hourly systolic and diastolic BPs and heart rate showed a highly significant effect with twice-daily therapy (p less than 0.001) for all of the 24 hours. Similar significant results were obtained with a single morning dose. There was no difference between the pattern or extent of BP reduction with the 2 regimens. The decrease in BP after bevantolol persisted during the physiologic tests (rest, tilt, isometric and dynamic exercise). Four patients developed minor side effects with the single morning dose, and only 1 patient with the twice-daily regimen. These effects included tiredness, fatigue and dizziness. Unlike pure beta-blocking agents, bevantolol controlled the early morning increase in BP, lending support to the belief that it possesses vasodilatory properties in addition to beta blockade. These results suggest that bevantolol may be useful as first-line therapy in a once-daily dosage for the treatment of essential hypertension.

Acute and sustained effects of isosorbide 5-mononitrate in stable angina pectoris.

Isosorbide 5-mononitrate (IS 5-MN) is an active metabolite of isosorbide dinitrate and is widely used as an antianginal agent. The acute and subacute (2 weeks) effects of IS 5-MN, 40 mg twice daily, were evaluated in 18 patients with stable angina pectoris using computerized exercise testing and a placebo-controlled, double-blind, randomized trial protocol. There were 2 phases of 2 weeks each in which patients received placebo or active IS 5-MN. Acute testing (8 patients) was performed 2 hours after the first dose and subacute testing 2 hours after the morning dose on day 14. Acute testing showed an increase in exercise time from a mean (+/- standard error of mean) of 8.2 +/- 0.6 minutes to 11.1 +/- 0.5 minutes (p less than 0.001) after a single dose of IS 5-MN. Time to 1 mm of ST depression increased significantly and peak exercise ST-segment depression decreased significantly. Rest and peak exercise heart rate increased significantly during acute testing with IS 5-MN; blood pressure did not change significantly. After 2 weeks of therapy, exercise time had not changed (9.9 +/- 0.6 with placebo to 9.7 +/- 0.6 minutes). The beneficial effects on ST-segment variables were sustained at 2 weeks. The data suggest that there is an attenuation of effect with respect to exercise time and sustained beneficial effect on the ST-segment variables. This may be a result of development of partial tolerance to IS 5-MN after 2 weeks of therapy.

Antianginal efficacy of carvedilol, a beta-blocking drug with vasodilating activity.

The efficacy of carvedilol, a new vasodilating beta-blocking drug, was evaluated in 20 patients with chronic angina using a single-blind, placebo-controlled protocol. A 2-week placebo phase was followed by therapy with carvedilol, 25 mg twice daily for 2 weeks, after which the dose was doubled. There was then a second placebo phase lasting 2 weeks. Treadmill exercise testing, 24-hour ambulatory electrocardiographic monitoring and drug blood level assays were performed at the end of each phase. Exercise time (mean +/- standard error of mean) increased from 7.4 +/- 0.5 minutes during placebo to 9.0 +/- 0.5 minutes carvedilol, 25 mg twice daily (p less than 0.001), and to 9.2 +/- 0.4 minutes with 50 mg twice daily (p less than 0.001). Mean time to 1 mm of ST depression in both bipolar leads CM5 and CC5 increased significantly, but peak ST depression did not change. Heart rate at rest was reduced at both dose levels, from 86 +/- 4 beats/min during placebo to 70 +/- 2 beats/min with 25 mg twice daily (p less than 0.001) and to 67 +/- 3 beats/min with 50 mg twice daily (p less than 0.001). Systolic blood pressure at rest was significantly reduced at both doses (p less than 0.05; p less than 0.01), but blood pressure during exercise was decreased only with the larger dose (p less than 0.001). The exercise rate-pressure product was 182 +/- 9 with placebo and decreased to 153 +/- 5 with 25 mg twice daily (p less than 0.001) and to 138 +/- 6 with 50 mg twice daily (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and pharmacokinetics of ioversol in healthy volunteers.

Ioversol 320, a new nonionic iodinated contrast medium, was injected intravenously into 24 healthy male volunteers using saline as a control. Physical examination, vital signs, electrocardiogram, biochemical and hematological data were recorded before and at intervals after injection. No significant changes were observed. Seventeen volunteers reported no side effects; six volunteers had mild transitory symptoms considered to be related to the contrast medium. The authors conclude that broader clinical trials can be safely conducted to determine safety and tolerability of ioversol.