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The purpose of this phase I, dose-escalation study was to determine the toxicity, maximum tolerated dose, pharmacokinetics, and pharmacodynamic end points of 5,6-dimethylxanthenone acetic acid (DMXAA). In all, 46 patients received a total of 247 infusions of DMXAA over 15 dose levels ranging from 6 to 4900 mg x m(-2). The maximum tolerated dose was established at 3700 mg x m(-2); dose-limiting toxicities in the form of urinary incontinence, visual disturbance, and anxiety were observed at the highest dose level (4900 mg x m(-2)). The pharmacokinetics of DMXAA were dose dependent. Peak concentrations and area under the curve level increased from 4.8 microM and 3.2 microM h, respectively, at 6 mg x m(-2) to 1290 microM and 7600 microM h at 3700 mg x m(-2), while clearance declined from 7.4 to 1.7 l h(-1) x m(-2) over the same dose range. The terminal half-life was 8.1+/-4.3 h. More than 99% of the drug was protein bound at doses up to 320 mg x m(-2); at higher doses the percent free drug increased to a maximum of 6.9% at 4900 mg x m(-2). Dose-dependent increases in the serotonin metabolite 5-hydroxyindoleacetic acid were observed at dose levels of 650 mg x m(-2) and above. There was one unconfirmed partial response at 1300 mg x m(-2). In conclusion, DMXAA is a novel vascular targeting agent and is well tolerated.

This paper reviews the major elements of the WHO Framework Convention on Tobacco Control and considers those that can be applied to diet and nutrition. Tobacco and food policy have important differences: the two commodities have distinctly different health impacts, and food companies may be more responsive to public concerns than the tobacco industry. Nevertheless, both food and tobacco policy address public health issues surrounding legal products. Both require comprehensive and multi-sector approaches at global and national levels. The degree of flexibility possible in interacting and partnering with the private sector and food and related industries and the related implications for regulations and laws are reasons for a more nuanced approach to diet and physical activity policy.

A common objective of longitudinal clinical trials is to compare rates of change in a continuous response variable between two groups. The power realized for such a study is a function of both the number of people recruited and the planned number of measurements for each participant. By varying these two quantities in opposite directions, power can be kept at the desired level. We consider the problem of how best to choose the sample size and frequency of measurement, with a view to minimizing either the total number of measurements or the cost of a study. Some general guidelines are first developed for the situation in which all participants have complete observations. In practice, however, longitudinal studies often suffer from dropout, where a participant leaves the study permanently so that no further observations are possible. We therefore consider the impact of unanticipated dropout on power and also ways of allowing for dropout at the design stage. Based on our results, we propose some general design guidelines for longitudinal trials comparing rates of change when dropout is present.

It is estimated that by 2020 two-thirds of the global burden of disease will be attributable to chronic noncommunicable diseases, most of them strongly associated with diet. The nutrition transition towards refined foods, foods of animal origin, and increased fats plays a major role in the current global epidemics of obesity, diabetes and cardiovascular diseases, among other noncommunicable conditions. Sedentary lifestyles and the use of tobacco are also significant risk factors. The epidemics cannot be ended simply by encouraging people to reduce their risk factors and adopt healthier lifestyles, although such encouragement is undoubtedly beneficial if the targeted people can respond. Unfortunately, increasingly obesogenic environments, reinforced by many of the cultural changes associated with globalization, make even the adoption of healthy lifestyles, especially by children and adolescents, more and more difficult. The present paper examines some possible mechanisms for, and WHO's role in, the development of a coordinated global strategy on diet, physical activity and health. The situation presents many countries with unmanageable costs. At the same time there are often continuing problems of undernutrition. A concerted multisectoral approach, involving the use of policy, education and trade mechanisms, is necessary to address these matters.

The immune responses of cattle inoculated with either a virulent or an attenuated vaccine strain of rinderpest virus (RPV) were examined by measuring the proliferation of peripheral blood mononuclear cells (PBMC) to whole RPV antigen preparations and to individual RPV major structural proteins expressed using recombinant adenoviruses. Responses to the T cell mitogen concanavalin A (ConA) were also measured as a control to monitor non-specific effects of infection with RPV on T cell responses. Infection with the vaccine strain of RPV was found to induce a strong CD4(+) T cell response. A specific response was detected to all RPV proteins tested, namely the haemagglutinin (H), fusion (F), nucleocapsid (N) and matrix (M) proteins, in animals vaccinated with the attenuated strain of the virus. No one protein was found to be dominant with respect to the induction of T cell proliferative responses. As expected, vaccination of cattle with an unrelated virus vaccine, a capripox vaccine, failed to produce a response to RPV antigens. While profound suppression of T cell responses was observed following infection with the virulent strain of RPV, no evidence of impairment of T cell responsiveness was observed following RPV vaccination, or on subsequent challenge of vaccinated animals with virulent virus.

In the cerebral circulation, endothelin-A receptor activation mediates marked prolonged vasoconstriction whereas endothelin-B (ETB) receptor activation effects dilation. In contrast to some peripheral vascular beds, ET(B) receptor-induced vasoconstriction has not yet been demonstrated in brain vessels. In this study in chloralose-anesthetized cats, with perivascular microapplications of ET(B) selective agonist (BQ-3020) and antagonist (BQ-788), we investigated whether ET(B) receptor-mediated constriction could be uncovered in cortical arterioles in vivo. In addition, we examined whether normal dilator response to ET(B) receptor activation is preserved in postischemic cerebral arterioles. The first microapplication of the selective ET(B) receptor agonist BQ-3020 (1 micromol/L) onto a pial cortical arteriole elicited marked dilation (caliber increased by 26.3 +/- 15.1% from preinjection baseline). A second application of BQ-3020 (10-minute interval) onto the same vessel failed to evoke any significant vasomotor response. Subsequent (third and fourth) adventitial microapplication of the ET(B) receptor agonist on the same arteriolar site effected a significant constriction of cerebral arterioles (-15.3 +/- 12.7% and -9.7 +/- 6.3% from preinjection baseline, respectively, at 20 and 30 minutes after the first application). The pial arterioles did not display tachyphylaxis to repeated applications of potassium (10 mmol/L). The perivascular application of the ET(B) receptor antagonist BQ-788 (0.001 to 1 micromol/L) had no effect on arteriolar caliber per se but blocked both BQ-3020-induced dilation (inhibitory concentration approximately 5 nmol/L) and vasoconstriction elicited by repeated activation of ET(B) receptors. After middle cerebral artery occlusion, most of the arterioles examined displayed a sustained dilation. The microapplication of BQ-3020 into the perivascular space surrounding postischemic dilated arterioles elicited a constriction of a similar magnitude to that induced by application of CSF (-17 +/- 7% and -17 +/- 7% from preinjection baseline, respectively). The adventitial microapplication of the ET(B) receptor antagonist (BQ-788, 0.1 micromol/L) on postocclusion dilated pial arterioles effected no change in the arteriolar caliber when compared with preinjection baseline. This BQ-788-induced response was significantly different from that induced by perivascular microinjection of CSF (P < 0.001, analysis of variance). These investigations indicate that (1) repeated activation of ET(B) receptors displays tachyphylaxis of the vasodilator response but also uncovers significant constriction of cerebral arterioles in vivo; (2) the ability of BQ-3020 to elicit dilation is lost within 30 minutes of induced focal ischemia; and (3) ET(B)-mediated contractile tone contributes in a small but significant manner in limiting postischemia dilation of cortical pial arterioles.

These investigations characterised the cerebrovascular effects of an endothelin ETA-receptor antagonist PD156707 in normal and ischaemic cat brain. A dose of PD156707 that inhibited the effects of exogenous endothelin-1 was established in nonischaemic cerebral resistance arterioles. Perivascular microapplication of the endothelin-receptor antagonist PD156707 (0.03-3 microM) had a minimal effect on nonischaemic pial resistance arterioles. The perivascular co-application of PD156707 and ET-1 (10 nM) effected a dose-dependent attenuation of the ET-1 vasoconstrictive response (IC50 = 0.1 microM). Intravenous administration of PD156707 (3 mumol/kg bolus + 5 mumol/kg/h infusion) attenuated the vasoconstriction elicited by perivascular ET-1 (10 nM) in normal pial arterioles (ET-1 vasoconstriction: -37 +/- 13% from preinjection baseline; after intravenous PD156707: 6 +/- 10% from preinjection baseline). In the focal ischaemia studies, cerebral perfusion was measured in the suprasylvian and ectosylvian gyri (by laser Doppler flowmetry). Occlusion of the middle cerebral artery reduced cerebral perfusion in the suprasylvian and ectosylvian gyri by approximately 50%. Intravenous administration of PD156707 (3 mumol/kg bolus + 5 mumol/kg/h infusion), initiated 30 min after middle cerebral artery occlusion, effected a progressive increase in cerebral perfusion up to preocclusion baseline levels, whereas cerebral perfusion in vehicle-treated animals did not vary from its postocclusion level. In these animals, the intravenous administration of PD156707 reduced the hemispheric volume of ischaemic damage by 45% (vehicle: 2,376 +/- 1,107 mm3; PD156707: 1,307 +/- 548 mm3; p < 0.05). Our investigations indicate that endothelin receptor antagonism may be a new therapeutic strategy for the amelioration of focal ischaemic damage.

The actions of Bosentan and PD155080, nonpeptide endothelin receptor antagonists, were examined in feline pial arterioles in situ following middle cerebral artery (MCA) occlusion to gain insight into the cerebrovascular influence of endogenous endothelins in focal cerebral ischaemia. Immediately following permanent MCA occlusion, all pial arterioles overlying the suprsylvian and ectosylvian gyri displayed marked dilatations, which were maintained in a population of vessel but differentiated into sustained constrictions in others. Perivascular subarachnoid microinjections of Bosentan (30 microM), PD155080 (30 microM), and artificial CSF (pH 7.2) were performed between 30 and 210 min following MCA occlusion. The perivascular microapplication of Bosentan (30 microM) and PD155080 (30 microM) around pial vessels overlying the suprasylvian and ectosylvian gyri, which are within the territory of the occluded MCA, elicited in increase in the calibre of postocclusion dilated and constricted pial arterioles. The perivascular microapplication of PD155080 (30 microM) around postocclusion constricted arterioles overlying the ectosylvian and suprasylvian gyri elicited an increase in the calibre of arterioles (69 +/- 49% from preinjection baseline; n = 8). The perivascular microapplication of Bosentan (30 microM) around postocclusion constricted arterioles overlying the ectosylvian and suprasylvian gyri also elicited an increase in the calibre of arterioles (68 +/- 60% from preinjection baseline; n = 13). In contrast, the microapplication of CSF (pH 7.2) elicited small reductions in pial arteriolar calibre of postocclusion constricted arterioles (-8 +/- 13% from preinjection baseline; n = 8). The perivascular microapplication of PD155080 (30 microM) around postocclusion dilated pial arterioles overlying the ectosylvian and suprasylvian gyri elicited an increase in the calibre of arterioles (11 +/- 10% from preinjection baseline; n = 38). The perivascular microapplication of Bosentan (30 microM) around postocclusion dilated arterioles elicited an increase in the calibre of arterioles (16 +/- 15% from preinjection baseline; n = 36). In contrast, the microapplication of CSF (pH 7.2) elicited small reductions in pial arteriolar calibre of postocclusion dilated arterioles (-9 +/- 6% from preinjection baseline; n = 44). Perivascular microapplication of Bosentan or PD155080 had minimal effect on the calibre of pial arterioles on the parasagittal gyrus (anterior cerebral artery territory), although these arterioles had also displayed sustained dilatation following MCA occlusion. These results indicate that contractile factors (whose effects can be reversed with endothelin receptor antagonists) constrict or impair dilatation of cortical resistance arterioles in an acute cerebral ischaemic episode.

Parathyroid hormone-related protein (PTHrP) was discovered as a result of a search for the circulating factor secreted by cancers which causes the common paraneoplastic syndrome humoral hypercalcemia of malignancy. Since the identification of the peptide in 1982 and the cloning of the cDNA in 1987, it has become clear that PTHrP is a prohormone that is posttranslationally cleaved by prohormone convertases to yield a complex family of peptides, each of which is believed to have its own receptor. It is also clear that the PTHrP gene is expressed not only in cancers but also in the vast majority of normal tissues during adult and/or fetal life. In contrast to the situation in humoral hypercalcemia of malignancy in which PTHrP plays the role of a classical "endocrine" hormone, under normal circumstances PTHrP plays predominantly paracrine and/or autocrine roles. These apparent physiological functions are also complex and appear to include 1) regulation of smooth muscle (vascular, intestinal, uterine, bladder) tone, 2) regulation of transepithelial (renal, placental, oviduct, mammary gland) calcium transport, and 3) regulation of tissue and organ development, differentiation, and proliferation. In this review, the discovery of PTHrP, the structure of its gene and its cDNAs, and the posttranslational processing of the initial translation products are briefly reviewed. Attention is then focused on a detailed organ system-oriented review of the normal physiological functions of PTHrP.

Objective: Our purpose was to determine whether vaginal misoprostol 7 days rather than 3 days after methotrexate injection increases the percent of successful abortions on the day of misoprostol administration., Study Design: A randomized controlled trial was performed in women requesting an abortion at < or = 56 days' gestation. Eighty-six women were treated with methotrexate 50 mg/m2 intramuscularly followed 3 days (group 1) or 7 days (group 2) later by vaginal misoprostol 800 micrograms. The misoprostol dose was repeated if the abortion did not occur., Results: Complete abortion occurred in 38 of 46 (83%) patients in group 1 and 39 of 40 (98%) in group 2 (p = 0.033). Of the women with complete abortions, 30 of 46 (65%) in group 1 and 27 of 40 (68%) in group 2 aborted the same day as the first or second dose of misoprostol (p = 0.823). Vaginal bleeding lasted 14 +/- 5 (mean +/- SD) days in group 1 and 17 +/- 9 days in group 2. The remaining women aborted after a delay of 24 +/- 6 days in group 1 and 28 +/- 13 days in group 2. For these women vaginal bleeding lasted 18 +/- 17 and 14 +/- 7 days, respectively, and the human chorionic gonadotropin-beta level was < or = 25 IU/L by 22 +/- 7 days after the abortion in group 1 and 19 +/- 9 days in group 2. Treatment failures in group 1 were four continuing pregnancies (9%), two incomplete abortions (4%), and two women who requested surgical termination after receiving both medications (4%). The treatment failure in group 2 was an incomplete abortion. Methotrexate and misoprostol side effects were infrequent., Conclusions: Methotrexate and vaginal misoprostol are more effective abortifacients when the misoprostol is given 7 days rather than 3 days after methotrexate. This treatment regimen may offer an alternative to surgical abortion or the use of antiprogestins and prostaglandin for medical abortion.

Twenty active amateur boxers were studied seeking evidence of neurological dysfunction and, if present, the best method for detecting it. Seven of these boxers had an abnormal clinical neurological examination, eight an abnormal EEG and nine of 15 examined had abnormal neuropsychometry. The CT scan was abnormal in only one. An abnormal clinical examination correlated significantly (p less than 0.05) with an increasing number of fights, and an abnormal EEG with decreasing age (p less than 0.05). In several of the neuropsychometric tests, the boxers were significantly worse than controls (p less than 0.05). Neuropsychometry was the best method for detecting neurological dysfunction.

The authors retrospectively reviewed all cases of acquired hydrocephalus admitted to the Institute of Neurological Sciences, Glasgow, Scotland, within a 5-year period and encountered 17 cases of posttraumatic hydrocephalus. These represented 0.7% of 2374 cases of severe head injury. Hydrocephalus became symptomatic within 1 year from the time of injury in 16 of 17 cases. Meningitis, traumatic subarachnoid hemorrhage, posterior fossa mass, supratentorial clot with contralateral ventricular dilatation, and craniotomy contributed to the development of posttraumatic hydrocephalus. After shunting, eight patients (50%) improved markedly and four (25%) slightly.

In a prospective study to correlate initial burn wound appearance with burn wound appearance after 21 days of conservative wound care, it was found that all burn appearances (except the presence of thrombosed capillaries and charred, "leathery" skin) were associated with a high probability of spontaneous healing. These findings emphasize the difficulty of selecting those burn wounds likely to benefit from early excision and grafting unless, of course, the burn is obviously full-thickness.

Two infants are described with intractable, drug-resistant seizures from birth associated with an enlarged cerebral hemisphere. The first died at sixteen months and demonstrated arrested head growth. Histology of the abnormal hemisphere showed disturbed cortical architecture, and subcortical heterotopias with multinucleate cells resembling tuberous sclerosis cells. Continuous fitting persisted in the second infant following callosal section. Hemispherectomy was undertaken in an attempt to preserve function of the "normal" hemisphere. Seizures ceased and head growth velocity accelerated. The neuropathology of the excised hemisphere is compared with the first case. From the literature this is the first report of a favourable outcome after hemispherectomy for hemimegalencephaly. The finding of an echodense enlarged hemisphere may allow presumption of this diagnosis in a neonate with unilateral seizures. After CT scan the diagnosis may be confirmed histologically providing that a precisely orientated frontal biopsy is submitted to the neuropathologist. We suggest that very early hemispherectomy may be the treatment of choice for this condition.

Computed tomography demonstrated a haematoma in the region of the basal ganglia in 61 of 2000 head injured patients. In 41 the haematoma occurred as an isolated lesion while in 20 there was another associated intracranial haematoma. Clinical and radiological differences within these groups are discussed. The patients with basal ganglia haematoma were more severely injured than those in a group who had an intracranial haematoma evacuated by craniotomy and the findings closely resembled those of a group of patients who had sustained diffuse brain damage. They share many features with those of patients with diffuse white matter injury and have a worse prognosis than other traumatic intracranial haematomas.

307 cases of acute traumatic intracranial haematoma in patients admitted to the Institute of Neurological Sciences in Glasgow have been analysed for various presenting features. 57 (19%) had no fracture, and 14 had neither a fracture nor neurological symptoms and signs immediately after the injury. Apart from the children, immediate admission and observation of these 14 cases for a period of 24 hours rarely led to the early detection of a haematoma.

The configuration of the intracranial pressure (ICP) pulse wave represents a complex sum of various components. Amplitude variations of an isolated component might reflect changes in a specific intracranial structure. Fifteen awake patients suffering from hydrocephalus, benign intracranial hypertension, or head injury underwent ICP monitoring through a ventricular catheter and were subjected to three standardized maneuvers to alter the intracranial dynamics: head elevation, voluntary hyperventilation, and cerebrospinal fluid (CSF) withdrawal. A 12 degrees head elevation and fractionated CSF withdrawal caused a mild ICP drop and a proportionate amplitude reduction of all the wave components. Voluntary hyperventilation caused a comparable fall in ICP, and a disproportionate reduction in the amplitude of the wave components, especially the P2 component. It is postulated that the decrease in amplitude of the P2 component reflects the reduction of the cerebral bulk caused by hyperventilation. Head elevation and CSF withdrawal caused a decrease of global ICP but no specific changes in any intracranial structure, and consequently the configuration of the pulse wave remained unchanged. The establishment of relationships between anatomical substrate and particular wave components is promising since potentially it could be useful for monitoring conditions such as vasoparalysis, impaired cerebrovascular reactivity, and cerebral edema.

Neuropsychological examinations were carried out on 29 amateur boxers and 19 controls matched for age, ethnicity, and education. There was no evidence of significantly impaired performance in the boxers. Within the boxing group, a variety of features of boxing history were examined as possible predictors of cognitive performance (such as number of knockouts, duration of boxing). No feature was a significant predictor of lower cognitive performance.

The authors have studied the effect of a low-dose (0.28 gm/kg) bolus infusion of mannitol on brain water in man. In eight patients with severe head injury, small pieces of subcortical white matter were taken at craniotomy both before and after infusion of mannitol. The tissue specific gravity was measured using a graduated specific-gravity column, and from it the brain water content was calculated. White matter specific gravity rose from a mean (+/- standard error of the mean) of 1.0325 +/- 0.0012 before mannitol infusion to 1.0352 +/- 0.0011 after mannitol administration, and the brain water content fell from a mean of 80.94% +/- 2.5% to 75.28% +/- 2.3%. The differences were significant (p less than 0.01). This study shows that, after head injury in man, mannitol increases the white matter specific gravity and probably does so by reducing brain water.

The incidence of head injury has risen in recent years and now accounts for almost one-third of acute male surgical admissions to the Western Infirmary, Glasgow. A prospective study has established that in Glasgow alcohol is a major associated factor, 62% of males and 27% of females having detectable levels in the blood (greater than 5 mg/100 ml); in these patients the mean level was 193 mg/100 ml in men and 165 mg/100 ml in women. The alcohol level was significantly higher in patients who had had 'a fall under the influence', or had been the victims of an assault, than in those involved in traffic or other accidents. This suggests that alcohol may be an important contributroy cause of head injuries in this city. Depression of the conscious level occurred at blood alcohol levels aroung 200 mg/100 ml, but a significant number of patients in coma had a serious head injury.

The outcome of operations in nine patients with meningiomas who presented with dementia was studied. Two patients died within 6 months of their operations. Six out of the remaining seven patients improved; two of these patients had normal intellectual function confirmed by psychometry. Our results show that recovery can be expected in most patients who present with dementia due to a meningioma.

Two neurosurgeons concerned with the emergency management of patients with head injury correctly diagnosed the presence or absence of an acute intracranial haematoma in 97 scans that were presented to them without knowledge of the patients' clinical details. There were no false-positives or false-negatives, although identification of the type of haematoma was not always possible. The impact of the EMI scan on patient management demands new approaches to the care of head injuries.

Deciding which head-injured patients should be transferred to a neurosurgical unit can be difficult. Traditional criteria emphasise the development of deteriorating responsiveness but lead to delayed diagnosis and to avoidable mortality and morbidity. To discover if a more liberal admission policy improved results a study was conducted analysing data collected prospectively from 683 patients who had a traumatic intracranial haematoma evacuated in the Glasgow neurosurgical unit between 1974 and 1980. In the first four years, before the change in policy, mortality was 38% but decreased to 29% afterwards. This reflected a reduction in the proportion of patients who talked after injury but who deteriorated into coma before operation--that is, 31% before the change in policy, 16% afterwards. If the potential benefits of CT scanning in the management of head injuries are to be realised patients must be scanned sooner than in the past. This will usually mean that more patients should go to a neurosurgical unit and that simple criteria for transfer should be established.

Out of 51 patients with traumatic intracranial haematoma admitted to a teaching hospital 11 (22%) died undiagnosed, and out of 307 such patients transferred to the West of Scotland Regional Neurosurgical Centre 111 (36%) had been deteriorating for more than 12 hours in another hospital. In two-thirds of these cases the delay was due to an erroneous diagnosis, either of cerebrovascular accident or of alcoholic intoxication.

This article as the series title suggests focuses our attention on decisions, both medical and ethical, which face doctors and related personnel in the medical profession daily. Many of these decisions take the form of a choice to one thing or another without being very sure of the outcome of either action. Mr Galbraith explores the pros and cons of what he calls the 'no lose' philosophy in medicine and which plays a large part in medical decision making. He concludes that possibly we may need a new philosophy rather than continuing to use more and more of our resources on care, which is perhaps being carried out as a means of avoiding making value judgements and thus possibly, prevents us from solving some of today's difficult ethical problems.