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Two routes to the synthesis of various norbornene containing amino acid derivatives are described. The methodology also allows the preparation of the 7-oxonorbornene analogues, and a kinetics study of the racemisation of one of the monomers is reported.

The cyclic dipeptide cyclo-[( S )-His-( S )-Phe] is found to catalyse the oxidation of benzaldehyde to benzoic acid. A mechanism is proposed both for this reaction, and for the asymmetric addition of HCN to aldehydes catalysed by this peptide based on a common intermediate for bothreactions.

A shape analysis technique has been developed to quantify intracranial deformation as a means of objectively assessing treatment for brain tumor. Conventional measurements of tumor volume are prone to ambiguity and error, so instead the authors are investigating the secondary space occupying effects of tumor, namely the deformation of structures within the brain. In order to avoid surface segmentation problems in MR images and to facilitate computation, the B-splines method has been introduced to approximate digital 3-D image surfaces. Using the mean curvature and the Gaussian curvature the authors classify a surface into 4 basic types: planar, parabolic, elliptic, and hyperbolic. The deformation of a surface can be described by measuring the geometric changes in these basic types. The method is independent of size, domain (translation), and viewpoint (rotation). These invariance properties are important as they overcome problems caused by wide variations in brain size within the normal population as well as small differences in patient orientation during acquisition. Experimental results show the potential of the technique in objectively monitoring patient response to treatment. >

The cyclic dipeptide cyclo-[( S )-His-( S )-Phe] is found to catalyse the oxidation of benzaldehyde to benzoic acid. A mechanism is proposed both for this reaction, and for the asymmetric addition of HCN to aldehydes catalysed by this peptide based on a common intermediate for bothreactions.

Two routes to the synthesis of various norbornene containing amino acid derivatives are described. The methodology also allows the preparation of the 7-oxonorbornene analogues, and a kinetics study of the racemisation of one of the monomers is reported.

Professor Cohadon talked about the mechanisms and pathophysiology of ischaemic damage, and Dr Dearden presented evidence that these events occur in patients. These insults leave their mark on the brain and are detected both at post-mortem (which has been known for a long time) and using modern ways of detecting ischaemic insults, in living patients.

Cortical contusions are one of the most common characteristics in head injury and are regarded by many as the hallmark of significant injury. No experimental study has clarified the roles of mechanical forces, haemorrhage and ischaemia in the process of progressive acute brain damage and later neurobehavioural dysfunction. We have devised a new, simple reproducible rodent model of focal cortical injury which employs a 'pure' mechanical/physical force applied through the intact dura. Using this model we have investigated the time course and pattern of changes in neurons, glia and microvasculature. With the exception of haemorrhage, this model closely reproduces the light- and electron microscopy features of human contusion. In the absence of perivascular haemorrhage we have demonstrated delayed perivascular protein leakage and polymorphonuclear-leukocyte infiltration of the damaged cortex. We postulate that a component of the delayed blood brain barrier breakdown demonstrated in human focal head injury (which may contribute to swelling and brain damage) is due to an acute inflammatory response, the magnitude of which is dependent on the amount of tissue injury.

Modern understanding and care of head injuries began in the 1960s when artificial ventilation, originating in use in polio, was applied to severely injured victims. The impetus to research and advances in management is still evolving. Better understanding of the pathology and patho-physiology of traumatic brain damage identified the fundamental structural and functional components. The distinction between primary and secondary damage pointed to the reduction of avoidable deaths and disability as the target of many efforts in management. Reliable clinical assessment and with the Glasgow Coma Scale, advances in intracranial imaging and their combination in guidelines such as those of SIGN and NICE have had clear success in the early diagnosis and surgery for intracranial haematoma. Outcome has also been improved by better management of extra cranial complications through trauma systems and intensive care. Despite extensive fundamental research, less progress has been made in the “neuroprotective” management of primary diffuse damage resulting from axonal shearing or from the consequences of ischaemic insults. The recognition that survivors of intensive care could face substantial subsequent problems led to the need to move beyond mortality as an index of outcome. The multi-dimensional consequences of brain damage, spanning mental, physical and social fields led to the creation of many descriptive systems and classifications. It is important to recognise the purpose for which each was introduced. The Glasgow outcome scale was developed to provide a short, simple overview categorisation, particularly applicable to groups of patients. The approach has proved valuable in research linking outcome to early severity, in developing predictive systems and in comparing series of patients managed in different ways. Its utility has been advanced by the development of an extended and structured, more consistent approach. Although initially introduced for severe injuries, a prospective study of a representative cohort of all head injuries admitted to hospital showed that it is able to portray the consequences of even so called mild injury, including the remarkably high incidence and persistence of incomplete recovery. The factors leading to this, the influence of adverse “emotional indices” and their potential amelioration are a priority for further research, as is the high rate of mortality, which continues for many years after the acute stage.

Neuroimaging with CT and MRI is a basis for decision making in individual head-injured patients and also provides a classification of patients according to severity of damage, patterns of injury, pathophysiologic mechanisms and prognosis. Such classifications can be based on the intracranial lesions identified: subdural, extradural, and intracerebral hematomas, contusions, and shearing lesions, or indirect indications of raised intracranial pressure and brain swelling: shift, obliteration of the third ventricle and basal cisterns, and signs of ischemia. The appropriate classification for early diagnosis and acute decision making may differ from the assessment of severity of damage, prognosis and late sequelae. Parallel systems of classification, suitable for these purposes, are proposed.

The basic aspects of care and organization are going to be most important in these patients: determining who is best suited to provide the care, determining the best treatment, and determining the best venues for treatment. With regard to newer treatments, it will be necessary not only to definitely establish the efficacy of treatment but also to convince the individuals supporting what will be large, expensive trials that this extra benefit is worth the effort and expense required.

Our studies showed that in an appropriate dose, nimodipine increased local cerebral blood flow with no corresponding increase in local metabolism. Nimodipine treatment given before experimental ischemic insult, resulting from either vascular occlusion or intracranial hemorrhage or after subarachnoid hemorrhage, maintained or improved blood flow and minimized the severity of subsequent brain damage. Lack of benefit from nimodipine treatment after the insult may occur because the inexorable progression of events leading to ischemic neuronal damage, once initiated, cannot be arrested. On the other hand, pharmacokinetic factors may be important, and post-treatment efficacy may depend on administration protocols that achieve an adequate concentration in ischemic tissue sufficiently soon after an insult. Our findings are compatible with the benefit of nimodipine being due to an improvement in blood flow that reduces the severity of ischemia. However, they do not exclude the possibility that treatment may minimize the accumulation of calcium in damaged cells as a result of "cytoprotective" effects.

A review of 16 recent publications purporting to provide the relaxation times of CSF reveals a considerable disparity in the quoted results, by a factor of 5 in terms of T1 (range 1000–5500 ms) and by a factor of 18 for T2 (range 166–3052 ms). In this article measurements are performed independently on both a spectrometer and an imager. The results indicate that for CSF Ti is greater than 3000 ms and T2 is greater than 2000 ms at an operating frequency of 6 MHz. The vast differences in relaxation behaviour between CSF and other body tissues have considerable clinical implications and present profound diagnostic opportunities. The application of this knowledge to ventriculography, myelography and image contrast methodology is discussed. (J Comput Assist Tomogr 11: 203–207, 1987)

The CRASH trial (Corticosteroid Randomisation After Significant Head injury) is a large simple placebo controlled trial, among adults with head injury and impaired consciousness, of the effects of a short term infusion of corticosteroids on death and on neurological disability. The trial has been funded by the Medical Research Council and has Multicentre Research Ethics Committee approval for the UK. The trial is due to start recruiting patients in the spring of 1999. World wide, some millions of people are treated each year for serious head injury, of whom close to a million die, and a similar number are disabled,' often with profound effects on the subsequent quality of life of the affected individuals and their carers.' If a treatment as simple as short term corticosteroids produces just a moderate benefit, this could be worthwhile. For example, if corticosteroids reduced the risk of death by just 2% (for example from 15% to 13%), and reduced the risk of permanent disability by a similar amount, then treatment of 500 000 patients would avoid 10 000 deaths and prevent 10 000 permanent disabilities. But, such a benefit would be impossible to demonstrate reliably without large scale randomised evidence. If, for example, 10 000 patients were randomly allocated to receive a corticosteroid infusion and 10 000 a placebo infusion, then a reduction from 15% to 13% dead should be detectable-and a reduction from 15% to 12% would certainly be detectable. By contrast, a trial involving only 2000 patients would probably miss such differences. So far, all of the randomised trials of corticosteroids in head injury have been small: the largest included only a few hundred patients, and even in aggregate they have involved only about 2000 patients.' When all previous trials are combined, the risk of death in the corticosteroid treated group appears to be about 2% lower than in the control group, but the 95% confidence interval (CI) runs from 6% lower to 2% higher mortality. (This overall reduction from 39% dead to 37% dead corresponds to an "odds ratio" of 0.91, with 95% CI 0.74 to 1.12; the corresponding odds ratio for either death or disability in those trials is 0.90, with 95% CI 0.72 to 1.11.) Hence, the overall result from the previous trials is compatible with there being no real benefit, but it is easily compatible with a benefit of a few per cent. However, the existing trials are too small to demonstrate or to refute either possibility. Recent evidence of benefit from corticosteroids in acute spinal cord injury has renewed interest in their possible role in brain injury. The Second US National Acute Spinal Cord Injury Study (NASCIS 2) compared 24 hours of methylprednisolone with placebo in 333 patients with acute spinal cord injury.4 At six months, patients who had received steroids rather than placebo appeared to have greater improvement in motor ftunction, and in sensation to pinprick and touch. Similar results were reported in a Japanese trial of the same regimen.5 The CRASH trial has therefore been designed to determine reliably: the effects of high dose corticosteroid (methylprednisolone) infusion on death and on disability after significant head injury, and the effects of such infusion on the risk of infection and of gastrointestinal bleeding. Accurate diagnosis of a traumatic brain injury is often not possible in the critical stages of assessment and management. Indeed the treatment provided by an emergency physician is based on the assumption of a "worst case scenario" while trying to identify the nature of the underlying pathological changes. Paradoxically, early treatment is likely to be most effective. The CRASH trial has been designed, therefore, as an early intervention when it is possible that the doctor will have a broad working diagnosis but may not have determined the final diagnosis. It follows that the range of clinical scenarios to be included in the trial should be wide and that their exact description does not need to be known to the investigators. While this apparent lack of rigour in such an important clinical trial may appear counterintuitive, the logic of this approach does stand up to scientific scrutiny. This is, of course, good news for emergency physicians and nurses. Since they are busy, and working in emergency situations, the trial involves them in almost no extra work; no special investigations or changes to usual management are required, and data collection is absolutely minimal. Head injured adults with impaired consciousness are eligible for inclusion in the trial if the responsible doctor is for any reason substantially uncertain whether or not to use corticosteroids. Patients with head injury and impaired consciousness will be unable to give properly informed consent, and in this emerUK Trauma Network, University of Manchester D Yates

Homochiral norbornene monomers derived from amino acids undergo ring-opening metathesis polymerisation with [Mo(CHCMe2Ph)(NC6H3Pri2-2,6)(OBut)2] to give homochiral polymers with narrow molecular mass distributions.

✓ Computerized tomography scanning has shown that acute traumatic intracranial hematomas are more common than was previously realized, but whether all hematomas must be removed remains controversial. About half of this series of 26 patients who were not clinically deteriorating and who were initially managed without operation had to undergo hematoma removal because they subsequently deteriorated. Features present at the time of diagnosis (age, type and site of hematoma, presence of focal signs, level of responsiveness, and degree of midline shift) were not helpful in predicting that operation would be needed. The only discriminatory factor was the level of intracranial pressure (ICP). All the patients with ICP greater than 30 mm Hg deteriorated and required operation, but only one patient whose ICP was less than 20 mm Hg deteriorated. Half the patients with ICP between 20 and 30 mm Hg did not require an operation. Intracranial pressure monitoring can, therefore, be useful in managing patients with an occult intracranial hematoma.

The effect of GH-releasing factor(1–44) (GRF) alone, or together with somatostatin (SRIF), dopamine (DA), vasoactive intestinal peptide (VIP) or cycloheximide was studied in a total of ten human somatotrophinomas using a static cell culture system. Growth hormone-releasing factor (2·0×10−8 mol/l) significantly (P−10−2·0×10−8 mol/l) was observed in five tumours thus studied. Repeated GRF (2·0×10−8 mol/l)-mediated GH release was seen during 96% (n = 25) of experiments performed on six tumours over 4 h and up to 27 days in culture. Growth hormone-releasing factor (2·0×10−8 mol/l) also stimulated GH release from five out of seven somatotrophinomas during 60-min incubations. Somatostatin (6·1×10−9 mol/l) completely inhibited GRF-induced GH secretion from four tumours studied over 4 h, but in each case there was significant (PP< 0·01) enhanced GRF-stimulated release of GH during a 60-min incubation, but inhibited both basal and GRF-stimulated release over 4 and 8 h. We conclude that a static cell culture system can be used successfully to study the action of GRF on human somatotrophinoma tissue for up to 27 days in culture. Human somatotrophinomas seem to be only rarely unresponsive to the stimulatory action of GRF, which is itself significantly modulated by SRIF, DA and VIP. De-novo protein synthesis appears to be necessary for the full expression of GRF activity on human somatotrophinoma tissue. J. Endocr. (1985) 105, 269–276

Cell culture methods were used to assess whether human pituitary adenomas secreting GH and associated with clinical acromegaly also secreted the structurally unrelated glycoprotein hormone alpha-subunit. Thirty-two tumours, together with peri-adenomatous tissue from two of them and three normal pituitaries were studied. Anterior pituitary hormones were measured by radioimmunoassay and included PRL, TSH, LH, FSH, and ACTH, as well as GH and alpha-subunit. Normal pituitary tissues secreted all hormones assayed. All 32 tumours secreted GH ranging from 241 to 5556 ng/2 X 10(5) cells/24 h and 12 (37.5%) secreted alpha-subunit in amounts which could not be accounted for by cross-reaction of other hormones or contamination by normal pituitary tissue, and which ranged from 10.3 to 73.5 ng/2 X 10(5) cells/24 h. Ten other tumours also secreted alpha-subunit but in very small amounts, not exceeding 1.8 ng/2 X 10(5) cells/24 h. PRL was secreted from 21 tumours (66%), and small amounts of other hormones, chiefly LH and TSH, were occasionally secreted from tumours. These cell culture studies would suggest that pituitary adenomas causing acromegaly are hormonally heterogeneous and that PRL and glycoprotein alpha-subunit are commonly detected in addition to GH.

Prognosis depends on establishing a relationship between the patient's state in the early stages and the ultimate outcome. Both the severity of the initial damage (including early complications) and the degree of recovery need to be defined, but practical and statistical considerations impose a limit on the number of variables which can be manipulated. Variables chosen should be those likely to be relevant, and pilot studies are more reliable than intuition in indicating which items should be included. Data chosen should be of a kind likely to be readily available for most patients and should not therefore depend on complex laboratory investigation. The most reliable indicant of initial severity appears to be the depth and duration of coma or altered consciousness, and a scale has been devised for measuring these. Measures of outcome should include separate assessment of mental and physical disability as well as the overall social consequence of the brain damage. Prognosis should be expressed as the probability (mathematically expressed) that a patient will reach certain defined outcome categories, five of which are recognized in the present study. Predictions should begin only after initial resuscitative measures are complete (say six hours after ictus); they need not be limited to the early stages but can include estimates of the degree of further improvement expected in the light of progress in the early weeks after injuries. New methods of management cannot be critically assessed unless factors influencing prognosis are reliably identified and can be matched in comparative patient groups. An estimate of prognosis is also required for the selection of patients for intensive treatment, both in the acute and in the rehabilitation stage. Without such data there is a tendency to deploy an unduly high proportion of scarce resources on patients who have little prospect of recovery; this may deny the best chance of recovery to patients with severe, but less overwhelming, brain damage.

Since the Glasgow Coma Scale was described1 a great number of other contres have adopted it, and Langfitt2 has recommended its widespread use in assessing head injured patients. The scale consists of three separate responses: eye opening (E). verbal (V), and motor responses (M), each classified by a series of grades of responsiveness. Each subdivision of responsiveness can be allocated a number, better grades scoring higher.

Each of 62 females were studied for a period of between two and 72 months (mean 36 months) following the removal of a prolactinoma by transsphenoidal pituitary surgery. Our aims were to define the relationships between pre- and post-operative features, the operative findings and the functional outcome. Pre-operative serum prolactin (PRL) concentrations correlated with tumour diameter (r = 0.55, p less than 0.001). Following surgery two groups of patients were identified: Group 1, 46 spontaneously and regularly menstruating patients and Group 2, 16 patients with persistent amenorrhoea. The patients in Group 1 had significantly lower pre-operative and post-operative serum (PRL) concentrations (p less than 0.02 and p less than 0.001 respectively) and significantly greater PRL responses to thyrotrophin releasing hormone (TRH) and metoclopramide stimulation after surgery (p less than 0.001). There was not a significant difference in tumour size between the groups. Forty-four (96 per cent) of the patients in Group 1 had normal post-operative serum PRL concentrations within one week of surgery. By comparison (p less than 0.001) only 42 and 20 per cent respectively of Group 1 patients who were tested had normal TRH and metoclopramide evoked PRL secretion following surgery. Return of regular menstruation was associated with cessation of galactorrhoea in 44 patients (96 per cent) and ovulation occurred in 37 of 38 menstruating patients for whom data are available. All patients with normal TRH and metoclopramide stimulation tests menstruated spontaneously. Nevertheless most patients who menstruated did so in spite of retaining suppressed PRL responses. Of 46 patients followed to date whose serum PRL was normal one week after surgery, seven later were found to have an elevation of serum PRL outside the normal range but in only two has this been persistent. We suggest that a single measurement of serum PRL one week following transsphenoidal pituitary surgery for prolactinoma provides a good basis for deciding about the future management of patients who desire menstruation and pregnancy.

The achievement of fertility is a major aim in the treatment of patients with hyperprolactinaemia. When this is considered to be due to a prolactin-producing pituitary adenoma, beneficial effects of treatment may also include removal of the risk that the tumour will enlarge and cause compression on adjacent important structures, either during any subsequent pregnancy or in later life. Of the various methods of treatment that are available, only operation offers the prospect of combining a rapid resolution of hyperprolactinaemia in the short term with the likelihood of long-term avoidance of tumour expansion.

The lack of a standard, quantitative method of assessing the degree of visual deficit hinders comparison of the results of the different methods available for treating visual failure due to pituitary tumour. This report describes a simple, semi-quantitative and precise approach and illustrates its use in 34 patients treated by transsphenoidal hypophysectomy and radiotherapy. Visual improvement occurred in 85 per cent of cases and no patient sustained deterioration of vision. The degree of pre-operative visual loss was scored at a mean of 51.4 per cent which reduced to a mean of 27.4 per cent at a minimum of twelve months' follow up. The factor that had the greatest influence on visual recovery was the degree of visual loss on presentation. It is therefore essential to be able to compare this variable before attempting to assess if outcome is different in a series treated by alternative methods.

Dopamine inhibits the secretion of prolactin from the pituitary. We have examined the relation between plasma dopamine and serum prolactin in 12 patients with hyperprolactinaemia during the infusion of dopamine at low doses (0.01, 0.1 and 1 microgram/kg/min). Plasma dopamine levels were raised from less than 100 pg/ml at the lowest rate of infusion to more than 20 000 pg/ml at the highest. Suppression of prolactin secretion was seen in some patients even at the lowest rate of infusion (0.01 microgram/kg/min); marked suppression of prolactin secretion (60%; 17--83%) was found at the intermediate dose (0.1 microgram/kg/min) in 11 of the 12 subjects with little further decrease in serum prolactin (70%; 50--87%) in those in whom the rate of dopamine infusion was increased ten-fold. One patient with the highest serum prolactin (82 500 mu/l) showed no decrease in prolactin either at the lowest or intermediate rates of dopamine infusion. Serum prolactin levels returned to values similar to or greater than basal on cessation of dopamine infusion. Infusion of dopamine at doses much lower than previously used in man exposes the pituitary to a concentration of dopamine sufficient to suppress prolactin secretion. These observations have important implications in understanding the pathophysiology of prolactin secretion from the pituitary gland and for future investigations of the control of hormone release by dopamine.

Head injuries are an important aspect of health care which impose considerable burdens on the hospital service; in the UK they comprise 1 in every 10 new patients in accident and emergency departments, and account for 150,000 hospital admissions every year. In Europe most admissions are to accident or general surgery wards, only the minority of obviously serious injuries coming to neurosurgeons. Even after mild injury there is the threat of serious complications which can develop rapidly, and are associated with considerable mortality and morbidity rates. The reason why so many mildly injured patients are admitted to hospital is in the hope that clinical observation will result in early detection of complications.

Nineteen patients thought to have Cushing's disease were treated by transsphenoidal microsurgery; the type of operation performed depended upon the findings in the individual patient. Seventeen patients remitted. Failures occurred in a patient with an invasive macroadenoma and in a patient who was subsequently found to have a thymic carcinoid tumour secreting ACTH. One patient who remitted suffered a recurrence during pregnancy, 30 months after operation. The ten patients (Group I) who had a selective removal of a microadenoma or a limited resection of the gland were often GH deficient, but seven regained cortisol reserve and all ten regained normal pituitary-thyroid and pituitary-gonadal responses. By contrast abnormalities of pituitary function were common in nine patients who had a radical or total hypophysectomy. We conclude that transsphenoidal microsurgery is the best treatment for Cushing's disease and that, when feasible, a selective microadenomectomy is the most appropriate operation.

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.