Biomedical subjects
Publications and source records attributed to I Ford.
Statistical issues in the analysis of neuroimages are reviewed. These include biological questions of interest, basic problems of measurement and experimental design, normalisation, standardisation and transformation, and statistical methodology. Finally, three data sets are reviewed to illustrate some of the issues raised in the report.
The variability of eight linear and five angular dimensions measured on 124 lateral skull radiographs of 10-year-old boys was assessed by means of Bartlett's test for homogeneity of variances and Pitman's test for the comparison of correlated standard deviations. The linear dimensions which demonstrated the greatest variability within the four constituent Angle classes (N = 31) were mandibular body length, total cranial base length, total mandibular length and lower face height. The dimensions which demonstrated the least intra-group but greatest inter-group variability were maxillary length and Angle SNB. The Class II division 2 group exhibited the greatest variation in skeletal morphology; it is therefore postulated that its etiology is mainly dentoalveolar and soft tissue in origin.
Traumatically induced subtotal hippocampal neuronal loss traditionally has been considered a consequence of intracranial hypertension and impaired cerebral perfusion. We have examined the frequency and distribution of hippocampal lesions in an acceleration model of brain injury in 54 anesthetized nonhuman primates undergoing physiologic monitoring and subjected postinjury to comprehensive neuropathologic examination. Hippocampal lesions occurred in 32/54 animals (59%). These lesions always involved the CA-1 hippocampal subfield and were bilateral in 24 animals. Hippocampal involvement was not associated with marked elevation of intracranial pressure or depression of cerebral perfusion pressure. These lesions occurred in the absence of involvement of other brain regions considered selectively vulnerable to hypoxic insults. Hippocampal damage occurred in 46% of animals with mild injury characterized by brief periods of unconsciousness and no residual neurologic deficit. Ninety-four percent of animals with severe injuries and prolonged posttraumatic coma had hippocampal involvement. Traumatically induced selective neuronal necrosis of the hippocampus is a specific lesion not explained by the conventional mechanistic theories of head injury. An alternative hypothesis, such as excitotoxicity involving glutamate or other neurotransmitters, may account for the lesions demonstrated in this study.
To examine the relationship between diabetic vascular disease and haemostasis, a set of sensitive assays has been used to assess in vivo activation of coagulation in 62 diabetic patients (41 Type 1 and 21 Type 2), aged 19-68 years, who had been screened for the presence of complications. Fibrinopeptide A, an index of thrombin activity, was significantly increased in diabetic patients compared with control subjects (p less than 0.05), in both plasma (with complications mean 8.04 +/- 11.87 (+/- SD); without complications 7.21 +/- 10.13; control subjects 2.11 +/- 1.40 micrograms l-1) and urine (with complications mean 1.48 +/- 0.74; without complications 1.35 +/- 0.62; control subjects 0.98 +/- 0.39 micrograms l-1). Activated factor VII (VIIa ratio 1.21 +/- 0.39; 1.13 +/- 0.23; 1.01 +/- 0.11) and fibrinogen (3.15 +/- 0.59; 3.11 +/- 0.69; 2.70 +/- 0.57 g l-1) were also elevated in diabetic patients with and without complications (VIIa p less than 0.05, fibrinogen p less than 0.01). The only difference between Type 1 and Type 2 patients was in fibrin degradation products (Type 1 0.28 +/- 0.18; Type 2 0.40 +/- 0.18 mg l-1, p less than 0.01). Plasma levels of fibrin degradation products were elevated in diabetic patients (p less than 0.05 vs control subjects), and correlated with age (r = 0.44, p less than 0.01) but were unrelated to the presence of complications. There were no significant differences in any coagulation variables between diabetic patients with and without complications.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of intensified dietary measures and subsequently insulin therapy upon haemorheological measures were studied in Type 2 diabetic patients with secondary sulphonylurea failure. Coagulation factors VIIc and VIIIc, fibrinogen, plasma viscosity, whole blood viscosity, beta-thromboglobulin, platelet factor 4, von Willebrand factor, and euglobulin clot lysis time were measured at baseline, after 3 months intensified dietary therapy and after 4 months insulin therapy. During intensified dietary therapy there was a significant fall in serum cholesterol (p less than 0.05) and a small decrease in weight, but no significant change in blood glucose control. Factor VIIc levels fell significantly (1.22 (SE 0.07) vs 1.42 (0.08) u ml-1, p less than 0.01), and plasma viscosity and whole blood viscosity (23 s-1) also improved (both p less than 0.05). Insulin therapy was instituted with either continuous subcutaneous insulin therapy or twice daily injections of soluble and isophane (NPH) insulin. During this period glycosylated haemoglobin improved (mean (SE) 49.5 (1.4) vs 65.0 (2.1) mmol-HMF mol-Hb-1, p less than 0.001; normal range 29-39 mmol-HMF mol-Hb-1) as did serum triglyceride (p less than 0.01), but weight increased (p less than 0.001). The only haemorheological changes with insulin were increased levels of the platelet release proteins beta-thromboglobulin (37 (3) vs 28 (2) micrograms l-1, p less than 0.01) and platelet factor 4 (median 7.5 (range 3.0-18.0) vs 4.5 (2.0-10.5) micrograms l-1, p less than 0.01).
This paper reviews the general structure of clinical trials with special reference to those in the area of angina. In particular, aspects of experimental design in exercise testing, ambulatory monitoring and mortality studies are examined critically. Parallel group and crossover studies are compared and contrasted. Sensitivity analysis of the power of any proposed trial is recommended, and problems that can arise in the area of event rate estimation are illustrated. Additional problems associated with trials involving combination therapies, trials with no placebo group and regression to the mean are discussed.
All patients who presented to our Accident & Emergency Department over a 6-month period with an acute knee injury were randomly assigned to receive either immediate physiotherapy or not prior to further follow up at an out-patient clinic. Patients with trivial injuries not requiring follow up and patients with severe injuries requiring immediate admission were excluded from the study. Patients not immediately referred for physiotherapy could be referred if this was thought necessary at later follow up. There was no statistical difference in the number of outpatient follow up appointments or the length of time to discharge from the clinic between the groups. Those patients referred for physiotherapy immediately had a significantly greater number of total attendances at the physiotherapy department. However more patients in the 'no physiotherapy' group ultimately required arthroscopy for suspected meniscal injury. We conclude that a blanket referral of all acute knee injury patients is unjustified and wasteful of resources. However physiotherapy may be indicated in patients initially suspected of having meniscal injury.
Many exercise protocols are in use in clinical cardiology, but no single test is applicable to the wide range of patients' exercise capacity. A new protocol was devised that starts at a low workload and increases by 15% of the previous workload every minute. This is the first protocol to be based on exponential rather than linear increments in workload. The new protocol (standardised exponential exercise protocol, STEEP) is suitable for use on either a treadmill or a bicycle ergometer. This protocol was compared with standard protocols in 30 healthy male volunteers, each of whom performed four exercise tests: the STEEP treadmill and bicycle protocols, a modified Bruce treadmill protocol, and a 20 W/min bicycle protocol. During the two STEEP tests the subjects' oxygen consumption rose gradually and exponentially and there was close agreement between the bicycle and the treadmill protocols. A higher proportion of subjects completed the treadmill than the bicycle protocol. Submaximal heart rates were slightly higher during the bicycle test. The STEEP protocol took less time than the modified Bruce treadmill protocol, which tended to produce plateaux in oxygen consumption during the early stages. The 20 W/min bicycle protocol does not take account of subjects' body weight and consequently produced large intersubject variability in oxygen consumption. The STEEP protocol can be used on either a treadmill or a bicycle ergometer and it should be suitable for a wide range of patients.
Detailed neurohistological studies were undertaken on 35 cases of cardiac arrest, 17 of hypoglycaemia and 16 of status epilepticus. It was found that the frequency and pattern of selective vulnerability in the hippocampus were similar following cardiac arrest, hypoglycaemia and status epilepticus with the exception that the lateral limb of the dentate fascia was more frequently involved in hypoglycaemia than in the other two groups of cases. Within each group, however, CA1 was the most vulnerable. The cerebellum was less frequently affected in hypoglycaemia and status epilepticus than after cardiac arrest. These findings are compared with recent experimental studies in the rodent which have suggested that the pattern of neuronal damage in each of the three conditions is different.
Diffuse axonal injury is one of the most important types of brain damage that can occur as a result of non-missile head injury, and it may be very difficult to diagnose post mortem unless the pathologist knows precisely what he is looking for. Increasing experience with fatal non-missile head injury in man has allowed the identification of three grades of diffuse axonal injury. In grade 1 there is histological evidence of axonal injury in the white matter of the cerebral hemispheres, the corpus callosum, the brain stem and, less commonly, the cerebellum; in grade 2 there is also a focal lesion in the corpus callosum; and in grade 3 there is in addition a focal lesion in the dorsolateral quadrant or quadrants of the rostral brain stem. The focal lesions can often only be identified microscopically. Diffuse axonal injury was identified in 122 of a series of 434 fatal non-missile head injuries--10 grade 1, 29 grade 2 and 83 grade 3. In 24 of these cases the diagnosis could not have been made without microscopical examination, while in a further 31 microscopical examination was required to establish its severity.
A comprehensive neuropathological study was undertaken on 87 children aged between 2 and 15 years with fatal head injuries to identify those features which occurred at the time of head injury (fractured skull, contusions, intracranial haematoma and diffuse axonal injury) and those which were subsequently produced by complicating processes (hypoxic brain damage, raised intracranial pressure, infection and brain swelling). The types of brain brain damage identified were remarkably similar to those seen in adults. The only difference was the prevalence of diffuse brain swelling in children.
A detailed neuropathological examination has been undertaken on a consecutive series of head injuries dying in the Institute of Neurological Sciences, Glasgow, between 1968-72 (151 cases) and 1981-82 (112 cases) in order to determine the frequency and distribution of any ischaemic brain damage. Ischaemic damage was found in the brains of 92% of the 1968-72 cases and in 88% of the 1981-82 cases: there was no statistical difference in the amount of moderately severe and severe ischaemic damage in the two groups, 55% and 54% respectively. There was evidence, however, that an increased number of patients with severe ischaemic brain damage was admitted in 1981-82 as a result of a changed admission policy of the Department of Neurosurgery that resulted in an increased detection of intracranial haematomas. It is concluded that ischaemic brain damage is still common after severe head injury, and it seems likely that it remains an important cause of mortality and morbidity.
Brain damage in a series of 635 fatal non-missile head injuries has been analysed with particular reference to the age of the patient and the type of injury. The differences in the type of brain damage in relation to age were less than we had anticipated, lending further support to the contention that the aged brain has a reduced potential for recovery. The analysis confirms the relationship between road traffic accidents, diffuse axonal injury, gliding contusions and 'basal ganglia' haematomas, and the importance of diffuse brain swelling resulting from a head injury in children.
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One hundred and fifty two patients with chronic heart failure caused primarily by left ventricular dysfunction were followed prospectively in an open study for a mean period of 21 months. The effects of several clinical variables on subsequent outcome were examined, including the effects of treatment, which was determined by the clinician caring for the patient and was not randomly allocated. In order of importance, frequent ventricular extrasystoles, non-treatment with amiodarone, low mean arterial pressure, and a diagnosis of coronary artery disease were associated with a poor prognosis, with each of these variables providing extra predictive information independently of the others. Initial serum potassium concentration and treadmill exercise time also carried further weak but independent prognostic information. Neither treatment with angiotensin converting enzyme inhibitors nor digoxin appeared to affect outcome. Left ventricular function (as reflected by M mode echocardiography) and the dose of diuretic also failed to predict outcome. There did, however, appear to be a reduction in the frequency of sudden death when angiotension converting enzyme inhibitors were given. Further studies are required to confirm the adverse prognostic significance of ventricular arrhythmias in patients with heart failure and the possible benefit associated with amiodarone treatment.
A method for the volumetric assessment of early cerebral infarction, together with its statistical and biological validation, is described. In halothane anaesthetised rats the stem of the right middle cerebral artery was occluded and 3 hours later (with full monitoring of respiratory and cardiovascular status) the animals were killed by perfusion fixation. In normotensive normocapnic animals the volume of infarction was 52 +/- 4 mm3 in the cerebral cortex and 21 +/- 1 mm3 in the corpus striatum. The reproducibility of the volumetric assessment was found to be excellent (coefficient of correlation 0.995 on 18 replicate measurements). The minimum number of stereotactic levels which must be assessed to yield accurate volumetric measurements of infarction is 8. The method is sensitive at detecting alterations in the amount of infarction. For example, it can readily detect the increase in amount of structural damage in cerebral cortex following a transient episode of hypotension. This approach allows an objective assessment of drug therapy and management strategies in the treatment of cerebral infarction.
To investigate the determinants of mortality in patients with chronic congestive heart failure, we prospectively evaluated 84 patients with this disorder who underwent detailed biochemical, clinical, and functional tests at the time of initial evaluation and were then followed for 12 to 52 months (mean 31). During this period of follow-up, 58% of the patients died, of whom 71% died suddenly. The most important pretreatment predictor of mortality in these patients was the frequency of ventricular extrasystoles, followed by echocardiographic fractional shortening, a diagnosis of coronary artery disease, and duration of treadmill exercise. The finding of hypokalemia and hyponatremia in these patients at the time of entry into the study was associated with a poor prognosis by univariate analytical methods, but these electrolyte abnormalities did not provide independent prognostic information. The presence of ventricular arrhythmias was related to the severity of left ventricular dysfunction, exercise intolerance, and neurohormonal activation, suggesting that such arrhythmias are multifactorial in origin and may not simply be related to electrolyte abnormalities.
The effects of diazepam (0.1-1.0 mg/kg i.v.) upon local cerebral glucose utilization, were analysed in 61 anatomically discrete areas of the conscious rat brain using [14C]-2-deoxyglucose quantitative autoradiography. The administration of diazepam resulted in significant reductions in the rate of glucose use in every region investigated. The regional pattern of alterations in glucose utilization was rather homogeneous, with the majority of brain regions analysed showing reductions of between 20 and 40% in response to 0.3 mg/kg diazepam. Only two regions of the central nervous system differed significantly from the widespread, homogeneous reductions. In the mammillary body, the rate of glucose utilization was more sensitive to depression than elsewhere in the brain (55% reductions following 0.3 mg/kg diazepam), whilst in the lateral amygdala, the rate of glucose use was less sensitive (8% reductions following 0.3 mg/kg diazepam). The effects of diazepam were compared to those elicited by i.v. injection of the gamma-aminobutyric acid (GABA) agonists, muscimol and tetrahydroisoxazolopyridinol (THIP), as reported previously by the authors. Although muscimol and THIP, like diazepam, reduced glucose use in every region of the brain, visual inspection of the autoradiograms suggested that whilst the patterns of regional responsiveness to the two GABA agonists were almost identical, they were different to the pattern of response evoked by diazepam. A rigorous system of analysis was devised making use of the dose-response profiles in each of the 61 brain areas to construct a regional hierarchy of responsiveness to the three drugs and allowing comparison of their effects on the brain as a whole. This critical form of data evaluation revealed that there was a more regionally homogeneous response to diazepam than to either muscimol or THIP, and whilst the regional hierarchy of responses to the GABA agonists was very similar, both differed from diazepam. It would appear that whilst benzodiazepines may interact with the GABA receptor, their effects upon the integrated functional activity of the brain as a whole differs markedly from that evoked by putative GABA receptor agonists.