Biomedical subjects
Publications and source records attributed to C S Robertson.
An intricate relationship normally exists between cerebral metabolism and energy substrate supply because of the brain's high substrate demand and limited storage capacity. In head-injured patients, this balance can be disrupted. The brain parenchyma directly involved by the injury is hypometabolic in respect to glucose and oxygen, whereas peri-injury tissue may have an elevated metabolic rate.
OBJECTIVES: Glucose is the primary substrate for the energy requirements of the nervous system. Nevertheless, administration of glucose to critically ill patients with central nervous system trauma may have adverse effects on their neurologic recovery. The purpose of this study was to evaluate the effects of other sources of nonprotein calories on spinal cord lactate accumulation and on electrophysiologic recovery after a period of severe spinal cord ischemia. DESIGN: Two randomized, blinded studies were performed: one of glycolytic energy substrates (fructose, xylitol, sorbitol, glycerol) and one of ketogenic energy substrates (beta-hydroxybutyrate, acetate, butyrate). SETTING: College teaching hospital laboratory. SUBJECTS: New Zealand albino rabbits (weight 3.5 to 4.5 kg). INTERVENTIONS: After infusion of the randomly assigned treatment, temporary ischemia was produced in the lumbosacral spinal cord by occluding the abdominal aorta with a balloon catheter. MEASUREMENTS AND MAIN RESULTS: Blood concentrations of glucose, lactate, pyruvate, and ketone bodies and spinal cord dialysate concentration of lactate were measured before and after infusion of the assigned treatment, and during ischemia and during the first 2 hrs after reperfusion. Spinal somatosensory evoked potentials were recorded during ischemia to assure a similar severity of ischemia in all animals and during the first 2 hrs after reperfusion as a measure of electrophysiologic recovery. Infusion of the glycolytic nutrients xylitol and fructose increased blood glucose and lactate concentrations, and resulted in increased lactate accumulation in the spinal cord during ischemia and resulted in a significantly poorer recovery of the spinal somatosensory evoked potential than infusion of saline. Infusion of sorbitol and glycerol did not have these adverse effects in the doses administered. None of the ketogenic nutrients increased blood glucose concentration or increased lactate accumulation in the spinal cord during ischemia when compared with infusion of saline. Infusion of butyrate and acetate caused arterial hypotension and resulted in a poorer recovery of the spinal somatosensory evoked potential than saline. Infusion of beta-hydroxybutyrate did not have an adverse effect on blood pressure or on evoked potential recovery. CONCLUSIONS: Glycerol, sorbitol, and beta-hydroxybutyrate deserve further evaluation as potential nonprotein calorie sources in patients with neurologic injury. Xylitol and fructose are not suitable since these substrates resulted in hyperglycemia and increased lactate accumulation in the central nervous system, and had detrimental effects on electrophysiologic recovery after ischemia. The short-chain fatty acids (acetate and butyrate) also had adverse effects on electrophysiologic recovery after ischemia, probably because of their hypotensive effects when given intravenously, rather than from the effects of their metabolism.
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Amino acid neurotransmitters (AANTs) play a major role in maintenance of muscle tone. Abnormal AANT concentrations are associated with hyper- or hypotonic states. Flaccidity from spinal shock commonly occurs after spinal cord injury (SCI) and may be associated with changes in AANT concentrations. Ischemic SCIs created in the lumbar region of rabbits by intraaortic balloon occlusion produced spastic or flaccid injuries. Microdialysis sampling of AANTs from the injured segmental structures was done 3 days after SCI. Evoked potentials were used to monitor spinal cord stability. No significant changes in AANT levels occurred in the spastic or flaccid group after 4 hour sampling. However, flaccid animals had baseline glycine levels 2-3 times higher (p < 0.001) than spastic animals or controls. High concentrations of the inhibitory AANT glycine is associated with flaccidity following SCI, or spinal shock, but not spasticity. Glycinergic compounds directed toward suppression of excess muscle tone deserve further study.
Ciliated metaplasia (CM) of gastric mucosa is common in Japanese individuals but rare in whites. We studied 36 consecutive gastrectomies from Chinese individuals for the presence of CM. The gastrectomies were performed for adenocarcinoma (n = 22), benign ulcer (n = 13), and malignant lymphoma (n = 1). Ciliated metaplasia was found in 16 (44.4%) of the stomachs, with equal distribution between male and female patients. Ciliated metaplasia was present in 11 cases (50%) of adenocarcinoma and in five cases (38.5%) of benign ulcer, the difference being statistically insignificant. Contrary to previous studies, there was no increased frequency of CM in gastric mucosa harboring an intestinal-type adenocarcinoma compared with those with non-intestinal-type tumors. Ciliated metaplasia always co-existed with intestinal metaplasia. Colonization by Helicobacter pylori was not associated with an increased incidence of CM. In five cases (22.7%) of adenocarcinoma ciliated tumor cells were found, and all of these cases showed CM in the gastric mucosa. In one of these cases the whole tumor was composed of glands formed by ciliated cells. In the other cases there was a morphologically different nonciliated component. The cilia in the tumor cells showed light microscopic and ultrastructural changes identical to those of the cilia seen in CM affecting the nonneoplastic gastric mucosa. This study documents for the first time the co-existence of CM and ciliated adenocarcinoma in the same stomach. It is concluded that in the Hong Kong Chinese population CM is commonly present in gastric mucosa harboring an adenocarcinoma or benign ulcer. Adenocarcinomas with ciliated cells are strongly associated with CM.
This report describes the results of a laboratory evaluation of a new device for monitoring intracranial pressure (ICP), consisting of a miniature pressure transducer mounted on a pressure sensing diaphragm. In in vitro tests, 6 microsensor transducers were monitored for drift at pressures of 10 mmHg and 20 mmHg. The maximal drift of any of the transducers was 1 mmHg over 9 days. In in vivo tests, the ICP measurement obtained with the microsensor transducer correlated well with pressures recorded from a catheter in the cisternal magna with a Statham transducer over a wide range of ICP values (n = 511, r = 0.998, P < 0.001). If these laboratory findings can be duplicated in clinical studies, this microsensor transducer may be a useful alternative to the ventriculostomy catheter and other currently used devices for monitoring ICP.
Ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, is induced in ischemic tissue and may mediate vasogenic edema and delayed neuronal death. We determined the effects of alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC, on infarct size and ODC activity in a rat model of transient focal ischemia. DFMO blocked the ischemia-induced increase in ODC and significantly reduced infarct volumes by 57-45%, depending upon the treatment regimen. These studies suggest that polyamine metabolism plays a role in the development of cerebral infarction after focal ischemia and that DFMO may be useful in limiting injury after a stroke.
Corticomotor evoked potentials have been suggested to accurately reflect neurological function, particularly with regard to the integrity of the spinal cord. However, the utility of these potentials to evaluate graded, chronic injury has received little attention. Using a rabbit model of ischaemic spinal cord injury we recorded corticomotor evoked potentials before, during, immediately after, and three days after producing an ischaemic spinal cord injury by inflating an intraaortic balloon. The animals sustained a stable mild, moderate, or severe neurological deficit. All ischaemic injured animals demonstrated near loss of the corticomotor evoked potential after the timed balloon occlusion period. Mildly injured animals did not demonstrate significant differences in corticomotor evoked potentials at reperfusion of three days post injury, when compared to controls. However, moderate and severely injured animals revealed significant reduction in late latency component amplitudes by > 50% and > 90%, respectively, when compared to controls. Changes in corticomotor evoked potential features are associated with altered neurological function after graded spinal cord injury.
A model of graded spinal cord injury using ischaemia has been developed by using balloon occlusion of the abdominal aorta in rabbits. This model has been used to test pharmacological agents thought to provide protection against spinal cord injury based on changes in corticomotor evoked potentials (CMEPs). These highly reproducible signals are percutaneously recorded from the spinal cord in response to cortical stimulation and accurately reflect the degree of residual spinal cord function. The present study focused on the power spectra of CMEPs to clarify alterations in post-injury signals. This added dimension of previously unreported CMEP analysis will augment future applications of the current model.
Corticomotor evoked potentials (CMEPs) have been suggested to accurately reflect neurological function, particularly with regard to the integrity of the spinal cord. However, the utility of these potentials to evaluate graded, chronic injury has received little attention. Frequency analysis has been suggested by the authors to be a method of simplifying interpretation of these complex signals. Ischaemic spinal cord injuries were produced in rabbits causing mild, moderate, or severe neurological deficits. CMEPs were recorded before, during, immediately following, and three days after injury. Alterations in the features of the power spectra reflected the degree of neurological injury. CMEP power spectra may predict neurological outcome and augment currently used electrodiagnostic tests.
Epidural spinal cord stimulation (SCS) has been used as an effective method for managing pain and spasticity for over two decades. However, the mechanisms of these beneficial effects are largely unknown. Since neurotransmitters are likely to be involved, we examined the relationship between SCS and local segmental amino acid release into the spinal cord extracellular space. Microdialysis was performed during continuous epidural SCS in animals subjected to ischemic spinal cord injury. Recovery of amino acid neurotransmitters from stimulated, injured animals was compared to that from a control group. Evoked potentials from the cortex and spinal cord were recorded to insure adequate stimulation and stable cord function. A significant increase in the concentrations of glycine and taurine was seen before, during, and after 90 minutes of continuous stimulation and was independent of the degree of injury. Levels of the other putative amino acid neurotransmitters were not significantly elevated. These results suggest that amelioration of pain or spasticity by epidural SCS may result from maintenance of post-injury elevation in baseline glycine and taurine levels.
The relationships of hormonal mediators to the systemic hypermetabolism and catabolism of head injury were studied in 15 patients with severe head injuries. Resting energy expenditure (REE), urinary nitrogen balance, and plasma glucose concentration were measured daily for the first 2 weeks after injury as the major indicators of hypermetabolism. These dependent variables were correlated with daily measurements of urinary epinephrine, norepinephrine, metanephrine, normetanephrine, dopamine, and cortisol, and with plasma levels of insulin, glucagon, and C-reactive protein. Urinary catecholamine and cortisol excretion were markedly elevated in these patients throughout the 2 weeks of study. Catecholamine excretion peaked between days 7 and 10, whereas cortisol excretion tended to be highest on day 5 after injury. Urinary levels of norepinephrine, normetanephrine, and cortisol were highest in the two patients with Glasgow Coma Scale scores of 4. Plasma insulin and glucagon concentrations were elevated on day 1 after injury and tended to increase throughout the 2-week period of study. The variables significantly associated with REE were the severity of injury, reflected by the GCS score, the urinary excretion of norepinephrine during the first 2 days after injury, and the urinary excretion of epinephrine and norepinephrine during days 3 to 7 after injury. A negative nitrogen balance was associated with the urinary excretion of epinephrine and norepinephrine, with caloric balance, and with plasma C-reactive protein during days 1 and 2 after injury. During days 3 to 7, a negative nitrogen balance was associated with the urinary excretion of epinephrine and norepinephrine and with caloric balance, and during days 8 to 14, a negative nitrogen balance was associated primarily with urinary cortisol excretion.
Prokinetic agents are being used increasingly in medical therapy for gastro-oesophageal reflux disease (GERD). This study examined the effect of 10 mg q.d.s., oral cisapride, or placebo, taken for 12 weeks, on 48 patients with symptoms and endoscopic evidence of GERD. Objective evaluation of benefit was obtained by endoscopy and biopsy, oesophageal manometry, acid reflux provocation test and 24-h oesophageal pH monitoring. Cisapride significantly increased lower oesophageal sphincter pressure (P = 0.003) against baseline and also against placebo, in patients (n = 9) with an hypotensive lower oesophageal sphincter pressure (P < 0.01). The frequency of dyspeptic symptoms was significantly improved in the cisapride group (P = 0.03). Antacid intake, global evaluation of symptoms and a VAS score for symptoms were all better than placebo but failed to reach significance (global evaluation by patients, P = 0.07). Overall, there was no significant improvement in oesophagitis at either 6 weeks (P < 0.05 > 0.3) or 12 weeks (P = 0.07). However, if patients with grades I and II oesophagitis at entry were excluded, cisapride had a significantly greater effect than placebo, 6 weeks (P = 0.05), 12 weeks (P = 0.04). In those with oesophageal ulceration, cisapride was significantly more effective than placebo in inducing healing. Gastro-oesophageal reflux was very variable on both 24-h pH monitoring and acid reflux provocation test. In spite of a 50% decrease in acid exposure on 24-h pH monitoring (cisapride group, mean % pH < 4 day: entry 18.9%, 12 weeks 9.6%), there were no significant intra- or intergroup differences for percentage of time < pH 4, or frequency and duration of episodes, neither pre- or post-prandially, day or night, except for the number of post-prandial episodes during acid reflux provocation tests, which decreased significantly more with cisapride than with placebo (P < 0.05). Thus, oral cisapride when taken for 12 weeks promoted healing of oesophagitis and improved symptoms in patients with GERD; although an increase in lower oesophageal sphincter pressure was observed and a reduction in acid reflux was measured, no significant decrease of acid exposure was seen.
In a search for past or present infection with herpes viruses, serum antibody titres to herpes simplex type 1 virus, cytomegalovirus, and varicella-zoster virus were measured by complement fixation test in 58 patients with achalasia. Serum was also taken from 40 age and sex matched patients without oesophageal symptoms who formed a control group. All titres were low, and those for herpes simplex type 1 virus and cytomegalovirus did not differ in the achalasia patients and the controls. However, the incidence of varicella-zoster virus antibodies was significantly greater in the achalasia than in the control group (p < 0.05). Using oesophageal tissue containing myenteric plexus removed at the time of cardiomyotomy in nine patients with achalasia, in situ DNA hybridisation showed evidence of varicella-zoster virus in three, but all were negative for the other two viruses. No positive results were obtained for herpes simplex type 1 virus, cytomegalovirus, or varicella-zoster virus in oesophageal tissue from 20 patients undergoing oesophageal resection for diseases other than achalasia. The incidence of positivity for varicella-zoster virus was significantly increased in the achalasia group compared with the controls (p < 0.02). The findings indicate that varicella-zoster virus DNA may persist in the oesophageal myenteric plexus in some patients with achalasia and raise the possibility that this virus is of aetiological importance in achalasia.
Near-infrared spectroscopy (NIRS) of the cerebral hemispheres, applied transcranially through the intact scalp and skull, was evaluated for its ability to detect the presence of an intracranial hematoma in 46 head-injured patients. In 40 patients intracranial hematomas (22 subdural, 10 epidural, eight intracerebral) were identified on computerized tomography (CT); in all 40 cases, NIRS demonstrated greater absorption of light at 760 nm on the side of the hematoma. The mean difference in optical density (OD) between the hemisphere with the hematoma and the normal hemisphere was 0.99 +/- 0.30 for epidural hematomas, 0.87 +/- 0.31 for subdural hematomas, but only 0.41 +/- 0.11 for intracerebral hematomas. In 36 patients, the asymmetry in OD resolved after surgical evacuation of the hematoma or with spontaneous resorption of the hematoma. Four patients who developed postoperative or delayed hematomas exhibited persistence of the asymmetry in OD. Six patients had only diffuse injuries and exhibited only minor differences in OD between the hemispheres, similar to 10 patients in the control group with no head injury. It appears that NIRS is useful in the initial examination of the head-injured patient, as an adjunct to CT, and in following patients postoperatively in the intensive care unit.
The survival of patients with oesophageal cancer diagnosed during the period 1982-1985 in Nottingham has been studied. Of 496 patients identified from endoscopy, histopathology and hospital activity analysis records, 268 (171 men) lived in the catchment area and had primary oesophageal cancer. Compared with previous studies the proportion of adenocarcinoma (35 per cent) was twice that expected, although survival was similar (hazard rate ratio at 2 years 1.0 (95 per cent confidence interval (c.i.) 0.8-1.4)) whether a squamous cell carcinoma or adenocarcinoma was present. Based on the original treatment intention, surgery was attempted in 34 per cent of cases and was associated with a median survival from diagnosis of 293 (95 per cent c.i. 232-367) days, with 41, 19 and 11 per cent surviving 1, 2 and 3 years respectively. Radical radiotherapy was attempted in 13 per cent of patients and was associated with a median survival of 190 (95 per cent c.i. 136-253) days, with 14, 6 and 6 per cent surviving 1, 2 and 3 years. Intubation alone was performed in 40 per cent of patients, of whom 44 per cent were aged over 75 years and 29 per cent had evidence of metastases, compared with 13 and 11 per cent respectively of those undergoing surgery or radical radiotherapy. The median survival for intubation alone was 100 (95 per cent c.i. 81-122) days, with 6, 3 and 0 per cent of patients surviving 1, 2 and 3 years respectively. Although patients treated surgically had the longest survival, these data indicate that overall survival after any active intervention is modest. Intubation alone is a reasonable option in those not suitable for surgery; randomized trials are needed to compare intubation with new methods of palliation.
Oesophageal carcinoma has a very poor prognosis unless detected at a pre-symptomatic stage. This can only be done by screening and patients with Barrett's columnar lined epithelium of the oesophagus (CLO) are high risk candidates for an endoscopic screening programme. Surveillance studies in CLO patients, when reviewed, showed that the incidence of adenocarcinoma was between 1 in 52 and 1 in 81 patient years, with a mean of 1 in 76. This paper describes the Nottingham experience with an endoscopic screening programme that was established in 1976. To date it has detected four adenocarcinomas at a mean cost similar to that of detecting breast cancer by screening.