Biomedical subjects
Publications and source records attributed to D A Gilbert.
Upper gastrointestinal bleeding is a common gastrointestinal emergency associated with significant socioeconomic impact, morbidity and mortality. The aetiology of upper gastrointestinal bleeding has been reviewed, including the pathophysiological mechanisms of acid peptic and gastric mucosal disease. The initial diagnosis and therapeutic approach to the bleeding patient has been outlined.
A new model of an acute bleeding gastric ulcer with a single bleeding artery in its base has been developed. A suction ulcer defect is created over a large, submucosal artery. Small bleeding marginal vessels are electrocoagulated with a fine-tipped bipolar forceps. The artery in the base of the ulcer is dissected free and then incised longitudinally; brisk bleeding results. A combination of heparin, aspirin, and dipyridamole is used to prevent spontaneous hemostasis. Bleeding from the incised artery of the single vessel ulcer does not decrease over a 10-min interval. No damage to the muscularis externa of the underlying gastric wall results from preparation of the ulcer. The effect of Nd:YAG laser photocoagulation in this new model was compared with the results of photocoagulation in the standard suction ulcer model. In both models the Nd:YAG laser stopped equivalent bleeding from all ulcers. However, there was a marked difference in the depth of tissue injury, with much less damage observed in the single vessel ulcer. This model may provide a better method to assess depth of tissue injury resulting from endoscopic hemostatic techniques.
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A prospective, randomized, controlled experiment using a canine model of severely bleeding gastric ulcer was performed to compare the hemostatic efficacy and tissue damage produced by one bipolar and two monopolar electrodes. Both monopolar electrodes were insulated to their tips; they differed with respect to their surface area (3 mm2 vs. 4 mm2). The force of electrode application was controlled. An analog computer monitored the energy per electrode application and predetermined the duration of each application. Fifty-nine standard acute bleeding ulcers were made and treated one at a time in six heparinized foxhounds at sterile laparotomy. Treatment was randomized to the bipolar or to one of the monopolar electrodes within each of three bleeding strata. No significant difference was observed in hemostatic efficacy among the three electrodes. Treated ulcers were examined histologically after 5 to 7 days to determine the maximum tissue damage produced: Bipolar electrocoagulation caused significantly less damage than electrocoagulation with either monopolar electrode. We conclude that with these electrodes, bipolar electrocoagulation is equally effective for stopping bleeding but results in less tissue injury than monopolar electrocoagulation in this experimental model.
During the past five years we have evaluated argon laser photocoagulation in various canine models of upper gastrointestinal hemorrhage. In gastric erosions, the eight-watt argon laser was uniformly effective in stopping bleeding. In our standard acute ulcer model the seven-watt argon laser was effective in stopping bleeding from most ulcers and only occasionally produced deep injury. With the addition of a jet of CO2 exiting the laser catheter coaxial to the laser beam, the argon laser was 100% effective and no deep injury resulted. The application of the argon laser in a more physiologic canine bleeding model using a single bleeding vessel in an ulcer base is currently under study. The development of improved animal models of gastrointestinal bleeding should contribute to the identification of effective and safe endoscopic hemostatic methods.
Of 29 patients whose endoscopic retrograde cholangiopancreatogram (ERCP) led to a diagnosis of pancreatic neoplasia, 7 presented with steatorrhea. Steatorrhea may be the initial sign of pancreatic malignancy and aggressive evaluation including ERCP should be considered.
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A neodymium YAG (Nd:YAG) laser was evaluated in a dog ulcer model used in the same manner as is recommended for bleeding patients (power 55 W, divergence angle 4 degrees, with CO2 gas-jet assistance). The experiments were performed during sterile laparotomy in heparinized dogs. Bleeding gastric ulcers were photocoagulated until bleeding stopped and then examined histologically 7 days later when depth of tissue injury was maximal. In the first series of experiments, the Nd:YAG laser was compared with the 7-W argon laser in the same dogs. Both lasers stopped bleeding from all experimental ulcers. The 55-W Nd:YAG laser caused full-thickness injury to the gastric wall beneath 11 of the 14 treated ulcers, whereas the 7-W argon laser caused no full-thickness injury beneath 14 treated ulcers. In a second series of experiments, we tried to determine whether varying exposure times with the 55-W Nd:YAG laser would make it less injurious; it did not. In a third series of experiments, the 55-W Nd:YAG laser was tested with and without CO2 gas-jet assistance in order to determine if this would affect the depth of injury; it did not. In the final series of experiments, the wattage of the Nd:YAG laser was varied to see if this would reduce depth of injury; lower wattage did not stop bleeding, and intermediate and higher wattages did stop bleeding but did not reduce depth of injury. We conclude that the 55-W Nd:YAG laser as it is currently used clinically produces deeper tissue damage than the argon laser in our animal model. This damage is not reduced by changes in power, duration of exposure, or the presence of gas-jet assistance.
The oscillator concept of the cell cycle suggests that regulation of replication is achieved through a switch-like process. This is triggered when the values of parameters governing the behaviour of an intracellular control system exceed thresholds (bifurcations) which separate oscillatory and non-oscillatory (or damped oscillatory) modes of operation. On this basis it becomes possible to explain (a) how a given regulator can have diverse effects, (b) how distinct agents can have similar responses and (c) how various agents interact when controlling replication. The relevance of the malignant transformation is also briefly discussed.
The oscillator concept of the cell cycle predicts the existence of threshold conditions within the cell which must be exceeded before replication is initiated. It is shown (a) that if the conditions are subthreshold, random disturbances can trigger a cycle of the oscillation (round of replication) and (b) that the probability of this occurring increases as the state of the system approaches the threshold. It is concluded that the oscillator concept explains the data on which the transition probability model is based. It also accounts for the ability of cells to replicate even when the mitogen is present for a limited period only.
A cellular oscillator can be expected to modify the levels of other constituents. In turn, some of these are likely to modulate the behaviour of the oscillating system. Under appropriate conditions this feedback can temporarily quench the periodicity. By such means the frequency of the oscillation can be effectively reduced by a factor of ten or more.
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If the initiation/suppression of cell replication results from the operation of an intracellular switch, then proliferation control can be expected to occur through the modulation of its threshold setting or sensitivity. Assuming the existence of a threshold and the uptake of regulators by an equilibrium process, one can explain various types of dependency of the maximum cell density on the initial level of the regulator (e.g., serum) in the medium. Moreover it becomes theoretically possible to distinguish whether an altered threshold or equilibrium constant is responsible for modified proliferation characteristics. It is pointed out that some published data on transformed cells are more consistent with an altered threshold than the permeability change invoked. Other data suggests that transformation has produced more complex effects. The arguments presented indicate that while some cells may be more susceptible to control via changes in the relevant equilibrium constant, others may respond more markedly to threshold modulation. If control occurs through inhibition of replication, it is possible for the system to exhibit a critical "mass": if this is exceeded (in ways discussed) proliferation could continue indefinitely provided adequate nutrients are available. An oscillator concept of the cell cycle accounts for the existence of a threshold and also permits a general understanding of its modulation by multiple agents. It is concluded that at least some forms of cancer are the result of altered thresholds.
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