Applying to graduate school.
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Biomedical subjects
Publications and source records attributed to R A Williams.
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The fructose 1,6-bisphosphate [Fru(1,6)P2]-dependent lactate dehydrogenase in cells of Streptococcus uberis N.C.D.O. 2039 was purified by a procedure that included chromatography on DEAE-cellulose and Blue Sepharose CL-6B in phosphate buffers. The enzyme appeared to interact with Blue Sepharose through NADH-binding sites. The homogeneous enzyme had catalytic properties that were generally similar to those of other Fru(1,6)P2-dependent lactate dehydrogenases, and it had no catalytic activity in the absence of Fru(1,6)P2. Its existence in different forms, depending on conditions, was investigated by ultracentrifugation, analytical gel filtration and activity measurements. It consisted of subunits with Mr 35,900 +/- 500 and, in the presence of adequate concentrations of Fru(1,6)P2, phosphate or NADH, it existed as a tetramer, whereas when these ligands were in lower concentrations or absent, the subunits were in a concentration-dependent association-dissociation equilibrium. Dissociation occurred slowly and inactivated the enzyme, and although added ligands reversed the dissociation, the lost activity was at best only partly restored. An exception occurred when dissociation was caused by a decrease in temperature, in which case the lost activity was fully restored at the original temperature. The tetramer also lost activity at certain ligand concentrations without dissociating. The results together indicated the presence on the enzyme of two classes of binding site for both Fru(1,6)P2 and NADH, and the likelihood that phosphate bound at the same sites as Fru(1,6)P2. Two different ligands together were much more effective at preventing inactivation and dissociation than was expected from their effectiveness when present separately. It was concluded that tetrameric forms of the enzyme rather than the enzyme in association-dissociation equilibrium were involved in the regulation of its activity in vivo.
Acute biliary tract disease complicated intrauterine pregnancy in 26 patients seen during a 5 year period. Biliary symptoms were distinct and occurred during the first trimester in 7 patients, the second trimester in 5 patients, the third trimester in 12 patients, and in two early postpartum patients. Nine patients had marked hyperamylasemia which resolved with medical management, and no severe cases of pancreatitis occurred. Ultrasonography was used to confirm the presence of gallstones in 18 patients and demonstrated dilated intrahepatic ducts in one of two patients with surgically proved choledocholithiasis. Nineteen patients had cholecystectomy and cholangiography, and 4 had common bile duct explorations. Only two of seven patients who presented in the first trimester had term pregnancy. Diagnosis of cholelithiasis in pregnancy by ultrasonography is accurate and reliable. The risk to the fetus of radionuclide scanning and conventional radiography is not justified. Secondary hyperamylasemia is common but responds to conservative therapy. Operation may be delayed until delivery in most patients, with urgent exploration reserved for uncertainty in diagnosis, choledocholithiasis, or acute cholecystitis that does not resolve with medical measures.
Fifty-one patients with the clinical diagnosis of acute pancreatitis were studied prospectively with early computerized tomography. It was found to be superior to ultrasonography for detecting acute pancreatitis and defining its extent. Grading of the initial computerized tomographic findings according to the extent of pancreatic inflammatory reaction identified patients with a high risk of local complications after onset of acute pancreatitis. Extension of the pancreatic inflammatory reaction into one or more peripancreatic areas with the simultaneous finding of pancreatic or extrapancreatic fluid collection or both was associated with a high frequency of pancreatic complications requiring surgical intervention and death. We believe that the severity of pancreatitis as shown by initial computerized tomographic scan is a more accurate predictor of clinical outcome than Ranson's criteria.
We report that the ability to detect a small vernier offset (less than 5 sec of arc in many individuals) between two small spots of light separated by a narrow gap can be disrupted by presenting additional targets in close proximity to the vernier stimulus. A rectangular background of light, centered on the vernier stimulus, elevates offset threshold by a factor of two when the total width of the background is 3-4 min arc. Backgrounds narrower or wider than 3-4 min have less or no effect on vernier threshold. These areas of spatial interaction extend to either side of a vertically-oriented vernier stimulus, or above and below a horizontally-oriented stimulus, and their extent is dependent upon the gap size of the two-dot stimulus. The effect of the presence of the background on vernier threshold cannot be accounted for by spatial interval cues nor by changes in the visibility of the stimulus. Two alternative interpretations of the results are presented to develop a description of the underlying mechanisms which produce hyperacuity spatial interactions.
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Using a computed video image analysis system, the staining intensity for both neurone specific enolase (NSE) and S100 protein was measured in sections from 19 malignant melanomas and 16 benign melanocytic lesions. The results of this study confirm previous reports that NSE and S100 protein are useful markers for malignant melanoma. NSE staining intensity in the cases of malignant melanoma was significantly higher than that in benign naevi (p = 0.011). Intensity of staining for S100 protein was not significantly higher in the malignant melanomas. There was, however, a significant S100 gradient when comparing superficial and deep intradermal portions of these tumours (p = 0.003). This feature was not seen in benign naevi. The greatest intensity of S100 protein staining was found in the deeper portions of the malignant melanomas. This gradient difference was not seen with staining for NSE. Although it seems that the overall intensity of staining for NSE is more effective in differentiating between benign and malignant lesions, the difference in staining intensity between the superficial and deep portions of the tumour may be the better indicator of adverse behaviour in lesions in which the diagnosis of malignancy is uncertain.
Examination of 33 cases of non-carcinoid epithelial tumours of the appendix and a review of the previous literature has led us to propose a new classification of these lesions. It is based on nomenclature currently used for similar mucosal proliferations in the colon, facilitating communication between pathologists and clinicians with respect to their nature and possible behaviour. The use of the term "mucocele" to describe any lesion in which there is mucinous distension of the appendiceal lumen, irrespective of the type of underlying mucosal pathology, is now largely discredited. Yet, although a resemblance of some appendiceal lesions to similar lesions in the colon has been recognized, current terminology is still confused by the use of "cystadenoma". We have been able to place all of the known non-carcinoid appendiceal mucosal tumours into 4 main diagnostic categories, these being--adenoma, hyperplasia, mixed adenoma/hyperplasia and adenocarcinoma, and propose these terms as the basis for a new classification.
Three patients with retinal lesions near or impinging on the optic nerve head are presented. Three different functional disruptions are demonstrated by quantitative layer-by-layer perimetry. In one, a patient who primarily exhibited subretinal neovascularization, inner retinal functions were anomalous; but the overlying nerve fiber bundle was as yet not affected. In the second patient, an individual with possible histoplasmosis causing an outer retinal/choroidal lesion, the overlying nerve fiber bundle was affected causing apparent retrograde changes in inner retinal function at remote visual field locations; but another aspect of optic nerve function (time-dependent response) was not anomalous. These apparently retrograde changes were essentially identical to functional changes previously demonstrated in patients with established open-angle glaucoma. In the third patient, with presumed toxoplasmosis, there were clear-out time-dependent anomalous responses consistent with optic nerve involvement, as previously reported in patients with optic neuritis. There were also modest, time-stable, nerve fiber bundle defects present in this third patient. Together, these results demonstrate that lesions in the area of the disc can have very different functional consequences, and that quantitative psychophysical techniques can elucidate these differences.
We have developed two related clinical tests that offer potential in better assessing visual function behind an ocular opacity. The tests are resistant to the effects of opacities because they utilize a localization task (vernier acuity) rather than a resolution task. In this paper we report the initial trials in which we apply the two tests together. Results from six case studies (some with actual opacities and some with simulated opacities) illustrate both the conduct of the tests and their potential capabilities in detecting even very modest retinal dysfunction in the presence of opacities. These techniques offer considerable potential in the separation of a given acuity loss observed in the presence of cataract into a portion due to the opacity and a portion due to retinal dysfunction.
Ninety-five patients with carcinoma of the esophagus and gastric cardia seen between 1979 and 1984 were managed in one of four ways: radiotherapy alone (6,000 rads), esophagogastrectomy alone, preoperative radiotherapy (4,000 rads over 4 weeks) followed by esophagogastrectomy, or no definitive treatment for patients with advanced disease. Patients who receive radiotherapy alone or no definitive therapy were considered unfit for operation; however, those patients who had operation only were equivalent with regard to histologic stage and risk to patients who received preoperative radiotherapy and surgery. Patients who received no definitive therapy died within 1 year, with a mean survival of 3.7 months. The mean survival for patients who received radiotherapy only was 8.3 months; for those who had surgery alone, 13 months; and for those who had preoperative radiotherapy, 24 months. Patients who received preoperative radiotherapy had significantly longer survival times when followed 12, 15, and 18 months postoperatively. Preoperative radiotherapy did not improve overall resectability, and postoperative mortality was similar in the two surgical groups. In comparable patients treated by esophagogastrectomy, preoperative irradiation prolonged the disease-free survival time and is advocated for all surgical candidates.
Iron-deficiency anaemia was induced in hamsters by feeding a low-iron diet coupled with weekly bleeding. Respiration, assessed by measuring oxygen uptake, was significantly reduced (p less than 0.002) in cheek-pouch epithelia from iron-deficient animals. To relate data on oxygen consumption to cell numbers, the cell densities of the basal and maturation compartments were measured. The cell density of the maturation compartment in iron-deficient animals was significantly reduced (p less than 0.05), whereas that of the basal cell compartment was marginally higher than in control animals. However, the cell density of the tissue as a whole was similar in both groups. Thus, the reduced oxygen consumption in iron deficiency was not due to a reduction in cell numbers. Although there was a significant reduction in epithelial volume in the iron-deficient group, this was not sufficient to account for the reduced oxygen uptake in cheek-pouch epithelia from these animals. It is concluded that iron-deficiency anaemia affects cell respiration directly, probably by interfering with the amounts and/or functions of iron-containing enzymes or cytochromes in the electron-transport chain.
The effect of light-induced retinal damage on the behaving rat's critical flicker-fusion frequency (CFF) was studied by determining the CFF at scotopic and photopic luminances both before and after exposure to damaging light. The CFF was reduced but not abolished following damaging light exposure. The shapes of the functions relating CFF to luminance before and after exposure suggested that scotopic visual function may have survived the light damage better than did photopic function. Anatomical and biochemical measures of retinal damage indicated that 91-93% of the outer nuclear layer (ONL) and 99% of the rodopsin had been lost.
Biochemical studies were conducted to compare the in vitro sensitivities of bovine and rodent brain and erythrocyte cholinesterases to inhibition by Dyfonate-oxon, paraoxon, and malaoxon. This comparison was done to determine if the reported greater sensitivity of cattle to Dyfonate might be explained by a greater sensitivity of the target enzyme, acetylcholinesterase, in cattle to inhibition by Dyfonate's toxic metabolite, Dyfonate-oxon. Studies were conducted with brain homogenates and lysed erythrocytes obtained from cows and from male and female rats. Additional studies were conducted with a commercially available sample of purified bovine erythrocyte acetylcholinesterase (ACHE). In all cases, the concentrations of organophosphates required to produce 50% inhibition (IC50) of enzyme activity were determined. Cow brain ACHE was 1.7 to 3.8 times more resistant to inhibition by Dyfonate-oxon, paraoxon, and malaoxon than was brain ACHE from male or female rats. For both species, paraoxon was 1.2 to 1.6 times more potent than Dyfonate-oxon and 3.8 to 6.9 times more potent than malaoxon. The bimolecular reaction rate constants (ki) were also determined for inhibition of brain ACHE of cows and male rats by the three organophosphates. In general, the ki data were in agreement with the IC50 data indicating that cow brain ACHE was less sensitive than rat brain ACHE to inhibition. Additional IC50 studies were conducted with lysed erythrocytes from cows and from male and female rats. Both quantitative and qualitative differences between species and among the organophosphates were in excellent agreement with the results of the brain ACHE studies. Also, in related studies with purified bovine erythrocyte ACHE, there was excellent agreement with the results of tests involving ACHE inhibition in erythrocyte lysates. This study demonstrated that, as an inhibitor of ACHE in vitro, Dyfonate-oxon was equal to or slightly lower in potency than paraoxon and more potent than malaoxon. In addition, the study demonstrated that, in general, ACHE from brain or erythrocytes of cows was less sensitive to in vitro inhibition by organophosphates than was that from male or female rats. Thus, the apparent greater susceptibility of cows to Dyfonate, in vivo, cannot be explained on the basis of an unusual target enzyme (ACHE) sensitivity to inhibition by Dyfonate-oxon.
The radiological effects of peripheral joint disease in 81 patients with seropositive juvenile chronic arthritis were studied retrospectively with an average length of follow up of 11 years. The patients comprised 63 girls and 18 boys with average ages of onset being 10.7 years and 12.1 years respectively. All had developed positive serology within the first year of the disease. X-rays available in 70 of these patients at five years from onset of the disease showed erosive change to be present in all but three. The sites most commonly affected included the carpus, the metacarpal, the metatarsal, and interphalangeal joints, though a third of the patients also showed erosive change in large joints such as hips, knees, or shoulders. Between five and 10 years after disease onset progression of x-ray changes was evident in most patients, with additional joints becoming involved in about one third, though the distribution of joints was similar. After 15 years or more of disease the radiological changes tended to be more stable, but various mechanical difficulties often secondary to poor growth and degenerative change and to primary destructive inflammatory arthritis were evident. No specific drug regimen was found to have been universally effective in suppressing disease, and the frequency of side effects was a significant factor in preventing treatment schedules being maintained for long enough to be effective.
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In the present study, 12 patients with non-insulin-dependent diabetes mellitus (NIDDM) consumed eucaloric, mixed food diets on three consecutive days. Diets provided 50% of the calories as carbohydrate, 35% as fat, and 15% as protein. The percent of carbohydrate fed as complex (starches) and simple (mono- and disaccharides) varied among the 3 days. On day 1, the diet contained 80% of the carbohydrate as complex and 20% as simple (80/20); another contained 50% complex and 50% simple (50/50); and the final diet contained 20% of the carbohydrate as complex and 80% as simple (20/80). All simple carbohydrates represent naturally occurring sugars in fruits, vegetables, and dairy products. No refined sugars were added to any of the diets. The three experimental diets were randomly assigned using a 3 X 3 Latin square design. Blood was obtained hourly from 0800 to 1700 h for day-long glucose and insulin concentrations, and 24-h urine collections were made for the measurement of urine glucose. Mean (+/- SEM) day-long glucose concentrations were significantly greater for the 80/20 diet (2245 +/- 199 mg/dl X h, P less than 0.05) than for either the 50/50 (2030 +/- 157 mg/dl X h) or the 20/80 diets (2008 +/- 160 mg/dl X h). No significant differences were noted between the 50/50 and the 20/80 diets. In contrast, day-long insulin concentrations were not significantly different with 401 +/- 62, 370 +/- 50, and 369 +/- 60 mu U/ml X h on the 80/20, 50/50, and 20/80 diets, respectively. Twenty-four-hour urinary glucose excretion paralleled plasma glucose concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
The present study demonstrated that less than three days of exposure to low levels of normally cycled ambient illumination are sufficient to cause death to photoreceptor cells in adult pigmented and albino rat. Cyclic light levels as low as 133 and 320 lux were found to destroy photoreceptor cells. A single mydriatic treatment with atropine immediately preceding the three-day exposure was sufficient to permit the effect in pigmented rats. No mydriasis was required for albino rats. When pigmented rats were reared in either 3 lux or 100 lux, it was found that these different light histories did not significantly affect the rats' subsequent susceptibility, during mydriasis, to retinal damage by cyclic illumination.