Biomedical subjects
Publications and source records attributed to D A Johnson.
The unique information provided by radionuclide techniques allows the noninvasive characterization of primary tumors and tumor-like conditions of the liver. A thorough knowledge of the mechanisms of radiopharmaceutical localization and the histologic abnormalities present in each condition is required to optimally use these techniques. A review of this subject is presented.
Esophageal acid sensitivity was evaluated in 15 patients with Barrett's esophagus and in 15 patients with reflux esophagitis uncomplicated by Barrett's. Patients with Barrett's esophagus had sensitivity to esophageal acid perfusion less frequently than those with uncomplicated reflux esophagitis (66 vs. 100%; p less than 0.05). Moreover, patients with Barrett's esophagus with acid sensitivity took longer to develop pain during acid perfusion (p less than 0.05), and overall, experienced less severe symptoms (p less than 0.01) than those with reflux esophagitis. Over a 2-week period, as judged by diary, the Barrett's group had less frequent (p less than 0.01) and less severe (p less than 0.01) heartburn symptoms than the other patients. These results indicate that patients with Barrett's esophagus have significantly reduced esophageal acid sensitivity and, as a consequence, have an impaired ability to recognize acid reflux.
We prospectively compared roentgenography and endoscopy of the upper gastrointestinal tract in terms of patient acceptance and tolerance. Endoscopy was significantly better tolerated and easier overall for patients. Patients found no difference between endoscopy and radiography with respect to pain or life-style interruption. Patients stated that they would prefer endoscopy to roentgenography if repeat evaluation were needed. We conclude that UGI endoscopy is better tolerated and more acceptable to patients than UGI roentgenography.
Social anxiety, social performance and self-esteem are suggested to be important factors in the social adjustment of severely head-injured patients. The present study attempted to remediate some of these deficits in social interaction and adjustment by adopting theoretical models of the development of self-understanding, and of the general process of recovery from head injury, together with the application of existing methodology from social skills training. Reassessment after one year of group treatment did not show any statistically significant results, but some important individual changes in social performance and social anxiety were found. Reasons for the apparent failure to change are discussed, with recommendations for more intensive treatment and refinement of measures.
Radionuclide esophageal scintigraphy is a sensitive test of esophageal function, but its usefulness is not well documented in Barrett esophagus. This technique was prospectively studied in 27 patients with histologically proved Barrett esophagus and 17 patients with biopsy-confirmed reflux esophagitis. The esophageal transit time and percentage of emptying were calculated. The only quantitative parameter of radionuclide esophageal scintigraphy to show a significant difference between the two conditions was the percentage of emptying, which was abnormal in 48% of patients with Barrett esophagus versus 31% of patients with reflux esophagitis. In the latter group, the mean percentage of emptying approached normal (89.5%), while in the former group it was decreased to 82.1% (P less than .05). Neither emptying parameter correlated with length of Barrett esophagus. These data support the hypothesis of inherent esophageal dysmotility in Barrett esophagus. Half of the patients with this condition have impaired esophageal clearance and may benefit from drug therapy.
"Nutcracker" esophagus is a syndrome consisting of chest pain and/or dysphagia with elevation of the mean distal esophageal contractile pressure amplitude (MDA) (greater than 120 mm Hg). Its existence as a disorder of esophageal function and the proper manometric diagnostic criteria have been debated. A correlative study of radionuclide esophageal scintigraphy (RES) and manometry was performed in 31 patients with this manometric diagnosis. RES results were abnormal in 13 of 16 (81%) patients with an MDA above 150 mm Hg, and in only three of 15 (20%) patients with an MDA below this level. There was a significant difference in RES parameters (mean transit time and percentage emptying) between these two groups. Repeat manometric and RES studies showed considerable variability, but only RES showed a significant correlation between baseline and repeat studies. RES confirms a functional disorder in a subgroup of patients with the manometric diagnosis of nutcracker esophagus and supports a change in the manometric criteria for diagnosis of this disorder to an MDA above 150 mm Hg.
Guanosine transport and metabolism were examined in adult rat cardiac myocytes. Myocytes transported guanosine via saturable [Km = 18 microM, maximum velocity (Vmax) = 3.61 pmol.mg-1.s-1] and nonsaturable (rate constant = 1.47 X 10(-2] processes. The saturable process was inhibited by nitrobenzyl-thioinosine, inosine [inhibition constant (Ki) = 180 microM], and adenosine (Ki = 112 microM). Extracellular guanosine taken up by myocytes was slowly phosphorylated to guanine nucleotides. The majority of guanosine (98%) existed as free intracellular guanosine after 60 s. Countertransport of nucleosides could not be demonstrated in these cells at physiological concentrations in the presence of up to a 10-fold gradient of nucleoside. These studies indicate that adult rat cardiac myocytes can be used to assess myocardial guanosine transport separate from its metabolism. Comparable inhibition of guanosine and adenosine transport by each other and by inosine support the hypothesis that guanosine and adenosine are transported by a common carrier.
Previous studies have shown that several factors--such as alloxan-induced diabetes, adrenalectomy, or removal of the thyroid-parathyroid gland complex--can influence the flow rate, protein concentration, and protein composition of rat parotid saliva. The present study was undertaken to explore further the influence of glucocorticoids and thyroxine on rat parotid saliva in hormonally intact animals. As compared with untreated animals, adult male rats treated with 10 micrograms dexamethasone per 100 g body weight for eight days demonstrated a 75% reduction in volume of parotid saliva secreted in response to a uniform stimulus. The protein concentration of the saliva was increased three-fold. Sodium dodecyl sulfate polyacrylamide gel electrophoresis showed relative decreases in acidic and basic proline-rich proteins and in a protein identified as Fraction V, while amylase was increased. The electron microscopic appearance of the granules was markedly different from that of the control, in that the granules exhibited an electron-dense periphery and core, with the remainder of the granule having an electronlucent appearance. In contrast, rats treated for eight days with 20 micrograms thyroxine per 100 g body weight exhibited a 50% increase in volume of saliva collected in response to a secretory stimulus. Although the concentration of protein was not different from that of the control, gel electrophoresis showed relative increases in acidic and basic proline-rich proteins and a decrease in Fraction V. Amylase was unchanged. The secretory granules of thyroxine-treated rats were electronlucent and amorphous. The granules appeared to coalesce within the cell.(ABSTRACT TRUNCATED AT 250 WORDS)
Previous studies have indicated that adrenal-intact rats treated for one week with pharmacological doses of the synthetic glucocorticoid, dexamethasone, show a significant reduction in the proportion of proline-rich proteins and an increase in the proportion of amylase in rat parotid saliva (Johnson et al., 1987). In order to understand more fully the role of glucocorticoids in the regulation of salivary proteins, we performed bilateral adrenalectomies on groups of rats. Some of the adrenalectomized rats were treated with replacement-level doses of the synthetic glucocorticoid, dexamethasone. The food intake was monitored daily for both groups, and sham-operated pair-fed controls were included so that the effects of alterations of food intake could be separated from those of the experimental procedures. After eight to 12 days, uniformly stimulated parotid saliva was collected from these animals as well as from sham-operated controls fed ad libitum. The volume of saliva collected in 30 min was recorded, and the saliva samples were analyzed for concentration and composition of protein. Although the volume of saliva was not affected, parotid saliva collected from adrenalectomized rats exhibited a two-fold greater proportion of proline-rich proteins and reductions in other major secretory proteins: DNase, Fraction I, and Fraction V. The parotid gland secretory granules of adrenalectomized rats were more electron-lucent than in the ad libitum-fed controls. Treatment of adrenalectomized rats with dexamethasone largely prevented the changes in salivary protein composition as well as the alterations in secretory granule morphology.(ABSTRACT TRUNCATED AT 250 WORDS)
A double-blind controlled trial of 50% dose reduction in maintenance treatment in stable out-patients with low BPRS scores and good social function shows a significantly higher relapse rate in the low-dose group at 12 months (P less than 0.05). After an interval of 24-36 months from dose reduction, 56-76% had experienced a relapse and 76-79% had resumed their former dosage. No clear advantage was shown for the lower dose in either a reduction of side-effects or improved social function, but a reduced prevalence or lower rate of symptom emergence for tardive dyskinesia was suggested.
Based on available knowledge, this study shows that alpha-1-proteinase inhibitor (alpha 1-PI) plays an important role in protecting lung elastin from elastolytic proteinases, particularly human neutrophil elastase (HNE). Studies previous to this one showed that alpha 1-PI was very susceptible to inactivation by oxidants. We sought to use this oxidant sensitivity as an in vivo marker for ozone (O3) and nitrogen dioxide (NO2) exposure. The mechanism of alpha 1-PI inactivation by O3 and NO2 was examined to provide insight concerning the pathogenesis of oxidant-mediated lung damage. Attention also was focused on the bronchial leukocyte proteinase inhibitor (BLPI), which inhibits HNE in the bronchial secretions. Careful examination of blood plasma samples from individuals exposed to 0.5 ppm O3 for four hours on two consecutive days failed to detect any inactivation of alpha 1-PI. This result showed that blood alpha 1-PI was not a satisfactory marker for O3 exposure, but, more importantly, demonstrated that inhaling O3 for short periods does not grossly inactivate this important protein. Studies on BLPI showed that it is a significant inhibitor of HNE and probably plays a more important role in protecting the lung than previously thought. BLPI, like alpha 1-PI, was found to be inactivated by oxidants, including O3 and NO2. The mechanism of O3 inactivation of leukocyte proteinase inhibitors was studied using alpha 1-PI, alpha-1-antichymotrypsin (alpha 1-Achy), BLPI, and Eglin C. While all these inhibitors differed in structure, the concentrations of O3 required for inactivation were essentially the same, except for alpha 1-Achy, which only lost half of its inhibitory activity. It would seem from these results that O3 can damage proteins via the oxidation of any of the following: tryptophan (Trp), methionine (Met), tyrosine (Tyr), or histidine (His) residues. Interestingly, Eglin C, which does not have oxidizable amino acids in its inhibitory active site, was inactivated by the same amount of O3 as BLPI, BLPI was easily inactivated by a methionine-specific oxidant, suggesting an important role for methionine in this inhibitor. In vitro exposure of alpha 1-PI and BLPI to 800 moles of NO2 per mole of inhibitor resulted in 35% and 50% losses of HNE inhibitory activity, respectively. Tryptophan was destroyed by NO2 and studies are in progress to examine effects on other amino acids.
Supine radionuclide esophageal scintigraphy (RES) and manometry were used to prospectively evaluate metoclopramide effect on esophageal function and pressure amplitudes in 14 patients (12 females and two males; median time since diagnosis: 2 yr) with progressive systemic sclerosis (PSS). Quantitation of RES included calculation of percent emptying at 30 sec, and standard manometric measurements were obtained. RES and manometry were performed before and 10 min following the i.v. administration of metoclopramide. RES showed a significant increase in mean percent emptying from 36% to 46% after drug administration (p less than 0.01), while mean lower esophageal pressure (end-expiratory) increased from 2 to 11 mm of Hg (p less than 0.001). Manometry failed to reveal a significant increase in either distal or proximal mean esophageal contractile amplitude, and no correlation was found between the increase in percent emptying at RES and the change in lower esophageal pressure in the individual patient. RES is the only quantitative method presently available to evaluate bolus propagation in the esophagus, and it documented improved esophageal function after metoclopramide administration in a PSS population. When drug therapy is directed at augmentation of esophageal emptying, RES is an ideal method to evaluate drug response.
Explore the source record for details and available documents.
Twelve patients with progressive systemic sclerosis (four with CREST [calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia] variant) underwent systematic evaluation to assess the esophagogastric effects of metoclopramide hydrochloride in this patient population. Esophageal manometry, esophageal radionuclide scintigraphy, solid-phase gastric emptying, and 24-hour esophageal pH monitoring were performed in all patients with and without metoclopramide. Metoclopramide improved lower esophageal sphincter pressure and reduced the gastric emptying delay and gastroesophageal reflux in most patients but had a less consistent effect improving esophageal transit or esophageal body pressures. Metoclopramide should be strongly considered in the pharmacologic approach to the gastroesophageal reflux-related complications of this disease.
A prospective study of patients with symptoms of gastroesophageal reflux was undertaken to determine the prevalence of Barrett's esophagus and reevaluate the diagnostic approach necessary to detect this complication. Endoscopy with mucosal biopsy was performed in 97 subjects. Twelve (12.4%) were found to have Barrett's esophagus. The sensitivity and specificity of the endoscopic and radiologic examinations for Barrett's esophagus were prospectively evaluated. Endoscopy (92%) was significantly more sensitive than radiology (24%) in detecting Barrett's esophagus (p less than 0.001). The frequency and severity of reflux symptoms among patients determined to have Barrett's esophagus, reflux esophagitis, or normal esophageal biopsies were quantitatively similar in all three groups, except for significantly greater daytime heartburn in those with reflux esophagitis (p less than 0.01). These data indicate that Barrett's esophagus complicates gastroesophageal reflux more often than previously believed.
The lysosomal cysteine proteinases cathepsin L and cathepsin B were examined for their effect on the neutrophil elastase inhibitory activity of human alpha 1-proteinase inhibitor (alpha 1PI). Human cathepsin L catalytically inactivated human alpha 1PI by cleavage of the bonds Glu354-Ala355 and Met358-Ser359 (the serine proteinase inhibitory site). Cathepsin B did not inactivate alpha 1PI, even when equimolar amounts of enzyme were employed. Cathepsin L is the first human proteinase shown to catalytically inactivate alpha 1PI. These findings, in conjunction with other reports, suggest that alpha 1PI contains a proteolytically sensitive region encompassing residues 350-358. Taken together with the discovery of the elastinolytic activity of cathepsin L (Mason, R. W., Johnson, D. A., Barrett, A. J., and Chapman, H. A. (1986) Biochem. J. 233, 925-927), the present findings emphasize the possible importance of cathepsin L in the pathological proteolysis of elastin and diminish the role that can be attributed to cathepsin B in such processes.
Explore the source record for details and available documents.
The hydrolysis of a tritiated elastin substrate by the human cysteine proteinases cathepsins B and L has been studied. Cathepsin L was found to be at least 100-fold more active on this substrate than cathepsin B. The specific activity of cathepsin L at pH 5.5 for hydrolysis of elastin was about the same as that of pig pancreatic elastase at its optimum pH of 8.8.