Biomedical subjects
Publications and source records attributed to G M Murphy.
We report a patient with long-standing polymorphic light eruption (PLE) who developed a photocontact allergy to mexenone and several contact allergies. The occurrence of multiple contact and photocontact allergies in PLE and the possible relationship of such allergies to the pathogenesis of PLE are discussed.
Polymorphic light eruption (PLE) is a very common photosensitive disorder, the most important differential diagnosis of which is lupus erythematosus (LE). One-hundred and forty-two patients with PLE were screened for circulating antinuclear (ANA), Ro and La antibodies over a 2-year period. Results were negative in 66 patients. Sixty-two patients had low-titre ANA of various patterns, ranging from trace to 1/80 without evidence of LE although one later developed subacute cutaneous LE. Fourteen had more significant findings, six with ANA ranging from 1/160 to 1/1280 but no anti-Ro antibodies, four with ANA ranging from 1/160 to 1/1280 and also with anti-Ro antibodies and four patients with anti-Ro antibodies but low-titre ANA, one of whom later developed discoid LE. Three of these 14 patients fulfilled the American Rheumatism Association criteria for the diagnosis of systemic LE, but it was not certain in any of the patients whether the PLE-like rash represented cutaneous LE or coincidental PLE. However the overall 10% incidence of definite or possible LE in patients with suspected PLE suggests that all PLE patients should be screened for LE.
Transforming growth factor-alpha (TGF-alpha) is a growth-promoting cytokine which enhances epithelial proliferation and is secreted by a wide variety of tumour cells. It is also present in normal human epidermis and its overproduction may be responsible for epidermal hyperproliferation in psoriasis. Ultraviolet (UV) B irradiation of human skin leads to epidermal damage and significant subsequent hyperplasia after approximately 24 h, whereas UVA irradiation has little such effect and predominantly damages the dermis. The relative efficacies of UVB and UVA in releasing TGF-alpha were studied in 10 subjects of skin types I and II using a skin-chamber technique and a specific TGF-alpha radioimmunoassay. Significantly elevated concentrations of immunoreactive TGF-alpha were detected in samples after 24 h in UVB-irradiated compared with unirradiated skin. Samples at earlier time points from UVB- and UVA-exposed skin contained measurable levels of TGF-alpha but these were not significantly elevated above the levels found in samples from unirradiated areas. These results, which suggest the UVB irradiation increases release of TGF-alpha from human skin at 24 h, indicate that TGF-alpha may be implicated in UVB-induced epidermal hyperplasia.
In this study gall bladder emptying patterns in response to a solid meal were studied using ultrasound. A similar triphasic pattern was seen in eight healthy control subjects and eight patients with gall stones, with 'early' and 'late' net emptying phases separated by a period of net refilling with peak postprandial gall bladder volumes occurring at (mean (SD)) 33.1 (17.9) minutes and 27.4 (18.8) minutes in control subjects and patients, respectively. A phase of slower net emptying followed, which was complete at 146 (33) minutes in control subjects and 125 (33) minutes in the gall stone patients (not significant). Superimposed upon this overall triphasic pattern, postprandial gall bladder emptying was punctuated by repeated short lived episodes of filling and emptying. The mean (SD) estimated postprandial bile outputs were 0.83 (0.34) ml/min in four control subjects and 1.2 (1.1) ml/min in seven patients with gall stones. We propose a 'washout' model to reconcile this large turnover of bile with the concentrating and storage functions of the gall bladder and predict that the extent rather than the rate of gall bladder emptying is important in determining stasis of bile in the gall bladder.
Chronic duodenogastric reflux induces gastric adenocarcinomas in the rat without the use of carcinogens. Altogether, 186 male Wistar rats were randomised to undergo either a simple gastrojejunostomy or a gastrotomy and sacrificed at eight weekly intervals for 56 weeks. No control animals developed dysplasia or carcinoma. All rats subjected to a gastrojejunostomy showed hyperplasia of the proliferative neck zone, with increased sulphomucin production adjacent to the scar. Low grade dysplasia was found at 16 weeks, and carcinoma was first seen at 32 weeks. Most carcinomas were well differentiated mucin secreting adenocarcinomas of the expanding type, which secreted a mixture of sialomucins and sulphomucins. Duodenogastric reflux was associated with a 100% increase in labelling index (assessed autoradiographically with tritiated thymidine) in the gastric mucosa when compared with corresponding tissue adjacent to a gastrotomy scar. This increase was significant at eight weeks and persisted for 56 weeks after surgery. This study supports the theory that, in this model, hyperplasia precedes the development of carcinoma.
Transforming growth factor alpha (TGF alpha) is a keratinocyte-growth-stimulating factor which may have a role in epidermal hyperproliferation, psoriasis, and wound healing. Since increased epidermal proliferation occurs in response to UV radiation, we have measured the amount of TGF alpha in exudates from normal and UVB-irradiated human skin. Cutaneous exudates were obtained using the skin chamber abrasion technique from one side of the back of volunteers (n = 10) with normal skin (collected following skin contact times of 2 and 30 min). Exudates were similarly obtained from the contralateral side of the back at sites irradiated 2 h previously with 3 x the minimum erythemal dose UVB. Levels of TGF alpha were measured by radioimmunoassay. Normal human skin released TGF alpha immediately after abrasion: unirradiated, 63 +/- 18 ng/ml; irradiated, 89 +/- 15 ng/ml. Levels of TGF alpha increased within 30 min to 110 +/- 14 ng/ml in unirradiated skin and to 190 +/- 17 ng/ml in irradiated skin. Irradiated sites at 30-min time points were significantly higher (p less than 0.05) than all other samples. The presence of releasable TGF alpha in normal skin suggests a role for TGF alpha in wound repair mechanisms.
For many years the exact nature of the pathophysiology of seborrhoeic dermatitis and dandruff was in doubt. Different schools of thought debated whether Pityrosporum yeasts were of primary pathogenic significance or a secondary phenomenon, with epidermal hyperproliferation as the primary pathology. Although effective therapy in seborrhoeic dermatitis and dandruff has for a long time been based on compounds whose only common link was antipityrosporal activity, proof of this relevance was lacking until the introduction of effective antifungal drugs, in particular ketoconazole. This article charts the swing of opinion towards the primary pityrosporal aetiology of seborrhoeic dermatitis and dandruff, reviews the evidence that antipityrosporal activity is the common link to various compounds which benefit these conditions, and compares the efficacy of these substances in treatment.
Most patients with Down's syndrome (DS) undergo a premature cognitive decline with aging, and eventually develop the neuropathologic changes of Alzheimer's disease (AD), including amyloid-containing neuritic plaques, and the formation of neurofibrillary tangles. The amygdala is a focus of marked neuropathologic change in older patients with DS and in AD. We examined the amygdala with immunocytochemical and histochemical methods in 6 cases with DS, ages 19, 20, 27, 29, 56 and 64 years and compared them to 4 cases with AD, ages 54, 76, 77 and 80 years. An antiserum to the A4 amyloid peptide demonstrated amyloid deposition in plaques in all 10 cases. Plaques were also revealed in all cases by the Alcian blue stain for glycosaminoglycans and by the Bielschowsky and Bodian silver stains. An antiserum to alpha-1-antichymotrypsin (ACT) showed plaques in the AD cases and in the 19, 56 and 64 year old DS cases. Neurofibrillary tangles were observed with silver stains only in the older DS and in the AD cases, and not in the 19, 20, 27 and 29 year old DS cases. Likewise, antisera to paired helical filament, to microtubule associated proteins tau and microtubule associated protein-2 (MAP-2), and to ubiquitin, all of which are components of neurofibrillary tangles, reacted with tangles and abnormal neurites only in the older DS and the AD cases. An antiserum to neurofilament epitopes labeled NFTs in the older DS cases and the AD cases, but not in the younger DS cases, except for two intraneuronal NFTs in the 27 year old case.(ABSTRACT TRUNCATED AT 250 WORDS)
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In animals, the distribution of the enzyme diamine oxidase is confined, almost exclusively, to the small bowel mucosa. In humans, plasma diamine oxidase is at or below assay detection limits but can be liberated into the circulation from binding sites in the intestine by i.v. heparin. Therefore, the authors wished to see if diamine oxidase could be released by a low and safe dose of heparin (5000 U) and if the resultant area under the concentration-time curve would provide a noninvasive marker of segmental intestinal disease. In 17 control subjects, the mean area under the curve (following administration of 5000 U i.v. heparin) was 35.9 +/- 5.0 (SEM) mU.L-1.2 h-1; in 6 individuals studied on two separate occasions, postheparin plasma diamine oxidase profiles were reproducible (r = 0.98; p less than 0.001). The longitudinal distribution of diamine oxidase in the gastrointestinal tract, measured in 12 gastric, 16 jejunal, 6 ileal, and 18 colonic biopsies, was similar in humans to that found in animals. In patients with normal peroral biopsies, there was a linear relationship between jejunal mucosal and postheparin plasma diamine oxidase activities (r = 0.84; p less than 0.01). The areas under the curve in controls were then compared with those in patients with segmental intestinal diseases: 21 with ileal disease with or without colonic Crohn's disease (10 unoperated and 11 with ileal resection), 7 with non-Crohn's ileal resection, 8 with ulcerative colitis, 10 with untreated and 7 with treated celiac disease (6 studied before and after a gluten-free diet), and 5 studied during total parenteral nutrition and again after resumption of oral feeding. The results in the 18 ileectomized patients were subdivided into those with major (arbitrarily greater than 75 cm) and minor (less than 75 cm) resections. Areas under the curve were markedly reduced in nonresected Crohn's patients (6.0 +/- 1.79 mU.L-1.2 h-1; p less than 0.001 vs. controls), correlating inversely, in a first-order relationship, with disease activity (r = 0.82; p less than 0.001) and returning toward normal in 4 patients achieving disease remission. Low areas under the curve in total parenteral nutrition patients (4.5 +/- 0.9; p less than 0.001) were also reversible on resumption of oral feeding. However, areas under the curve were not significantly lower in patients with limited ileal resection (less than or equal to 75 cm), with celiac disease (untreated and treated), or ulcerative colitis than in controls.(ABSTRACT TRUNCATED AT 400 WORDS)
1. Amyloid deposition is one of the pathologic hallmarks of Alzheimer's disease. Since the isolation of the beta-amyloid gene, which revealed that the amyloid forming 4 kD protein is part of a larger precursor, interest has focused on the process by which amyloid is generated and deposited. 2. The authors have developed an immunologic means of detecting amyloid precursor proteins in human brain. 3. The method involves the expression of human beta-amyloid precursor cDNA in a recombinant vaccinia virus, so that antibodies are produced against the precursor proteins in their native forms. 4. By using this expression system, the amyloid precursor immunogens incorporate post-translational modifications that normally occur in vivo; this cannot be achieved with small synthetic peptides. 5. Using antibodies to the 695 residue amyloid precursor, we have detected using Western blot analysis a protein of approximately 120 kD in samples of cerebral cortex from three subjects with Alzheimer's disease and one control subject. 6. Additional antibodies to other amyloid-related proteins have been developed. These are being used to assess the differential expression of the various amyloid precursors and subdomains in additional cases.
Limbic system structures are of central interest in many neuropsychiatric disorders. Magnetic resonance imaging (MRI) has a unique potential for imaging limbic system structures in vivo, but methodological constraints can limit the usefulness and interpretation of the collected image data. In this article, we present approaches for the acquisition and quantification of high resolution MR images of the limbic system. We used a long TR, cardiac gated, flow compensated, spin echo sequence to collect 22, 3-mm thick contiguous sections encompassing the limbic system. The sections were oriented relative to standard internal neuroanatomical landmarks. The sequence provided good gray matter/white matter/cerebrospinal fluid (CSF) and CSF/bone contrast; the latter is necessary for quantifying intracranial size and total CSF volume. Using operationalized criteria, we achieved high interrater reliability in volumetric measurement of temporal horn and hippocampus. This technique was then used to examine the effect of normal aging by comparing eight young (mean = 24 years) and seven old (mean = 73 years) healthy community members. We were able to demonstrate a significant age-related increase in temporal horn volume and a trend toward an age-related decrease in hippocampal volume.
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An abnormal metabolism of histamine has been suspected in urticaria and the role of diamine oxidase (DAO: histaminase) is therefore of interest. We have studied DAO activity in plasma and jejunal biopsy material and have measured the post-heparin DAO release in 11 control subjects and nine with recurrent urticaria, three of whom had had concurrent episodes of abdominal pain. Two of the nine urticaria subjects had only a minimal rise in plasma DAO activity after heparin, three had a response which was at the lower end of the normal range, and four were normal. In four out of five cases in which jejunal biopsy activity was obtained, there was concordance between mucosal DAO activity and the post-heparin plasma DAO response. Those with abdominal symptoms had abnormally low mucosal DAO activity and the subject who was most severely affected had proven episodes of small bowel oedema.
Immediate and delayed photocontact dermatitis from the UVA absorber isopropyl dibenzoylmethane is described in 1 patient. In a dose response study in a 2nd patient with delayed photocontact dermatitis, the minimal dose of UVA needed to elicit a positive photopatch to isopropyl dibenzoylmethane 2% was determined to be 2 J/cm2.
The aim of this study was to examine the relative importance of the enzymes ornithine decarboxylase (ODC) and diamine oxidase (DAO) in intestinal polyamine metabolism in normal rats. To study this we measured jejunal and ileal DAO and ODC activities and polyamine levels 2 h after injecting, in non-fasting male Wistar rats, either normal saline (controls) or a large dose of i.v. heparin to deplete intestinal mucosal DAO stores. We found that heparin significantly reduced mean DAO activity (p less than 0.001). As a result putrescine levels increased significantly in both jejunum (p less than 0.02) and ileum (p less than 0.01). Heparin-induced DAO depletion had no significant effect on spermine and spermidine levels at either site. The increased putrescine was associated with reduced ODC activity in both jejunum (p less than 0.01) and ileum (p less than 0.05). ODC activity correlated negatively with putrescine (p less than 0.001). These results suggest that (i) in normal rats, DAO is more important than ODC in regulating mucosal putrescine levels and (ii) putrescine exerts feedback inhibition of ODC.