Biomedical subjects
Publications and source records attributed to A Garner.
The case is described of a locally aggressive lipoblastic tumour presenting in the orbit of an 8-year-old boy. There do not appear to be any previous reports of a comparable tumour in this situation.
This report describes approaches for accurate determination of the comparative activities of stimulants of duodenal alkaline secretion. We screened about 200 standard pharmacological agents using a bullfrog-isolated mucosal preparation in order to characterize fully the mechanisms of duodenal alkaline secretion. A variety of eicosanoids, phosphodiesterase (PDE) inhibitors, adrenoreceptor agonists and benzodiazepines, together with forskolin, 6-hydroxydopamine, 2-chloroadenosine, dipyridamole, dihydropyridazinone and testosterone, caused a reproducible increase in the metabolism-dependent component of duodenal alkaline secretion. Prostaglandin E2 (ED50 of 0.02 micrograms ml-1 in vitro) was the most potent and efficacious stimulant in the isolated mucosa and in the perfused cat duodenum in vivo. In the isolated duodenum, the predominant mechanism for stimulating alkaline secretion appears to be via elevation of intracellular cAMP levels, but in vivo indirect effects, for example on mucosal blood flow, may determine the overall influence of agents on duodenal alkalinization.
cDNA clones encoding microtubule-associated proteins 1 (MAP1/MAP1A) and 5 (MAP5/MAP1B) were isolated and have been used to study their structural relationship as well as their regulated expression in developing rat brain. cDNA clones specific for MAP1 hybridized to a single 10-kb rat brain mRNA, and analysis of genomic DNA by Southern blotting indicated the existence of a single MAP1 gene. A second set of cDNAs specific for MAP5 hybridized to a single 11-kb mRNA in rat brain and also detected a single gene. By analysis of hybrid mouse-hamster cell lines, the MAP1 gene was located to mouse chromosome 2, designated Mtap-1, and the MAP5 gene to chromosome 13, designated Mtap-5. MAP1 and MAP5 mRNAs were expressed with different temporal patterns during rat brain development that mirrored the appearance of their protein products, suggesting that expression of these proteins is under transcriptional control. These results taken together demonstrate that although MAP1 and MAP5 have some properties that are similar, they are structurally distinct proteins whose transcription is differently regulated from separate genes.
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Acid and alkali secretion have been examined together with prostaglandin E2 production in response to two mucosal protective drugs, colloidal bismuth subcitrate and sucralfate. Doses of colloidal bismuth subcitrate in the therapeutic range (120 and 1200 mg) had no effect on alkali secretion or luminal PGE2 output when perfused into the stomach of human volunteers. Similarly, in the anaesthetised rat, neither gastric acid nor duodenal alkali secretions were influenced by iv (12 mg/kg) or topical (120 mg/ml) administration of colloidal bismuth subcitrate. In contrast, perfusion of the human stomach with 1 g sucralfate stimulated bicarbonate output by 50%, a response which was unaffected by indomethacin (25 mg/h). A rise of 64% in gastric PGE2 output after sucralfate was, however, prevented by indomethacin pretreatment. Alkali secretion by rat duodenum was also increased by sucralfate but the response depended on the basal secretory rate. Low basal secretors (less than 3 mumol) showed a 75% stimulation whereas rats with high basal secretory rates (greater than 3 mumol) showed no significant response. All duodenal preparations regardless of basal secretory rate showed a stimulation of bicarbonate output with topical PGE2. The results suggest that enhancement of gastroduodenal bicarbonate secretion may play a role in the protective action of sucralfate but is unlikely to explain mucosal protection by colloidal bismuth subcitrate.
Patients with Addisonian pernicious anaemia are alleged to generate antibodies directed against the gastrin receptor. We purified IgG from 15 patients with pernicious anaemia and 15 healthy controls in an effort to show attenuation of gastrin specific binding in vitro and inhibition of gastrin stimulated acid secretion in vivo. Binding of the IgG fraction was determined in a radioreceptor assay utilising the rat pancreatic carcinoma cell line AR42J which expresses high affinity gastrin binding sites (Kd = 5 x 10(-10)). In comparison with control serum, there was no significant displacement (p = 0.10) of human gastrin-17 binding by pernicious anemia samples at either 0.3 mg protein/ml (control (mean (SEM)) 1489 (131) cpm; patients 1858 (174) cpm) or 3 mg protein/ml (control 1930 (110); patients 2195 (107) cpm). The effect of intravenous and intragastric IgG on acid secretion in the anaesthetised rat was determined over a 60 minute period after stimulation with 1 microgram/kg human gastrin-17. A bolus injection of IgG (60-200 mg/kg) had no significant effect (p = 0.50) on gastrin stimulated acid output (29.21 (1.28) mumol H+/h) compared with control (27.48 (4.70) mumol H+/h). Similarly, instillation of 800 mg/kg IgG directly into the stomach for 90 minutes also failed to influence gastrin stimulated acid output (29.69 (3.22) mumol H+/h). Thus, we have been unable to confirm previous reports of an IgG from patients with pernicious anaemia capable of blocking gastrin receptor binding or gastrin stimulated acid secretion.
Sixty-seven invited participants involved in the development, evaluation, and use of therapies for acid-peptic disorders participated in a meeting to discuss the scientific basis for healing actions of ulcer drugs and the prospects for future developments ("Realities of Mucosal Protection in the Upper Gastrointestinal Tract," Lausanne, Switzerland, November 8-10, 1987). Eighty-one key statements were prepared and subsequently analyzed on the basis of a voting system. Of the 45 statements that dealt with existing therapies, only 3 statements showed positive consensus (agreement of two-thirds or more of voters) about mechanisms of ulcer healing. Participants agreed that both (1) hydrogen/potassium adenosine triphosphatase inhibitors and (2) histamine H2 antagonists healed ulcers solely by acid inhibition, and (3) that sucralfate works by topical action. Substantial uncertainty about the mechanisms by which bismuth compounds and antacids heal ulcers was noted as well as their wide range of effects. The mechanism of ulcer healing by prostaglandins and the clinical relevance of antiulcer effects of drugs demonstrated in acute studies with animals were also controversial. There was greater agreement among participants about unexplored drug effects that might produce ulcer healing. Of the 36 such mechanisms surveyed, the most support went to therapies aimed at enhancement of mucosal blood flow, epithelial restitution, and mucosal alkaline secretion or inhibition of luminal pepsin activity. The diversity of opinions among participants suggests a high level of empiricism in the development of ulcer healing drugs apart from those that inhibit acid secretion. This empiricism probably arises from inadequate understanding of processes of mucosal injury and repair.
Analogues of gastrin releasing peptide (GRP) and bombesin based on His-Trp-Ala-Val-D-Ala-His-Leu, the 20-26 heptapeptide sequence of [D-Ala24]GRP, have been synthesized and tested in vitro for their ability to inhibit GRP (18-27)-induced mitogenesis in Swiss 3T3 cells. Compounds identified as potent antagonists in this test system were also tested in vivo for their ability to inhibit bombesin-induced amylase secretion in rats. The Trp-Ala-Val sequence was found to be a very important feature of the antagonist activity; most substitutions in this region led either to much less potent or inactive analogues. In contrast, amino acid replacements in other parts of the molecule were more tolerated and sometimes led to marked increases in the in vitro and in vivo activity. The most potent analogues were obtained by replacing Leu26 by MeLeu and His25 by Lys(X) where X = Z, PhCO, PhCH2CO or Ph(CH2)2CO. Thus 4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(CO-CH2-CH2-Ph)-Leu- NHMe (86) and 4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(Z)-MeLeu-OMe (87) had IC50 values of less than 20 micrograms/kg s.c. in vivo, and their effects lasted for more than 3 hr.
The GRP receptor mediated growth response in Swiss 3T3 cells has been used to identify BN/GRP antagonists. Analysis of bombesin antagonism by substance P analogues and by truncated GRP analogues revealed that deletion of the C-terminal methionine residue was important for antagonism. Des-Met analogues showing potent antagonist activity in the in vitro 3T3 system (IC50 approximately 2nM) were synthesized. Further structural modification of these peptides led to the identification of (CH3)2CHCO-His-Trp-Ala-Val-D-Ala-His-Leu-NHCH3 (ICI 216140) which reduced bombesin-stimulated rat pancreatic amylase secretion to basal levels when administered subcutaneously at 2.0 mg per kg.
The histopathology of tumours originating at the corneoscleral limbus is reviewed with special reference to some 636 specimens examined over a 40 year period at the Institute of Ophthalmology, London. Over half the lesions involved melanocytes (351 cases) derived from the limbal conjunctiva and of these two-thirds were benign naevi. Conversely, benign squamous cell tumours were rare, only five unequivocal papillomas having been seen compared with 137 premalignant lesions and 73 carcinomas. Solid dermoids accounted for approximately 10 per cent of all tumours involving the limbus.
This study includes the fourteen Icelanders who had penetrating keratoplasty for macular corneal dystrophy during 1974 through 1988, and a further five patients whose deterioration of vision has so far not led to surgery. The clinical presentation, mode of inheritance and the course of the disease were similar to those seen in other studies. The genealogical part of this study indicates that the gene responsible for the disease was already present in Iceland in the 18th century. Though consanguinity, as usually defined, was found to be uncommon, the relatively small pool of genes in the Icelandic population which numbers at present about 250,000 has led to higher prevalence of macular corneal dystrophy than elsewhere. The histopathological findings concur with the conventional description of macular corneal dystrophy, with the exception of two patients with unusually severe photophobia. In these two cases, electron microscopy revealed that the most anteriorly situated deposits were sometimes associated with increased electron-density of small clusters of basal epithelial cells in the overlying epithelium, such cells also being reduced in size and exhibiting few organelles other than swollen mitochondria.
The guinea pig is frequently used for studies of the cellular mechanisms of pancreatic secretion. Despite this, little is known about the control of pancreatic secretion in this species. To remedy this omission, we have studied the effects of secretin, cholecystokinin (CCK) octapeptide, and bombesin on the secretion of fluid, electrolytes, and amylase in the anaesthetised guinea pig. While the actions of secretin were similar to those in other species, the actions of CCK were not. As well as stimulating amylase release, CCK evoked a marked fluid secretion whose electrolyte composition differed little from that evoked by secretin. Bombesin had actions similar to those of CCK. It is suggested that this fluid secretion is derived from pancreatic acini. Whether a similar secretory component exists in other species (including humans), albeit as a minor component, needs to be determined.
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The clinical, light microscopical, and electron microscopical features of a mesectodermal leiomyoma of the ciliary body are presented. This exceptionally rare and apparently benign tumour is considered to be of neural crest origin. In the case described the tumour cells were seen to contain thin filaments with focal densities and conspicuous numbers of mitochondria, and smooth muscle protein was demonstrated by immunohistochemical means.
A total of 104 eyes and 43 resected corneal discs from patients with failed intraocular lens implants (IOL) received over a period of 35 years were subjected to histopathological analysis. Eyes collected at necropsy from 18 people with clinically successful implants were also examined. Corneal decompensation leading to bullous keratopathy was the most frequent reason for failure, followed by glaucoma and intraocular inflammation. Of 18 cases in which inflammation was the principal clinical cause of failure 12 presented as infectious endophthalmitis, but minor degrees of sterile uveitis were fairly common. Retinal detachment was seen in seven cases. The interval between IOL implantation and the onset of serious complications varied from one month to 29 years, indicating that the presence of prosthesis will always entail a latent risk of an adverse tissue response, albeit slight.
Seven members of four families had nystagmus noted by 4 months of age, poor vision, photophobia, and a markedly reduced or absent electroretinogram. Six of these patients had a life threatening episode of cardiac failure in infancy. There were also two neonatal deaths, and one of the affected children died at 2 years and one at 19 years. The five surviving children are well, remain with nystagmus, and have visual acuities of less than 6/60, with the eldest two having lost perception of light. They have a short obese habitus distinct from that of their unaffected siblings and parents.