Biomedical subjects
Publications and source records attributed to D Grant.
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Heparin-binding fragments derived from the amino- and carboxyl-terminal regions of human plasma fibronectin appear to be at least relatively specific potent inhibitors of the growth of bovine aortic endothelial cells in culture by as yet unknown mechanisms. In order to understand better the sites which subserve this activity, we have compared the relative potency of other major fragments of fibronectin, most of which have dissimilar properties and do not bind heparin. We have also proteolytically digested and chemically modified the most potent of these fragments, the amino-terminal 29-kDa fragment, in order to test whether structural alterations that affect heparin-binding also affect the inhibitory property. Not all chemical modifications that abolished heparin-binding also abolished endothelial cell growth. Neither an amino-terminal 20-kDa nor a carboxyl-terminal 8-kDa subfragment of the 29-kDa fragment bound heparin; however, both were as inhibitory as native 29-kDa fragment. Reduction of the disulfides of the 20-kDa and 8-kDa fragments did not abolish inhibitory activity. We therefore conclude that the activity is not strictly conformation-dependent and that although the inhibitory activity is distributed throughout the 29-kDa segment, it can be expressed by an 8-kDa carboxyl-terminal segment containing residues of the last Type I loop structure.
Organ transplantation has become the treatment of choice for selected patients with end-stage failure of the heart, liver or kidneys. The expanding role for organ transplantation, however, has led to a corresponding increase in the complexity of patient management. In response to these changes, University Hospital, London, Ont., has established an interdisciplinary multi-organ transplant service (MOTS). MOTS coordinates donor organ procurement and patient management. Donor organs have been retrieved from as far south as Dalton, Georgia, as far west as Calgary and as far east as Halifax. As of Dec. 31, 1985, 485 transplants had been performed, including 387 kidney transplants, 51 heart transplants, 3 heart/lung transplants, 43 liver transplants (in adults and children) and 1 pancreas transplant. With current immunosuppressive protocols MOTS projects 1-year patient survival rates of 95% after kidney transplantation, 88% after heart transplantation and 81% after liver transplantation. Patient rehabilitation has been excellent.
Vitamin D-dependent rickets type II (VDDR II) is a rare syndrome resulting in severe rickets and is resistant to treatment with vitamin D and its derivatives. Patient with this disease, who are frequently the children of consanguinous marriages, present with elevated circulating concentrations of 1,25-dihydroxy vitamin D, the active metabolite of vitamin D, and in vitro studies have indicated a failure of intracellular binding of the hormone. Alopecia has been noted in many of these patients and it has been suggested that this feature may indicate a more marked resistance to treatment. However we describe a 3-year-old boy with this disease who, although having normal hair growth, displayed extreme resistance to treatment with active vitamin D metabolites. In vitro studies of skin fibroblasts disclosed not only an absence of hormone binding or 1,25(OH)2D3-induced 24-hydroxylase activity but reduced metabolism of 1,25(OH)2D3 itself. In this child, treatment with exogenous 1,25-dihydroxy vitamin D3 at doses of up to 24 micrograms/day, which increased the circulating concentration of the metabolite to greater than 100 times the normal adult mean, failed to alleviate his condition and he died at the age of 39 months. This would therefore suggest that absence of alopecia, in this condition, cannot be regarded as a constant predictive sign of a lesser resistance and of responsiveness to Vitamin D treatment.
Clinical results and manometric findings were compared in 82 patients following restorative proctocolectomy. There were 41 patients with long rectal cuffs measuring 8 to 10 cm. There were 39 J-shaped pouches and 2 S-shaped pouches in this group. Forty-one patients had short rectal cuffs measuring 2 to 3 cm. There were 28 J-shaped pouches and 13 S-shaped pouches in this group. Anal manometry was performed in ten patients with long rectal cuffs and in ten patients with short rectal cuffs matched for age, sex, and stool frequency. Postoperative complications were significantly greater in patients with long rectal cuffs. Functional results and manometric findings were similar. No patient demonstrated a normal rectoanal inhibitory reflex. The data in this study suggest that a short rectal cuff can be used safely for restorative proctocolectomy with satisfactory results. A normal rectoanal inhibitory reflex may be absent after restorative proctocolectomy, and this does not interfere with the attainment of continence.
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Tuberculosis of the adrenal glands can present as adrenal insufficiency. The computed tomographic (CT) findings of this disease both prior to and after therapy are presented.
Eighty children from the North West and North East Thames Regional Health Authorities who had been identified as having congenital hypothyroidism either by neonatal screening (76 cases) or by clinical symptoms (four) were seen for psychological assessments at 1 (60 cases), 3 (58), and/or 5 (20) years of age. Almost all the children's scores were in the normal range, and comparisons with matched controls suggested that they were doing only slightly less well than normal children in overall development. They were significantly slower, however, on a motor skills task. Moreover, a low initial serum thyroxine and triiodothyronine value, considerable delay in initial bone age, and an absence of thyroid tissue on isotope scan seemed to be associated with a somewhat poorer prognosis.
The gut hormone cholecystokinin (CCK) octapeptide stimulates the release of amylase from exocrine pancreas, a process believed to be the result of the breakdown of phosphatidylinositol lipids. To examine further the relationship between phosphoinositide (PI) breakdown and amylase release, we have investigated the effect of N-terminally protected CCK C-terminal fragments in these systems using guinea-pig pancreatic lobules. There was a good correlation between the ability of these fragments to elicit amylase release and their potency in enhancing PI breakdown. In general, the EC50 for amylase release is 10-fold lower than the EC50 for PI breakdown. In addition, a good correlation existed between amylase release and the affinity of CCK fragments for [125I]Bolton Hunter-CCK octapeptide binding sites in pancreatic membranes. We also discovered that N-carbobenzyloxy-CCK tetrapeptide was relatively inefficient in causing PI breakdown, but it caused a near maximal stimulation in amylase release. These findings might reflect an amplification mechanism between PI breakdown and amylase release or that N-carbobenzyloxy-CCK tetrapeptide-induced amylase release is independent of PI breakdown.
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The pelvic pouch and ileoanal anastomosis procedure should be considered a reasonable alternative for selected patients with ulcerative colitis and familial polyposis. Patients can expect an improved quality of life without a stoma, particularly those with ulcerative colitis. The long-term effects of the reservoir are not completely known; however, from previous reports and from experience with the Kock's ileostomy reservoir, it seems unlikely that there will be a long-term metabolic problems. It appears that a reservoir is essential in adults to minimize stool frequency to an acceptable level and that there is an inverse correlation between pouch size and stool frequency. We still consider this to be an evolutionary procedure and, as such, it should be confined to specialized centers where larger experiences can be accumulated. For the majority of patients who are being considered for proctocolectomy and ileostomy, we urge that they be made aware of alternative forms of therapy and that retaining the rectum should be considered in these patients due to the possibility of reconstructive surgery at a future date.
Male rats were given ethylene glycol monomethyl ether (EGM) or ethylene glycol monobutyl ether (EGB) po for 4 consecutive days at doses of 100 or 500 mg/kg body wt/day for EGM, and 500 or 1000 mg/kg body wt/day for EGB. Animals were killed on Days 1, 4, 8, and 22 after the final treatment. Both EGM and EGB produced thymic atrophy and lymphocytopenia and, in the case of EGM, neutropenia also. Hemolytic anemia induced by EGB resulted in splenic extramedullary hemopoiesis, hyperplasia of both spleen and bone marrow, and reticulocytosis. Apart from residual slight increases in spleen weight, mean red cell volume, and mean corpuscular hemoglobin at the end of the recovery period, other effects were reversible. With EGM, reduction in the numbers of circulating red cells was only slight. Treatment with EGM also abolished splenic extramedullary hemopoiesis which partially recovered on Day 4, followed by a marked response on Day 8, and return to the moderate control values on Day 22. Femoral bone marrow was hemorrhagic 1 day after treatment with EGM which appeared to be associated with sinus endothelial cell damage. By Day 4 the histologic appearance of the marrow was normal. Testicular atrophy was also produced in EGM-treated animals which persisted for the duration of the experiment. It is concluded that EGM and EGB differ considerably in the spectrum of toxic changes induced, and apart from testicular atrophy, these changes were largely reversible within a short time of the end of treatment.
A fraction of bovine vitreous extract is a potent inhibitor of mitogen induced lymphocyte proliferation in vitro. Proliferation of lymphocytes induced in culture by lipopolysaccharide was more sensitive to inhibition by this fraction than were cultures of lymphocytes stimulated by Concanavalin A. We were unable to demonstrate such activity in similarly prepared fractions of cornea and lens.
Two heparin-binding proteolytic fragments of fibronectin--an amino-terminal 29-kd segment and a carboxyl-terminal 40-kd segment-are apparently specific, potent inhibitors of the growth of cultured bovine aortic endothelial cells and inhibit growth in a reversible, dose-dependent manner. In contrast, native fibronectin at higher dosages neither inhibits nor interferes with the effects of the 29-kd fragment. The data, therefore, suggest that fibronectin fragments may participate in the regulation of vascular growth.
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Because diabetic eyes with proliferative retinopathy show an increased incidence of iris neovascularization after removal of the lens, we studied the effect of extracts of human and bovine lenses on one of the key events in the neovascular process, endothelial cell proliferation. Both human and bovine lens extracts demonstrated a dose-dependent inhibition of bovine aorta endothelial cell proliferation that was greatest in extracts with molecular weight of less than 100,000. This inhibition was reversible and the extracts did not significantly inhibit smooth muscle cell proliferation. Considerable endothelial cell inhibitory activity was present in bovine lens capsule extracts. These data suggested that the lens may play an active role in the prevention of iris neovascularization.
With such a variety of insecticides available, the veterinary surgeon will need to assess each case on its history, the owner, the patient and the severity of parasitical infestation. Without such an assessment there is more likelihood of problems, either failure to eradicate parasites or toxicity from incorrect use of the product. It must be remembered that two methods of application of insecticides should not be used together, eg, a collar and a spray.
The hypothesis that neuroendocrine stimulation after aversive handling can alter natural resistance was examined in the tail electroshock (TES) model, a procedure that can activate pituitary neuropeptide secretion. Immediately after a brief TES session, the resistance of DBA/2J mice was suppressed in proportion to the intensity of the shock. Initial suppression of the natural resistance was rapidly reversed in longer treatment protocols, and repeated aversive stimulation augmented the antitumor response, leaving the mice more resistant to lymphoma than unhandled animals. Corticosterone was released into the serum after all acute handling procedures, and hydrocortisone inoculation suppressed antitumor responses. However, serum corticosterone levels did not quantitatively correlate with the alterations in natural resistance. The observation that TES-induced suppression of natural resistance could be reversed by the opiate receptor antagonist naltrexone suggested that endogenous opiated released after TES stimulation were immunosuppressive.