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Biomedical subjects

D M Thomas

Publications and source records attributed to D M Thomas.

At least 19 recordsLinked to original sources
PubMed1996

Structural and stereoelectronic requirements for the inhibition of mammalian 2,3-oxidosqualene cyclase by substituted isoquinoline derivatives.

2,3-Oxidosqualene lanosterol-cyclase (OSC; EC 5.4.99.7) is an attractive target for the design of compounds that block hepatic cholesterol biosynthesis. (4a alpha, 5 alpha, 6 beta, 8a beta)-Decahydro-5,8a-dimethyl-2-(1,5,9-trimethyldecyl)-6- isoquinolinol (1) and simplified analogs have been devised to inhibit this enzyme by mimicking the postulated pro-C-8 high-energy intermediary carbocation occurring during the cyclization-rearrangement pathway. In order to gain an understanding into the mechanism by which these types of molecules inhibit OSC, we have synthesized a series of substituted isoquinoline derivatives 3 and investigated the structural and stereoelectronic requirements, and their stringency, that make 3 potential high-energy intermediate analogs of OSC. Determination of the IC50 values of the different compounds with rat liver microsomal cyclase, allowed the study of the relative importance of (i) the nature and the stereochemistry of the nitrogen side chain, (ii) the presence of methyl groups at C-5 and C-8a (ring junction), (iii) the presence and stereochemistry of the C-6 hydroxyl group, (iv) the nature of the ring junction, and (v) the absolute configuration of the bicyclic system. The resulting structure-activity relationships seem to validate the mechanism of action of these inhibitors as analogs of a pro-C-8 high-energy intermediate and delineate the minimal requirements for the design of efficient isoquinoline-based, or simplified, OSC inhibitors.

Animals↗
PubMed1996

A control problem in a polluted environment.

Due to the importance of remediating polluted environments, many mathematical models have been developed to describe population-toxicant interactions. This article considers the situation where the amount of pollution in the environment is restricted to lie below a certain value M. A model is presented and viewed as a control problem in which the toxicant input into the environment is the controllable variable. An explicit formula is computed for the input function that meets certain restrictions. By analytically studying the dynamics of the population, it is possible to provide conditions on how to set M in order to guarantee survival of the population without a significant reduction of its carrying capacity. Numerical and experimental data are described that support these results.

Animals↗
PubMed1996

Expression and regulation by insulin of GLUT 3 in UMR 106-01, a clonal rat osteosarcoma cell line.

Expression of the glucose transporter GLUT 3 is mainly restricted to neuronal tissues, with lower levels in testis and placenta. In addition, GLUT 3 has recently been reported in neonatal rat calvaria by in situ hybridisation. We report the co-expression of GLUT 1 and GLUT 3 mRNA and protein in UMR 106-01, a clonal osteosarcoma cell line. By semi-quantitative analysis we show that GLUT 3 protein is expressed at levels comparable to GLUT 1. Insulin stimulates glucose uptake in UMR 106-01 cells. GLUT 3 mRNA and protein are increased by chronic (16 h) treatment with insulin, and the increase in GLUT 3 mRNA is not inhibited by cycloheximide. Regulation of GLUT 3 mRNA by insulin has not been previously shown. UMR 106-01 represents a useful model for investigating regulation of GLUT 3 expression.

Animals↗
PubMed1996

Insulin receptor expression in bone.

Insulin is known to be an important osteotropic hormone. To date, no study has specifically addressed the possibility that insulin receptor expression may be regulated by differentiation in bone. We report a heterogeneous distribution of insulin receptor (IR) within neonatal rat calvaria using a specific monoclonal antibody to the beta-subunit of the rat insulin receptor (CT-1). Specific binding of CT-1 to mature osteoblasts was demonstrated, with little binding over periosteal tissues or osteocytes. Using enzymatically derived subpopulations of calvarial cells, we showed a correlation between alkaline phosphatase activity and insulin-stimulated 2-deoxyglucose (2-DOG) uptake and increased 125I-insulin binding. Since primary calvarial cultures contain many cell types, we compared 125I-insulin binding, insulin-stimulated 2-DOG uptake, and Northern blot analysis of IR mRNA in the clonal preosteoblast-like cell line UMR 201-10B and the mature osteoblast cell line UMR 106-01. It is shown that UMR 106-01 cells possess higher levels of IR mRNA, insulin binding, and insulin-stimulated glucose uptake, and that insulin up-regulated expression of mRNA of the glucose transporter GLUT1 by 3-fold. In contrast, insulin binding was negligible in UMR 201-10B cells, which expressed much lower levels of IR mRNA. UMR 201-10B cells did not possess an insulin-sensitive glucose uptake system, although they express GLUT1 mRNA. These data are consistent with the hypothesis that, as in muscle and fat, insulin receptor expression correlates with the stage of osteoblast differentiation in vivo and in vitro.

Alkaline Phosphatase↗
PubMed1996

Factors influencing plasma lipid profiles including lipoprotein (a) concentrations in renal transplant recipients.

Fasting plasma cholesterol, triglycerides, high-density lipoprotein (HDL) and apoprotein (apo) B were elevated in 214 nondiabetic renal transplant recipients when compared to a reference group. Apo (a) was slightly but not significantly lower in transplant recipients (median 118 mg/dl, range 16-1680 vs 130 mg/dl, 10-1176) and this difference could be predicted from Lp (a) isoform analysis. Cholesterol, triglyceride, apo B and apo (a) concentrations correlated negatively with creatinine clearance but none of these parameters showed a significant association with proteinuria. Patients treated with steroids had higher plasma HDL concentrations than those receiving cyclosporin monotherapy (P < 0.01). The use of diuretics was associated with raised triglycerides (P < 0.001) and cholesterol (P < 0.01) and with reduced HDL (P < 0.01) whilst patients receiving beta-blockers had significantly higher triglycerides (P < 0.01) and lower HDL levels (P < 0.02). In multiple regression analysis, age (P < 0.01), creatinine clearance (P < 0.05) and diuretic therapy (P < 0.005) were independent risk factors for increased cholesterol whilst apo (a) levels correlated negatively with creatinine clearance (P < 0.005). These results suggest that impaired renal function, steroids and non-immunosuppressive drugs contribute to lipid abnormalites in renal transplant recipients.

Adrenergic beta-Antagonists↗
PubMed1996

Malignant otitis externa in HIV and AIDS.

Malignant otitis externa is a necrotising infection of the external ear canal which may spread to include the mastoid and petrous parts of the temporal bone, leading to skull base osteomyelitis. It is almost exclusively caused by infection with Pseudomonas aeruginosa, and usually occurs in elderly non-insulin-dependent diabetic patients. However isolated cases have been reported in a small number of non-diabetic patients, particularly in children who are immunocompromised due to malignancy, malnutrition and severe anaemia. In 1984 a case of malignant otitis externa was reported in a child with an acquired immunodeficiency syndrome (AIDS)-like illness, prior to identification of the human immunodeficiency virus (HIV). Since that time further sporadic cases of this invasive infection have been reported in HIV and AIDS. We present two further cases and also a review of the current literature.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Integrin alpha 3 beta 1 participates in the phagocytosis of extracellular matrix molecules by human breast cancer cells.

The mechanisms and receptors involved in phagocytosis by nonhematopoietic cells are not well understood. The involvement of the alpha 3 beta 1 integrin in phagocytosis of the extracellular matrix by human breast cancer cells was studied. The possible role of this integrin was suggested since alpha 3 and beta 1 but not alpha 2 subunits are concentrated at membrane sites where local degradation of fluorescently labeled gelatin occurs. Strikingly, anti-alpha 3 integrin monoclonal antibodies (mAbs) stimulate the phagocytosis of fluorescently labeled gelatin films, gelatin beads, and Matrigel films in a quantitative phagocytosis assay. Stimulation of the gelatin uptake by the anti-alpha 3 mAb is dose responsive, saturable, and time dependent. Antibodies against other integrin subunits have a lower stimulatory effect (anti-beta 1) or no significant effect (anti-alpha 2, -alpha 5, -alpha 6, and -alpha v) on gelatin phagocytosis. The synthetic HGD-6 human laminin peptide that binds specifically the alpha 3 beta 1 integrin, but not the scrambled HSGD-6 control peptide, also markedly stimulates gelatin uptake in a dose-responsive way. Furthermore, the stimulatory effects of the HGD-6 peptide and the anti-alpha 3 mAb are additive, suggesting that they might promote phagocytosis in different ways. Other laminin (YIGSR, IKVAV) and fibronectin (GRGDS) peptides have no effect on gelatin phagocytosis. Immunofluorescence shows that the alpha 3 and the beta 1, but not the alpha 2 integrin subunit, concentrate into patches on the cell surface after treatment with their respective mAbs. And, both gelatin and the alpha 3 beta 1 but not the alpha 2 beta 1 integrin are cointernalized and routed to acidic vesicles such as lysosomes. In conclusion, we demonstrate that human breast cancer cells locally degrade and phagocytose the extracellular matrix and show for the first time that the alpha 3 beta 1 integrin participates in this phagocytosis. We hypothesize that the anti-alpha 3 antibodies and the laminin peptide HGD-6 activate the alpha 3 beta 1 integrin, which results in a downstream signaling cascade stimulating phagocytosis.

Amino Acid Sequence↗
PubMed1996

Dexamethasone modulates insulin receptor expression and subcellular distribution of the glucose transporter GLUT 1 in UMR 106-01, a clonal osteogenic sarcoma cell line.

Corticosteroids have profound effects on bone metabolism, though the underlying mechanisms remain unclear. They are also known to alter glucose metabolism, in part by induction of insulin resistance. To determine whether corticosteroids impair glucose metabolism in bone cells, we have examined the actions of dexamethasone (DEX) on glucose transport and insulin receptor expression using osteoblast-like UMR 106-01 cells. DEX was shown to inhibit basal 2-deoxyglucose uptake by up to 30% in a time- and dose-dependent manner. It inhibited insulin-stimulated glucose transport by 13%. By Northern and Western blot analysis, DEX was shown to stimulate insulin receptor mRNA and protein by up to 5.6-fold, but it had no effect on expression of the glucose transporter GLUT 1 mRNA or protein under basal conditions. However, DEX augmented insulin-stimulated GLUT 1 mRNA and protein levels. By Scatchard analysis of labelled insulin binding, DEX increased insulin receptor number per cell by 54%. Subcellular fractionation and Western blot analysis demonstrated that DEX caused a redistribution of immunoreactive GLUT 1 from plasma membrane to intracellular microsomes, resulting in a 21% decrease in GLUT 1 at the plasma membrane. These data suggest that (i) DEX impairs basal glucose transport by post-translational mechanisms in UMR 106-01 cells, (ii) DEX increases insulin receptor mRNA, protein and insulin binding and (iii) the inhibition of glucose transport by DEX dominates its effects on the insulin receptor. It is possible that DEX inhibition of glucose transport in osteoblasts may contribute to steroid-induced osteoporosis.

Animals↗
PubMed1996

Audit of pain after nasal surgery.

In our department, nasal packs have traditionally remained in place for a period of 24 h after routine elective nasal surgery. We decided to determine whether reducing the duration of nasal packing from 24 h to 2 h would reduce postoperative pain without a concomitant increase in haemorrhagic complications. A series of 72 patients undergoing elective nasal surgery were randomised to have either nasal packs for 24 h (n = 39) or for 2 h (n = 33). Pain was assessed using a visual analogue scale with the nasal packs in place and on their removal. The incidence of haemorrhage was noted. The results showed a significant decrease in mean pain score (MPS) with the packs in place, from 3.4 (range 0.8-6.8) to 1.16 (range 0-2.5); (P < 0.001) and also on pack removal from 5.3 (range 1.2-7.9) to 2.6 (range 0-5.4); (P < 0.05). There was no postoperative haemorrhage in either group. A new standard of 2 h for routine nasal packing was set and our departmental protocols were changed accordingly. Results in a further 36 patients gave a MPS with the packs in place of 1.12 (range 0-3.2) and a MPS of 2.36 (range 0-6.7) on their removal. There was no statistical difference between these and our previous findings. We conclude that postoperative nasal packing for only 2 h rather than 24 h significantly reduces pain without a concomitant risk of haemorrhage.

Adult↗
PubMed1995

Sequence 104-117 of myelin proteolipid protein is a cryptic encephalitogenic T cell determinant for SJL/J mice.

Immunization of animals with myelin proteolipid protein (PLP) causes experimental autoimmune encephalomyelitis (EAE), a disease model that shares many features with human multiple sclerosis (MS). The SJL/J (H-2s) mouse is widely used in EAE studies because of its high disease susceptibility. Previous studies have shown that sequences 139-151 HCLGKWLGHPDKF and 178-191 NTWTTCQSIAFPSK represent distinct co-immunodominant encephalitogenic determinants of PLP for SJL/J mice. In the present study, we identify a third distinct PLP encephalitogenic peptide for SJL/J mice. Following immunization with PLP 104-117 KTTICGKGLSATVT, 10/14 SJL/J mice developed clinical and histological EAE with a mean time of onset of 38 days (18-65 days). T cell lines generated from SJL/J mice immunized with p104-117 were predominantly (> 90%) CD3+, CD4+, alpha beta TCR+, CD8dim, gamma delta TCRdim T cells and responded in an Ag-specific, I-A(s)-restricted manner to p104-117. Upon adoptive transfer of 16-40 x 10(6) T line cells, EAE was produced in naive SJL/J recipients 20-34 days after transfer. The delayed onset of both active and passive disease may be related to the non-immunodominant, cryptic nature of p104-117 in SJL/J mice. Lymph node cells from SJL/J mice immunized with either whole PLP or with pooled encephalitogenic PLP peptides responded to challenge with the immunodominant PLP determinants p139-151 and p178-191 but did not respond to p104-117. The existence of three distinct PLP encephalitogenic T cell determinants for SJL/J mice suggests that susceptibility to EAE and perhaps MS may be related to promiscuous T cell recognition of multiple myelin protein determinants.

Amino Acid Sequence↗
PubMed1995

An unusual cause of cochlear implant failure.

We present a cochlear implant failure previously unidentified and unreported. Following successful implantation and activation of a Cochlear Mini 22 system, a distressing barrage of crackling noises was heard by the patient despite repeated programming with threshold and comfort level adjustment. The implant soon became nonfunctional and integrity testing showed deficient electrical responses and abnormal surface measured wave forms. Investigation of the explant, following reimplantation with an identical system, showed a defective trim capacitor, an electric component of the internal circuit in the stimulator. Paired Student's t-test showed a marginally significant increase (p = 0.047) in effective threshold level and a highly significant decrease (p = 0.0002) in maximum comfort level for the second implant compared to the first implant.

Cochlear Implants↗
PubMed1995

Atlanto-axial subluxation (Grisel's syndrome) following otolaryngological diseases and procedures.

Grisel's syndrome is a rare condition of uncertain aetiology characterized by atlanto-axial subluxation following an infection in the head and neck region. The condition most frequently affects children and characteristically presents in the post-operative period with cervical pain and torticollis. We describe three cases and discuss the aetiology and pathogenesis. A high index of suspicion may lead to early diagnosis in its natural history thereby preventing potentially serious complications.

Adenoidectomy↗
PubMed1995

Giant cell reparative granuloma of the cricoid cartilage.

Giant cell reparative granuloma (GCRG) is an uncommon benign lesion which has been reported at several sites in the head and neck. We present a case of a GCRG of the cricoid cartilage not previously described in the literature. It must be differentiated from the brown tumour of hyperparathyroidism and true giant cell tumours of bone. These were excluded on clinical, biochemical, radiological and histological grounds. The lesion responded well to surgical debulking and curettage and the patient remained disease-free 15 months after treatment.

Cricoid Cartilage↗
PubMed1995

Distinguishing homelessness from poverty: a comparative study.

To separate the characteristics of the homeless from those of the housed poor, 144 adults were randomly sampled from several sites, yielding 3 groups: the currently homeless (n = 59), the previously (but not currently) homeless (n = 31), and the never-homeless poor (n = 54). The homeless were significantly less likely to be receiving public benefits, were more likely to have a DSM-III (Diagnostic and Statistical Manual of Mental Disorders [3rd ed.; American Psychiatric Association, 1980]) diagnosis of substance abuse, showed higher levels of self-rated psychological distress and were more likely to be victims of recent domestic violence and to have been physically abused as children. The homeless did not differ from the comparison groups on DSM-III diagnosis of severe mental illness (schizophrenia or major affective disorder). physical health symptoms, and social support and social networks.

Adult↗
PubMed1995

Modulation of glucose transport by parathyroid hormone and insulin in UMR 106-01, a clonal rat osteogenic sarcoma cell line.

This study characterizes the actions of insulin and parathyroid hormone (PTH) on the glucose transport system in the rat osteogenic sarcoma cell line UMR 106-01, which expresses a number of features of the osteoblast phenotype. Using [1,2-3H]2-deoxyglucose (2-DOG) as a label, UMR 106-01 cells were shown to possess a glucose transport system which was enhanced by insulin. In contrast, PTH influenced glucose transport in a biphasic manner with a stimulatory effect at 1 h and a more potent inhibitory effect at 16 h on basal and insulin-stimulated 2-DOG transport. To explore the mechanism of PTH action, a direct agonist of cAMP-dependent protein kinase (PKA) was tested. 8-Bromo-cAMP had no acute stimulatory effect but inhibited basal and insulin-stimulated 2-DOG transport at 16 h. This result suggested that the prolonged, but not the acute, effect of PTH was mediated by the generation of cAMP. Further studies with the cell line UMR 4-7, a UMR 106-01 clone stably transfected with an inducible mutant inactive regulatory subunit of PKA, confirmed that the inhibitory but not the stimulatory effect of PTH was mediated by the PKA pathway. Northern blot data indicated that the prolonged inhibitory effects of PTH and 8-bromo-cAMP on glucose transport were likely to be mediated in part by reduction in the levels of GLUT1 (HepG2/brain glucose transporter) mRNA.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Determinant-regulated onset of experimental autoimmune encephalomyelitis: distinct epitopes of myelin proteolipid protein mediate either acute or delayed disease in SJL/J mice.

In the present study we address the question of whether distinct self-determinants can target alternative autoimmune disease patterns in experimental autoimmune encephalomyelitis (EAE), an animal model widely used for studying multiple sclerosis. We have found that the clinical course of EAE can be determined by the target peptide selected for induction of disease. In SJL/J mice, actively induced and passively transferred EAE mediated by the immunodominant PLP determinants p139-151 and p178-191 consistently produced a rapid onset of severe clinical signs. In contrast, a delayed onset of both active and passive EAE is associated with the nondominant cryptic PLP determinant p104-117. The delayed disease induced with p104-117 is not associated with any unusual peptide feature, with bystander immunoregulation, with inept class II MHC binding, or with failure to induce T cell expression of CD44, VLA-4, or IL-2 receptor upon activation. However, delayed disease is associated with innate qualities of the T cell repertoire responding to the p104-117 determinant. T cell lines responding to the cryptic p104-117 show limited TCR-V beta utilization compared to the diverse repertoire responding to the dominant p139-151 determinant. The repertoire deletions are accompanied by low level production of pathogenic Th1 cytokines (IFN gamma; IL-2) and increased production of regulatory Th2 (IL-4) cytokine in activated p104-117 primed T cells. Thus, the delayed encephalitogenicity of p104-117 may be due to TCR-V beta deletions and activation defects in the responding T cell repertoire. The development of "slow disease" mediated by autoreactivity against hidden self-determinants may have important implications in the pathogenesis of both relapsing and chronic autoimmune demyelinating disease.

Acute Disease↗