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Biomedical subjects

C J Bailey

Publications and source records attributed to C J Bailey.

At least 73 records · Page 4Linked to original sources
PubMed1995

Plasma sialic acid in animal models of diabetes mellitus: evidence for modulation of sialic acid concentrations by insulin deficiency.

An elevated circulating sialic acid concentration is a risk factor for cardiovascular disease. Serum sialic acid levels are elevated in NIDDM but not in uncomplicated IDDM. To study why sialic acid is increased in some types of diabetes, we assayed plasma sialic acid in various animal models of diabetes: obese (ob/ob) mice, before and after streptozotocin treatment, neonatal streptozotocin-treated (nSTZ) rats, and diabetic BB rats during and after insulin treatment. In obese mice, which exhibit moderate hyperglycemia and marked hyperinsulinemia, plasma sialic acid was decreased by 45% (fed) and 42% (fasted), compared to lean controls. Fasting reduced plasma glucose and insulin but increased sialic acid in the obese and lean mice. There was a negative correlation (r = -0.84, P < 0.001) between log plasma insulin and sialic acid in the lean and obese mice. The plasma sialic acid:globulin ratio was reduced by 35% in obese mice vs. lean controls, indicating that there may be altered sialylation of glycoproteins in obese mice. Streptozotocin treatment of obese and lean mice reduced plasma insulin but increased sialic acid. In nSTZ rats, hyperglycemia was associated with mild hypoinsulinemia, but not significantly different from control animals, and sialic acid was not altered. In diabetic BB rats, plasma glucose rose from a mean of 4.9 to 23.5 mM 48 hr after insulin withdrawal but sialic acid did not change. We conclude that an elevated plasma sialic acid level is associated with marked insulin deficiency, rather than hyperglycemia per se. The magnitude and speed of this change in sialic acid varies between species.

Animals↗
PubMed1994

Gene structure and amino acid sequences of alcohol dehydrogenases of Bacillus stearothermophilus.

Partial amino acid sequences of the two alcohol dehydrogenases of Bacillus stearothermophilus and the oligonucleotide sequence of a cloned fragment containing the gene for ADH 2334 were determined and compared with the known, derived ADH 1503 amino acid sequence. The two proteins are identical at 244 of 349 positions. ADH 2334 is encoded in a transcription unit containing an aldehyde dehydrogenase.

Alcohol Dehydrogenase↗
PubMed1994

Packed-column supercritical fluid chromatography of beta-blockers.

Packed-column subcritical and supercritical fluid chromatography (SFC) of a total of 10 beta-blocking drugs was investigated on four stationary phases using CO(2)-methanol based eluents. The stationary phases studied were all bonded silicas and included Diol, aminopropyl, cyanopropyl, and "C1". The SFC of some of these compounds was possible with simple CO(2)-methanol based mobile phases, but in general, it proved to be necessary to add triethylamine as a competing base in order to obtain acceptable peak shapes. The best chromatographic results were obtained on the aminopropyl bonded phase, with good results also seen on the Diol phase. Different selectivities were observed for the Diol and aminopropyl columns.

Adrenergic beta-Antagonists↗
PubMed1994

Neonatal renal candidiasis.

A case is presented of renal candidiasis complicated by obstructive uropathy in a 4 month old infant. Management was successful with surgical decompression combined with peri-operative amphotericin B, followed by 3 weeks of oral ketoconazole and subsequently 6 weeks of oral fluconazole. Fluconazole was substituted for ketoconazole owing to persistent candiduria, and achieved rapid urinary sterilization. Fluconazole is an effective and less toxic alternative to prolonged courses of amphotericin B in the treatment of neonatal renal candidiasis.

Amphotericin B↗
PubMed1994

Importance of the intestine as a site of metformin-stimulated glucose utilization.

1. The intestine has been implicated as a site of increased glucose utilization by the antihyperglycaemic drug, metformin. This study makes a quantitative assessment of this effect. 2. Glucose utilization by the intestine and hind limb region was determined by arterial-venous glucose difference adjusted for blood flow rate in fasted rats receiving a hyperglycaemic hyperinsulinaemic infusion. 3. Intrajejunal administration of metformin, 250 mg kg-1, increased glucose disposal during the infusion procedure, associated with increased glucose utilization in the intestine by 69% and in the hind limb region by 40%. 4. Metformin, 250 mg kg-1, increased glucose disappearance during an intravenous glucose tolerance test. This was accompanied by increased uptake of tritiated 2-deoxy-D-glucose into the intestinal mucosa to a greater extent than into skeletal muscles (per unit wet weight of tissue). 5. The results demonstrate that the intestinal mucosa is a quantitatively important site of increased glucose utilization during the blood glucose-lowering effect of metformin.

Animals↗
PubMed1994

Insulin requirement for the antihyperglycaemic effect of metformin.

1. Insulin-dependent diabetic BB/S rats with little or no endogenous insulin were used to determine whether insulin is required for the acute antihyperglycaemic effect of metformin (dimethylbiguanide). 2. Metformin (250 mg kg-1, intrajejunally) did not lower the hyperglycaemia in BB/S rats in the absence of exogenous insulin, but metformin increased by 69% (P < 0.05) the blood glucose-lowering effect of exogenous insulin. 3. Metformin (250 mg kg-1, intrajejunally) improved glucose disposal in rats with a normal insulin response to an intravenous glucose challenge. Plasma glucose disappearance was increased from 0.7 +/- 0.1 to 2.5 +/- 0.1% min-1 (P < 0.05). 3. When the insulin response to glucose was suppressed with somatostatin and diazoxide, metformin improved glucose disposal to a similar extent to that in rats with a normal insulin response. Plasma glucose disappearance was increased from 0.24 +/- 0.02 to 1.0 +/- 0.1% min-1 (P < 0.01). 5. The results indicate that insulin is required for the acute antihyperglycaemic effect of metformin, but the extent of this effect is not proportional to the prevailing insulin concentration.

Animals↗
PubMed1994

Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn's disease and normal intestine.

AIMS: To investigate the role of the matrix metalloproteinases (MMPs) in the connective tissue changes seen in the intestine in Crohn's disease. METHODS: Indirect immunofluorescence microscopy using specific antibodies to the MMPs (collagenase, gelatinase A and B, and stromelysin) were used to assess the distribution of these enzymes in normal and diseased intestine. RESULTS: In normal intestine the matrix metalloproteinases were confined to a few isolated inflammatory cells, but in Crohn's disease, the inflammatory infiltrate was associated with increased numbers of polymorphonuclear leucocytes which stained positive for gelatinase B. Stromelysin was also detected extracellularly on the connective tissue matrix in regions of smooth muscle cell proliferation and mucosal degradation. Interestingly, in ulcerative colitis, another inflammatory bowel disease, stromelysin was localised in the lamina propria in regions of mucosal loss. CONCLUSIONS: The increased numbers of inflammatory cells containing gelatinase B, and the localisation of extracellular stromelysin in regions of fibrosis and mucosal degradation, suggest that these enzymes have a role in the pathological changes seen in Crohn's disease. In cases of ulcerative colitis stromelysin was also detected on the lamina propria in regions of mucosal loss, and seems to be associated with the connective tissue changes that precede mucosal loss.

Colitis, Ulcerative↗
PubMed1994

Insulin-releasing pituitary cells as a model for somatic cell gene therapy in diabetes mellitus.

Insulin delivery by somatic cell gene therapy was evaluated using murine pituitary AtT20MtIns-1.4 cells. These cells have been stably transfected to release human insulin by the introduction of a recombinant plasmid bearing a human preproinsulin cDNA under the control of a zinc-sensitive metallothionein promoter. 6 x 10(7) AtT20MtIns-1.4 cells were implanted subcutaneously into streptozotocin-diabetic mice immunosuppressed with cyclosporin A. Release of human insulin was assessed using a specific plasma human C-peptide assay. On days 1 and 2 after implantation human C-peptide concentrations were about 0.02 pmol/ml. Consumption of zinc sulphate solution (500 mg/l) as drinking fluid for days 3-5 increased plasma human C-peptide concentrations to 0.11 +/- 0.01 pmol/ml (mean +/- S.E.M.), n = 11, P < 0.01, and concentrations declined when zinc was discontinued. The extent of hyperglycaemia was slightly lower (P < 0.05) than in a group implanted with non-transfected AtT20 cells. The study was terminated after 9 days, and tumour-like aggregations of implanted cells were identified at autopsy. These comprised a large necrotic core with insulin-containing cells at the periphery. The study provides support for the view that somatic cell gene therapy offers a potential approach to insulin delivery in diabetes mellitus.

Animals↗
PubMed1994

Comparative tolerability profiles of oral antidiabetic agents.

The sulphonylureas and the biguanides are widely used as adjuncts to dietary measures in the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM). Adverse effect profiles differ markedly between the sulphonylureas and biguanides, reflecting differences in chemical structure and mode of action. Sulphonylureas are generally well tolerated, although pharmacokinetic differences between these agents have important clinical implications. The main adverse effect associated with sulphonylureas is hypoglycaemia. This effect is a predictable consequence of the principal pharmacological effect of these drugs, i.e. sensitisation of the islet beta-cell to glucose, resulting in enhanced endogenous insulin secretion. Sulphonylurea-induced suppression of hepatic glucose production may cause profound and protracted hypoglycaemia, especially in elderly patients, in individuals with intercurrent illnesses and reduced caloric intake, or when taken in combination with other compounds with hypoglycaemic potential, e.g. alcohol (ethanol). Sulphonylureas with a longer duration of action, notably chlorpropamide and glibenclamide (glyburide), are more liable to induce serious hypoglycaemia, particularly when drug elimination is reduced by renal impairment. Other drugs such as salicylates may potentiate the actions of sulphonylureas, thereby increasing the risk of hypoglycaemia. Biguanide therapy is associated with alterations in lactate homeostasis which under certain clinical circumstances may result in fatal lactic acidosis. Phenformin is associated with a markedly greater risk of lactic acidosis than metformin. Phenformin has been withdrawn in many countries for this reason. All biguanides must be avoided in patients with renal impairment, hepatic dysfunction and cardiac failure--conditions where drug accumulation or disordered lactate metabolism may predispose to lactic acidosis. Phenformin should not be given to individuals who exhibit a severe, genetically conferred hepatic defect of hydroxylation which impedes metabolism of this drug. Less seriously, the biguanides are associated with a relatively high incidence of gastrointestinal adverse effects which limit compliance. Acarbose, a competitive inhibitor of intestinal alpha-glucosidases, has recently been introduced. In contrast to the sulphonylureas and biguanides, acarbose has not been associated with life-threatening adverse effects. This reflects the low systemic absorption of the drug and, predictably, its principal unwanted effects are gastrointestinal disturbances resulting from iatrogenic carbohydrate malabsorption.

Acarbose↗
PubMed1994

Accumulation of metformin by tissues of the normal and diabetic mouse.

1. Tissue accumulation of the antihyperglycaemic agent metformin (dimethylbiguanide) was examined after oral administration to the normal and streptozotocin (STZ) diabetic mouse. 2. Metformin (50 mg/kg body weight containing 14C-metformin 25 microCi/kg body weight), which is stable and not metabolized, resulted in maximum plasma concentrations at 0.5 h which declined to < 5% of maximum by 24 h. Maximum plasma concentrations (mumol/l, mean +/- SE) in the hepatic portal vein (normal 51.7 +/- 5.4, STZ 61.5 +/- 8.0) were higher than in the inferior vena cava (normal 29.0 +/- 2.8, STZ 35.4 +/- 5.9). 3. The greatest accumulation of metformin occurred in tissues of the small intestine, where maximum concentrations were > 1000 mumol/kg wet weight at 0.5-2 h, but declined to < 2% of maximum by 24 h. 4. Stomach, colon, salivary gland, kidney and liver accumulated metformin more than two-fold, and concentrations of the drug in heart and skeletal (gastrocnemius) muscle were greater than plasma concentrations on some occasions up to 8 h. 5. In a separate study, i.v.-administered metformin was selectively accumulated by tissues of the small intestine. Thus, retention of metformin by tissues of the small intestine may represent a deep compartment for the drug.

Administration, Oral↗
PubMed1993

Metformin does not increase energy expenditure of brown fat.

The antihyperglycaemic agent metformin (dimethylbiguanide) increases metabolic energy expenditure. The possibility that this might involve increased fuel utilization by brown adipose tissue (BAT) was studied. Basal and noradrenaline-stimulated (10(-6) mol/L) oxygen consumption by isolated brown adipocytes from normal and streptozotocin diabetic mice was unaffected by incubation with metformin (10(-4) mol/L) for 30 min. Basal and insulin-stimulated (10(-8) and 10(-6) mol/L) aerobic and anaerobic glucose metabolism was also unaffected during 2 hr incubations of BAT with metformin (10(-4) mol/L). Treatment of normal mice with metformin (250 mg/kg/day) for 7 days did not significantly alter the amount or cytochrome oxidase activity of BAT, and a preliminary semi-quantitative estimation of mitochondrial uncoupling protein showed no apparent change. The results suggest that metformin does not increase energy expenditure of brown adipose tissue.

Adipose Tissue, Brown↗
PubMed1993

ELISA estimation of the binding of epidermolytic toxin to neonatal mouse skin.

A sandwich ELISA, with antisera from rat and rabbit, was used to determine epidermolytic toxin (ET) to a limit of about 0.01 ng at 0.1 ng/ml. The binding of ET to the epidermis of skin discs was measured in vitro. The ability of the assay to discriminate between the two forms of the toxin was used to demonstrate that there was a saturable component of toxin binding to the epidermis. The rate of uptake, the effect of the inhibitor EGTA and comparative experiments with the inactive nitrated toxin confirmed that the observed binding is associated with toxigenesis. From measurements at toxin concentrations from 0.25 microgram/ml to 100 micrograms/ml, it was calculated that the saturable binding component has a Kd of about 2 micrograms/ml (approximately 60 nM) and a capacity of 0.5 ng per skin disc (1 ng per cm2 of epidermis).

Animals↗
PubMed1993

Metformin--an update.

Metformin (dimethylbiguanide) is an antihyperglycaemic drug used to treat non-insulin dependent diabetes mellitus. It acts in the presence of insulin to increase glucose utilization and reduce glucose production, thereby countering insulin resistance. The effects of metformin include increased glucose uptake, oxidation and glycogenesis by muscle, increased glucose metabolism to lactate by the intestine, reduced hepatic gluconeogenesis and possibly a reduced rate of intestinal glucose absorption. Metformin appears to facilitate steps in the postreceptor pathways of insulin action, and may exert effects that are independent of insulin. In muscle, metformin increases translocation into the plasma membrane of certain isoforms of the glucose transporter. The effects of metformin are generally moderate, and do not cause clinical hypoglycaemia or increased weight gain. Metformin has an antihypertriglyceridaemic effect and exerts various potentially useful effects on haemostasis. A risk of lactic acidosis is negligible provided that the contraindications, particularly renal incompetence are respected.

Animals↗
PubMed1993

Increased neuropeptide-Y messenger ribonucleic acid (mRNA) and decreased neurotensin mRNA in the hypothalamus of the obese (ob/ob) mouse.

The obese hyperglycaemic ob/ob mouse exhibits hyperphagia and other abnormalities of hypothalamic function. We measured hypothalamic concentrations of four peptides implicated in the control of appetite and energy expenditure, neuropeptide-Y (NPY), neurotensin, galanin, and somatostatin, by RIA and their respective mRNAs using semiquantitative Northern blotting. Using lean (+/+) mice as controls, we found unchanged concentrations of NPY, galanin, and somatostatin and a 25% reduction in neurotensin (P < 0.01). Neurotensin mRNA was similarly decreased (by 30%; P < 0.02), while NPY mRNA was increased 3-fold (P < 0.01). Centrally administered neurotensin decreases food intake, whereas NPY potently stimulates food intake. An increase in NPY gene expression together with reductions in neurotensin concentration and mRNA in the hypothalamus may be implicated in the development of hyperphagia and other neuroendocrine abnormalities seen in the ob/ob mouse.

Animals↗
PubMed1993

Insulin delivery by somatic cell gene therapy.

The feasibility of somatic cell gene therapy as a method of insulin delivery has been studied in mice. Murine pituitary AtT20 cells were transfected with a human preproinsulin DNA in a plasmid containing a metallothionein promoter and a gene conferring resistance to the antibiotic G418. The AtT20MtIns-1.4 clone of cells was selected because of its higher insulin-releasing activity compared with other clones. After culturing for 24 h in Dulbecco's medium containing 10 mM glucose, the AtT20MtIns-1.4 cells released human insulin at about 5 ng/10(6) cells per 24 h. Insulin release was not significantly altered by raised concentrations of glucose, potassium or calcium, but insulin release was increased by 20 mM arginine, 5 mM isomethylbutylxanthine and 90 microM zinc. AtT20MtIns-1.4 cells (2 x 10(6)) were implanted intraperitoneally into non-diabetic athymic nude (nu/nu) mice, and the mice were made diabetic by injection of streptozotocin after 7 days. Release of human insulin in vivo was assessed using a specific plasma human C-peptide assay. Human C-peptide concentrations were maintained at about 0.1 pmol/ml throughout the 29 days of the study. The development of streptozotocin-induced hyperglycaemia was delayed in recipients of the cells releasing human insulin, compared with a control group receiving an implant of non-transfected cells. At autopsy the implanted AtT20MtIns-1.4 cells in each recipient had formed a tumour-like aggregation, with an outer region of insulin-containing cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Acute effect of benfluorex on glucose metabolism.

The antihyperlipidaemic agent benfluorex [1-(3-trifluoromethylphenyl)-2-(2-benzoyl-oxyethyl)-aminopropane] and its metabolite S422 [1-(3-trifluoromethylphenyl)-2-(2-hydroxyethyl)-aminopropane] were examined for an acute (after 1-2 hr) effect on glucose metabolism in normal rats. Enteral administration of benfluorex (25 mg/kg) did not affect basal plasma glucose and insulin concentrations. However, enteral and intravenous glucose tolerance were modestly improved without enhancing the insulin response to glucose. Hepatic gluconeogenesis from lactate was not acutely altered by benfluorex (25 mg/kg) in vivo or by S422 (1 mM) in vitro, but S422 (1 mM) slightly reduced (by 11%) hepatic glycogen mobilization in vitro after 2 hr. S422 (1 mM) increased (by 47%) glucose oxidation by diaphragm muscle in vitro. The effect was additive to that of insulin. Anaerobic glucose metabolism and glycogenesis of diaphragm muscle were not affected by S422. The results suggest that benfluorex can acutely improve glucose tolerance associated with increased glucose oxidation by muscle.

Animals↗
PubMed1992

The esterolytic activity of epidermolytic toxins.

The two epidermolytic toxins were shown to have intrinsic N-t-butyloxycarbonyl-L-glutamic acid alpha-phenyl esterase activity. The activity was dependent on free toxin pKa values of 6.6 and 6.8 for ETA and ETB respectively. ETB incorporated 0.97 mol of radiolabelled di-isopropyl phosphorofluoridate/mol of protein with loss of esterolytic and epidermolytic activities. The correspondence of epidermolytic and esterolytic activities in ETA and ETB during thermal inactivation and reaction with di-isopropyl phosphorofluoridate, together with the inactivity of the mutant protein ETA S195G, demonstrates that the two activities are dependent on a single active serine residue in each protein.

Animals↗