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Biomedical subjects

P McLean

Publications and source records attributed to P McLean.

At least 55 records · Page 3Linked to original sources
PubMed1991

Regulation of glucose metabolism in livers and kidneys of NOD mice.

Measurements were made of the levels of metabolic intermediates and activities of enzymes of the glycolytic route, pentose phosphate pathway, and polyol pathway in livers and kidneys of NOD mice. A 34% decrease in UDP-glucose, a 40% decrease in glucose-6-phosphate (G6P) and fructose-6-phosphate, and a 75% decrease in fructose-2,6-bisphosphate (F2,6P) were found in the livers of NOD mice. The fall in the level of F2,6P (the important regulator of glycolysis) is accompanied by a 20% reduction in the activity of phosphofructokinase. These changes are in agreement with previously reported liver depletion of glycogen and reduced synthesis of proteins and nucleic acids in the diabetic state. In the kidney, the increase in hexokinase activity is consistent with increased levels of G6P and glycogen content of kidney in diabetes. The decreased level of phosphoribosyl pyrophosphate was reported to be a regulator of kidney growth in the initial period of diabetes but can still be found in NOD mice 6 wk after development of hyperglycemia. The reported changes are similar to those seen in alloxan- or streptozocin-induced diabetic animals, but certain changes are more marked in NOD mice, especially those directed to increase nucleic acid and protein synthesis in the diabetic kidney.

Adenosine Triphosphate↗
PubMed1990

Effect of experimental diabetes on the activity of hexokinase isoenzymes in tissues of the rat.

The effect of experimental diabetes on the activity of hexokinase isoenzymes was studied in a wide range of tissues of the rat. In the tissues known to require insulin for glucose phosphorylation, the activity of hexokinase was markedly decreased; the fall being mainly in the Type IV (Glucokinase) in liver and Type II in other tissues, these tissues also exhibit glucose underutilization in diabetes. In the tissues which are commonly known not to require insulin, the activity of Type I hexokinase was significantly increased, these tissues exhibit aspects of glucose overutilization in diabetes in particular kidney and lens. These changes are discussed in relation to Spiro's hypothesis of glucose under and overutilization in tissues in diabetes.

Animals↗
PubMed1989

Olfactory neuroblastoma.

Fifteen patients with olfactory neuroblastoma were treated during the 17-year period of 1969 to 1986. Data was analyzed with respect to age at presentation, sex, presenting signs and symptoms, stage, and results of treatment. Age ranged from 4 to 67 years with the median age being 27 years. Median follow-up was 8 years. Local control was achieved in nine of nine patients or 100% with successful surgical resection, i.e., minimal residual disease, followed by postoperative radiation therapy (45 to 65 Gy) was employed. There were no distant failures when the primary site was controlled. Regional lymph node metastases were infrequent: only 13% (two of 15 patients) presented with positive nodes. Three of four patients treated initially with surgery alone had a local recurrence, two of which were successfully salvaged by combined therapy. There were four patients treated with radiation therapy alone: three had persistent disease after radiation therapy, and one patient was controlled with 65 Gy. Olfactory neuroblastoma has a propensity to recur locally when treated with surgery alone. The authors' experience suggests excellent local control can be achieved with surgery immediately followed by radiation therapy. Thus the authors recommend planned combined treatment for all resectable lesions.

Adolescent↗
PubMed1989

Living related renal transplantation in Ireland: a sixteen year review.

Between January 1972 and December 1987, a total of 777 transplants were performed of which 135 (17%) were living related. There were 108 sibling donors, 25 parent to child and 2 child to parent. All sibling transplants were HLA identical. Conventional immunosuppression with Prednisone and Azathioprine was used in all cases. Actuarial patient survival were 95%, 91% and 88% at 1, 5 and 10 years respectively. Corresponding actuarial graft survivals were 90%, 80% and 60%. Graft survival in the sibling compared to the parent to child group was 87% versus 60% at 5 years. There were 13 deaths during the study interval and 32 grafts were lost. Five year patient/graft survivals of 91/80% compare favourably with other reported series. The poorer outcome in parent to child transplants has led us to modify the immunosuppressive protocol to include Cyclosporin A in this group. The increased availability and improved survival of cadaveric grafts in recent years and our one year patient/graft survival of 92/88% has led us to reduce emphasis on living related transplantation in our renal replacement programme.

Adolescent↗
PubMed1989

Double-blind trial of imipramine in Alzheimer's disease patients with and without depression.

The authors divided 61 subjects with primary degenerative dementia of the Alzheimer's type into a group who also met DSM-III criteria for depression (N = 28) and a group who did not (N = 33). Both groups were randomly assigned to an 8-week double-blind trial of imipramine or placebo. Scores on the Hamilton Rating Scale for Depression, administered at baseline and weeks 2, 4, 6, and 8, indicated significant improvement in both groups. Two measures of cognitive function yielded differing results. The results suggest that moderate depression is a treatable condition in patients with Alzheimer's disease.

Aged↗
PubMed1989

Changes in pathways of pentose phosphate formation in relation to phosphoribosyl pyrophosphate synthesis in the developing rat kidney. Effects of glucose concentration and electron acceptors.

Phosphoribosyl pyrophosphate (PPRibP), required in nucleotide synthesis, increases 2-fold in rat kidney from 1 day post partum to adult stage; there is no accompanying increase in PPRibP synthetase activity measured in vitro. Ribose 5-phosphate is a key factor in the regulation of PPRibP synthesis. The activity and regulation of 3 routes of ribose 5-phosphate formation have been measured in renal growth: (i) the flux through the oxidative pentose phosphate pathway was high in the neonatal period but increased only +50% thereafter; (ii) the non-oxidative pentose phosphate pathway, including transketolase, increased by +145%; (iii) the rate-limiting enzymes of the glucuronate-xylulose route increased +200% from 1 day to the adult stage. The importance of systems reoxidizing NADPH was shown by: (i) the stimulation of renal PPRibP formation from glucose by phenazine methosulphate; (ii) the early involvement of the oxidative pentose phosphate pathway at the stage where NADPH is used for biosynthetic routes; (iii) the increasing involvement of the glucuronate-xylulose route, which acts as a transhydrogenase producing NADP+ in addition to pentose phosphate formation and (iv) the correlation between renal PPRibP content and the activity of aldose reductase, which, by utilization of NADPH, stimulates ribose 5-phosphate formation via the oxidative pentose phosphate pathway. Evidence is adduced that the contribution of the 3 routes of ribose 5-phosphate formation in the kidney varies at different stages of development.

Animals↗
PubMed1989

Lipoprotein, apolipoprotein, and lipolytic enzyme changes following estrogen administration in postmenopausal women.

To test whether estrogen can modulate the cholesterolemic response to an Occidental diet, six healthy postmenopausal women were studied for 84 days while ingesting a solid food diet of constant composition high in cholesterol content (995 mg/d). In the middle of the study, estrogen (17 alpha-ethinyl estradiol, 1 microgram/kg per day) was administered orally. Ingestion of the diet for the initial 28 days did not alter lipoprotein lipid or apolipoprotein (apo) levels. However, with just 4 days of estrogen use there were significant decreases in apoE (-36%), low density lipoprotein cholesterol (-26%), and postheparin plasma hepatic triglyceride lipase activity (HTGL) (-61%), and an increase in high density lipoprotein (HDL) triglyceride (72%). These changes persisted throughout the estrogen use. The percent change in HTGL with 4 days of estrogen correlated inversely with the percent change in HDL triglyceride (rs = -0.94). After 28 days of estrogen there were also significant increases in HDL cholesterol (21%), HDL2 cholesterol (42%), apoA-I (37%), and apoA-II (9%), and a decrease in apoB (-11%). The level of apoE at this juncture correlated inversely with the level of HDL cholesterol (rs = -0.90), and the levels of HTGL and apoA-I correlated with HDL2 cholesterol (rs = -0.89 and rs = 0.89, respectively). Thus, HTGL may play a role in both the early estrogen-related changes in HDL triglyceride and apoE and the late estrogen-related changes in HDL cholesterol, apoA-I, and apoA-II.

Aged↗
PubMed1988

The effect of aldose reductase inhibitor Statil (ICI 128436) on the glucose over-utilization in kidney of diabetic rats.

The present study examined the effect of the aldose reductase inhibitor Statil (ICI 128436, ICI, Cheshire, U.K.) on the levels of metabolites and activities of enzymes involved in the glycolysis, polyol pathway and pentose phosphate pathway and on the flux of radioactive glucose through these pathways in kidney of streptozotocin diabetic rats. In kidneys of diabetic rats of 30 days duration the level of sorbitol was increased by +82% and fructose concentration was raised by +42%. After treatment with Statil for 9 days (reversal study) a significant fall in kidney sorbitol concentration and kidney fructose concentration was found. Lactate and UDP-glucose concentrations which were both significantly raised in diabetes by +80% and +23% respectively decreased by 20% after Statil treatment, together with a decline in UDP-glucose dehydrogenase activity. Aldose reductase and sorbitol dehydrogenase activities were also significantly lowered by Statil. In the reversal study there was no significant effect of Statil on the flux of glucose via alternative routes in the kidney cortex. In kidneys of diabetic rats of 9 days duration, the level of sorbitol increased by +61% and the concentration of fructose was raised by +30%. The treatment with Statil (25 mg/kg) from the day of induction of diabetes (prevention study) prevented the accumulation of sorbitol, fructose and UDP-glucose. The increase in the incorporation of radioactive glucose through the pentose phosphate pathway seen in diabetes was less marked in the renal cortex of diabetic rats treated with Statil ab initio.

Animals↗
PubMed1988

Comparative effects of insulin and proinsulin in vitro on pathways of glucose utilization and lipid synthesis in the lactating rat mammary gland.

The effects of insulin and proinsulin have been measured on the rates of glucose oxidation via the pentose phosphate pathway and incorporation into lipid in slices of lactating rat mammary gland. Half-maximal stimulation of glucose oxidation was observed with 1-3 x 10(-8)M insulin while 1 x 10(-7)M proinsulin was required to achieve half-maximal stimulation. A similar, approximately 10-fold, difference in potency was observed in relation to lipid synthesis. The present results appear to indicate that the maximum stimulation of either glucose oxidation via the pentose phosphate pathway or lipid synthesis by proinsulin did not reach the same level as that found for insulin.

Animals↗
PubMed1988

The effect of a somatostatin analogue (SMS 201-995, Sandostatin) on the concentration of phosphoribosyl pyrophosphate and the activity of the pentose phosphate pathway in the early renal hypertrophy of experimental diabetes in the rat.

The effect of a long-acting somatostatin analogue on the acute renal hypertrophy following induction of experimental diabetes in the rat has been studied. The kidney weight increase occurring at 2 and 7 days after alloxan injection was significantly lower in the diabetic group receiving somatostatin. Similarly, the previously reported increase in glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (EC 1.1.1.44) found in the kidney at 2 and 7 days of diabetes was less marked in the group receiving SMS 201-995. The fall in renal phosphoribosyl pyrophosphate associated with early diabetic renal hypertrophy (7) was also lessened by administration of SMS 201-995. No effects of the drug were found in the normal rat on the same regimen of treatment. These observations indicate involvement of glucagon and/or growth hormone in the initiation of kidney growth in diabetes.

Animals↗
PubMed1988

Antioxidant status in an in vitro model for hyperglycemic lens cataract formation: effect of aldose reductase inhibitor statil.

A decrease in glutathione content followed by a fall in ATP content of lens occurring at approximately 7 days after the onset of diabetes has been demonstrated in an earlier study. This pattern is repeated under more controlled conditions and at shorter time intervals, 24-48 hr, in lenses incubated in vitro under hyperglycemic conditions. Inclusion of aldose reductase inhibitors in the incubation medium not only prevented the accumulation of sorbitol and fructose but also prevented the decrease in glutathione and ATP. It is proposed that the drain on NADPH by the polyol pathway operating at high glucose concentrations results in a perturbation of the system for regenerating reduced glutathione. This aspect of polyol formation is considered to be deleterious to the lens in hyperglycemia, since it may contribute to free radical damage by depressing the system responsible for their removal.

Aldehyde Reductase↗
PubMed1988

Regulation of pathways of glucose metabolism in the kidney. The activity of the pentose phosphate pathway, glycolytic route and the regulation of phosphofructokinase in the kidney of lean and genetically obese (ob/ob) mice; comparison with effects of diabetes.

The activities of enzymes of the glycolytic route, the pentose phosphate pathway and NADPH-linked enzymes have been measured in the kidneys of genetically obese (ob/ob) mice and their lean litter mates. The renal content of glucose 6-phosphate (G6P), fructose 6-phosphate (F6P), fructose 1,6-bisphosphate (Fru-1,6-P2) and fructose 2,6-bisphosphate (Fru-2,6-P2) were also measured. Increases were found in hexokinase and enolase with an upward trend in pyruvate kinase in the ob/ob mouse kidney; a significant decline in malic enzyme was also seen. The renal content of G6P and Fru-1,6-P2 increased. There was no renal hypertrophy despite a degree of hyperglycaemia, which was, however, considerably below that observed in experimental diabetes. Comparison of the renal changes in the hyperglycaemic-hyperinsulinaemic ob/ob mice with the hyperglycaemic-hypoinsulinaemic diabetic group showed two distinct groupings. Firstly, changes which were similar in the two groups included: increases in hexokinase, G6P and Fru-1,6-P2, and a decrease in malic enzyme. Secondly, opposite changes were seen in enolase and in enzymes at the G6P crossroads, phosphoglucose isomerase and phosphoglucomutase. The elevated hexokinase and G6P in both ob/ob and diabetic groups may be involved in the eventual accumulation of basement membrane material in the glomerulus which is a common feature of the two conditions.

Animals↗
PubMed1988

Function and regulation of the pentose phosphate pathway in brain.

Although the quantitative contribution of the pentose phosphate pathway to glucose metabolism in adult brain is small, numerous experiments using specific inhibitors and developmental studies (Table VI) confirm the importance and the "functional" role of this pathway in brain (for details, see reviews by Baquer et al., 1975, 1977). In this article, an attempt has been made to bring together the important findings regarding the localization, operation, and functional significance of the pentose phosphate pathway in nervous tissue. The presence of these enzymes in synaptosomes and their linkage with peroxidative mechanisms, monoamine oxidase, and glutathione pathways suggest that they may be serving an important role in brain in vivo. There are a number of aspects that require further study for an understanding of the role of the pentose phosphate pathway in brain, including its role in inhibitory and excitatory synapses, in the control of synaptic plasticity, and the relationship between the electroencephalogram and the pentose phosphate pathway in various neural populations.

Aging↗
PubMed1987

Hepatic phosphoribosyl pyrophosphate concentration. Regulation by the oxidative pentose phosphate pathway and cellular energy status.

Measurements have been made of the tissue content of phosphoribosyl pyrophosphate (PPRibP) and of a range of metabolic intermediates involved in the energy charge of the cell, the glycolytic and pentose phosphate pathways, and of the activity of the enzymes of the pentose phosphate pathway and of PPRibP synthetase (EC 2.7.6.1) in the livers of normal, diabetic, insulin-treated diabetic and starved rats and in livers of rats previously starved and then re-fed with high-fat or high-carbohydrate diets. Diabetes, starvation and high-fat diet all caused a fall in the hepatic PPRibP content, whereas insulin treatment and high-carbohydrate diet raised the tissue content. A positive correlation was shown between the PPRibP content and ATP, energy charge and the cytosolic [NAD+]/[NADH] quotient. A positive association between the PPRibP content and the flux of glucose through the pentose phosphate pathway and the synthesis of ribose 5-phosphate via the oxidative enzymes of that pathway, including ribose-5-phosphate isomerase (EC 5.3.1.6), was also observed. A negative correlation was found between the ADP, AMP and Pi contents, and no correlation existed between PPRibP content and the enzymes of the non-oxidative branch of the pentose phosphate pathway. There was no correlation between hepatic PPRibP content and the activity of PPRibP synthetase measured in vitro. These results are considered in relation to the control of PPRibP synthetase in the liver in vivo.

Adenine Nucleotides↗
PubMed1987

Regulation of enzymes of glucose metabolism and lipogenesis in diabetic rat liver by thyroid hormones.

Experimental diabetes in rats is associated with a degree of hypothyroidism. Hepatic enzymes involved in carbohydrate and lipid metabolism were estimated in control (untreated), control +T3 treated, alloxan diabetic and alloxan diabetic + T3-treated rats. The key glycolytic enzymes, phosphofructokinase and pyruvate kinase, were decreased in activity in diabetes and unchanged by further treatment with T3. In contrast, certain enzymes involve in lipogenesis, ATP-citrate lyase 'malic' enzyme and 6-phosphogluconate dehydrogenase, which were decreased in activity in diabetes, were increased to, or above, control values when diabetic rats were treated with T3. It is suggested that T3 deficiency may play a role in the decrease in enzyme activities observed in experimental diabetes, in particular, some enzymes associated with lipogenesis and the provision of NADPH.

Animals↗
PubMed1986

Concentration of phosphoribosyl pyrophosphate in renal hypertrophy. Contrasting effects of early diabetes and unilateral nephrectomy.

Studies were made of the renal phosphoribosyl pyrophosphate (PPRibP) content and PPRibP synthetase (EC 2.7.6.1) activity in rats diabetic for 5, 14 or 20 days, or unilaterally nephrectomized (UN) for 5 days, and in doubly lesioned animals. Approximately equal degrees of renal enlargement were found after 5 days diabetes or 5 days UN. In the doubly lesioned animals the increment of growth was additive. Unilateral nephrectomy of 5 days duration, in contrast with diabetes, had no effect on the PPRibP content of the contralateral kidney, nor did it modify the renal PPRibP content when performed on animals diabetic for 5, 14 or 20 days. The activity of PPRibP synthetase was unaffected by diabetes, UN or diabetes +UN. The results pinpoint a stage of nucleotide synthesis which is differentially affected by the two stimuli, in line with evidence for differences in regulation of nucleic acid turnover in the two conditions.

Animals↗