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Biomedical subjects

P McLean

Publications and source records attributed to P McLean.

At least 19 recordsLinked to original sources
PubMed1992

Severity of unipolar depression and choice of treatment.

The National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program (Elkin et al., Archives of General Psychiatry, 46, 971-982; 1989) reported treatment-by-severity interactions favouring pharmacotherapy for more depressed outpatients, on a minority of relevant comparisons. The present study reports secondary analyses from a similar, preexisting data set in which treatment-by-severity interactions are systematically investigated with depressed outpatients treated either with nondirective psychotherapy, behaviour therapy, pharmacotherapy, or relaxation/placebo. Despite multiple severity measures and variable severity cut scores, no treatment was differentially effective in improving more severely depressed patients. Also, there was little difference across symptom severity levels in the proportions of recovered patients between treatment groups. Finally, dynamic cluster analysis demonstrated that the proportion of pharmacotherapy nonresponders (20%) did not differ from the proportion of nonresponders in behaviour therapy or placebo groups. It is concluded that this failure to replicate the NIMH trial findings can not be attributed to treatment differences, populations or statistical power. The suggestion that pharmacotherapy be the treatment of choice for more severely depressed outpatients appears to be unjustified on the basis of available evidence.

Adult↗
PubMed1992

Uridine and cytidine nucleotide synthesis in renal hypertrophy: biochemical differences in response to the growth stimulus of diabetes and unilateral nephrectomy.

The effects of unilateral nephrectomy (UN) and streptozotocin (STZ) diabetes on the activities of enzymes involved in uridine and cytidine synthesis in early renal growth (3-14 days after stimulus to growth) have been compared. Measurements were also made of glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) and of glucose 6-phosphate (G6P), UDP-glucose, and glycogen, in relation to phosphoribosyl pyrophosphate, ribonucleotide, and complex carbohydrate formation. There were striking differences in the activities of CTP synthetase, G6PDH, and 6PGDH in the two conditions, with a three-fold increase in all three enzymes at 3 and 5 days and a two-fold increase above basal values at 14 days of STZ diabetes. The UN group showed no significant change in CTP synthetase at any stage and the activity of G6PDH and 6PGDH only kept pace with renal growth. Changes in routes of uridine synthesis were less marked, with a more rapid rise in carbamoyl-phosphate synthetase (glutamine) and a lesser response of dihydroorotate dehydrogenase in the UN relative to the STZ-diabetic groups. The enzymes of complex II and of uracil phosphoribosyltransferase showed essentially similar patterns during renal hypertrophy in UN and STZ diabetes. The parallel increase in CTP synthetase, G6PDH, and 6PGDH in the kidney in diabetes, also known to increase in growth situations in hepatomas and in renal tumors, is discussed in relation to hormone signals involved in renal growth. The importance of the concentration of CTP, and thus of CTP synthetase, in the CTP-cytidyltransferase reaction, an enzyme with a high Km for CTP, makes the present observation of the striking increase in CTP synthetase in STZ diabetes of particular interest in relation to phosphatidylcholine formation and hormone signal transduction.

Animals↗
PubMed1992

Pyrimidine nucleotide synthesis in the rat mammary gland: changes in the lactation cycle and effects of diabetes.

Measurements have been made of the activities of the enzymes of the de novo and salvage pathways of pyrimidine synthesis (carbamoyl phosphate synthetase II (glutamine) (EC 6.3.5.5); dihydroorotate dehydrogenase (EC 1.3.99.11); the overall activity of Complex II (orotate phosphoribosyl pyrophosphate transferase (EC 2.4.2.10) and orotidine 5-phosphate decarboxylase (EC 4.1.1.23); uracil phosphoribosyltransferase (EC 2.4.2.9)) in the mammary gland of rats at different stages of the lactation cycle and the effects of diabetes on the activity of these enzymes in lactation have been studied. From a consideration of the changes in enzyme activities and the changes in the tissue concentration of phosphoribosyl pyrophosphate, an activator of the de novo pathway and substrate for both the de novo and salvage routes, it is concluded that the de novo pathway is the major route of pyrimidine synthesis in mammary tissue. Diabetes decreases the activity of the enzymes of the de novo pathway; the effects are particularly marked for Complex II. The present results on pyrimidine synthesis are compared to the pattern for purine synthesis previously published.

Animals↗
PubMed1992

Phosphoribosyl pyrophosphate formation in the rat adrenal gland in relation to adrenal growth in experimental diabetes.

Adrenal growth occurs in experimental diabetes, and evidence exists for increased adrenal function. The concentration of PPRibP has been examined in the rat adrenal gland at various times after induction of diabetes with STZ, in view of the key role it plays in the synthesis of Purs and Pyrs. The PPRibP level was exceptionally high in the adrenal gland and increased faster than the rate of growth during the initial rapid growth phase--the first 7 days after STZ was given; PPRibP synthetase showed a parallel increase. Formation of R5P via the oxidative and nonoxidative segments of the PPP also was measured. The oxidative enzymes, G-6-PD and 6-PGD, increased in parallel with growth during the early phase, but showed a more marked rise during the secondary, slower, growth phase seen 6 wk after STZ was given, when this may be associated with the known sustained rise in plasma corticosteroids. The nonoxidative enzymes of the PPP, an alternate route for the production of R5P, showed smaller changes. The specifically high adrenal concentration of PPRibP may be related to the high Km for PPRibP (250 microM) of the first enzyme of the de novo pathway of Pur synthesis, as such synthesis may be required in the rat to replace the net loss of ATP associated with catecholamine secretion. Factors controlling PPRibP synthetase and their potential relative importance in the adrenal gland have been considered.

Adrenal Glands↗
PubMed1992

Vanadate treatment increases the activity of glycolytic enzymes and raises fructose 2,6-bisphosphate concentration in hearts from diabetic rats.

The present study examined the effect of vanadate on the activity of key enzymes of glycolysis and the level of fructose 2,6-bisphosphate (F-2, 6-P2) in the hearts of diabetic rats. A 20% decrease in the total hexokinase activity and 66% decrease in the type II isoenzyme was found in diabetic rat hearts. Vanadate treatment doubled the activity of type II hexokinase. Pyruvate kinase and phosphofructokinase 1 activity was reduced by 20% in diabetes, vanadate treatment restored the activity of the enzymes to normal. A 43% decrease in the cardiac F-2, 6-P2 level was found in diabetes of four weeks duration. A significant inverse correlation between blood glucose of experimental animals and the level of heart F-2, 6-P2 was observed. Vanadate treatment doubled the amount of F-2, 6-P2 in diabetic rat hearts.

Animals↗
PubMed1991

Bovine papillomavirus E5 oncoprotein binds to the 16K component of vacuolar H(+)-ATPases.

The major transforming protein of bovine papillomavirus type 1, E5, is mainly associated with endomembranes, specifically binding to a cellular protein of relative molecular mass 16,000 (16K). At the same time as transformation, E5 causes the phosphorylation of tyrosine residues in epidermal and platelet-derived growth factor receptors. We show here that the 16K protein associated with E5 is the 16K component of vacuolar ATPases. This protein is known to be an integral membrane protein in endosomes, bovine chromaffin granules, synaptic vesicles, fungal and plant vacuoles and clathrin-coated vesicles, as well as a component of gap-junction-like membrane complexes. Because proton pumps are critical for the function of cellular compartments that process growth-factor receptors, the interaction of E5 with the 16K protein could explain the pleiomorphic features of cells transformed by E5.

Adenosine Triphosphatases↗
PubMed1991

Pyrimidine nucleotide synthesis in the rat kidney in early diabetes.

Early renal hypertrophy of diabetes is associated with increases in the tissue content of RNA, DNA, and sugar nucleotides involved in the formation of carbohydrate-containing macromolecules. We have previously reported an increase in the activity of enzymes of the de novo and salvage pathways of purine synthesis in early diabetes; the present communication explores the changes in the pathways of pyrimidine synthesis. Measurements have been made of key enzymes of the de novo and salvage pathways at 3, 5, and 14 days after induction of diabetes with streptozotocin (STZ), phosphoribosyl pyrophosphate (PPRibP), and some purine and pyrimidine bases. Carbamoyl-phosphate synthetase II, the rate-limiting enzyme of the de novo route, did not increase in the first 5 days after STZ treatment, the period of most rapid renal growth; a significant rise was seen at 14 days (+38%). Dihydroorotate dehydrogenase, a mitochondrial enzyme, showed the most marked rise (+147%) at 14 days. The conversion of orotate to UMP, catalyzed by the enzymes of complex II, was increased at 3 days (+42%), a rise sustained to 14 days. The salvage route enzyme, uracil phosphoribosyltransferase (UPRTase), showed a pattern of change similar to complex II. The effect of the decreased concentration of PPRibP on the activities of CPSII, for which it is an allosteric activator, and on activities of OPRTase and UPRTase, for which it is an essential substrate, is discussed with respect to the relative Ka and Km values for PPRibP and the possibility of metabolite channeling.

Animals↗
PubMed1991

Imipramine in the treatment of depressed Alzheimer's patients: impact on cognition.

A double-blind study evaluated the impact of imipramine on cognitive function in 61 patients with Alzheimer's disease. Twenty-eight patients had coexistent depression and dementia; 33 had dementia only. All were randomly assigned to an 8-week trial of imipramine or placebo. For both depressed and nondepressed subjects, the effect of imipramine on cognition was minimal. A subtle decrement in general cognitive function was evident in those treated with imipramine, as compared with those treated with placebo. No effects were observed on memory. Clinicians are advised that very low doses of imipramine (25 mg/daily) may be tolerated in depressed Alzheimer patients, but that cognitive changes do occur in some patients and should be carefully monitored.

Aged↗
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↗