Biomedical subjects
Publications and source records attributed to P McLean.
We report two cases for which computer interpretation of nonstress test indicated a flat decelerative trace in spite of normal fetal heart rate variability. Fetal behavioral state in the first case and signal loss in the second case were possibly responsible for this computerized interpretation of the tracings in the absence of fetal distress.
Of 1,048 renal transplants performed between 1971 and 1990, transplant nephrectomy was performed in 86 (8.2%). Mean patient age was 33 years (range 3.8 to 66.5). Postoperative complications occurred in 60% of the patients, including wound infection in 20% and major hemorrhage in 4 patients. The external iliac artery was ligated in 4 patients. The incidence and severity of the complications were greater in patients with acute rejection. Four patients died: 1 of ischemic bowel and metastatic carcinoma, 1 of pulmonary embolism, and 2 of sepsis and disseminated intravascular coagulation. The nephrectomy rate increased significantly (p < 0.005) when cyclosporine A was initially introduced. Added care is necessary when new immunosuppressants are used. The majority of our failed transplants were left in situ without compromising overall patient well-being.
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The mechanisms by which cellular receptors can elicit different biological responses in a maturation state-dependent manner is one of the central problems in cell differentiation which remains to be resolved. The signals generated are likely to be due to additional (as yet unknown) transmembrane signalling pathways. In addition, the recent observation that a single growth factor receptor can activate a whole family of different putative second messengers and that the combinatorial interactions and stoichiometric ratios between the different messengers determine the resulting biological activities has opened up a whole new area of cell biology. It has been proposed that membrane GPI-anchors may function in signal transduction. We have recently confirmed the presence of a family of inositolphosphoglycan second messengers. Partial structural data suggests that these second messengers are not derived from known GPI membrane anchors and may thus constitute a novel class of non-protein-conjugated GPI.
The content of phosphoribosyl pyrophosphate (PPRibP) and of intermediates involved in its synthesis has been measured in the livers of obese (ob/ob) mice 2 months and 3-4 months of age, a period of dynamic growth and marked hepatic hypertrophy and hyperplasia, and comparison made with the values found in the lean age-matched control groups. The total hepatic PPRibP content and PPRibP/mg DNA was significantly increased in the 3- to 4-month-old obese mice relative to both the lean control groups and the 2-month-old obese mice, illustrating the significant changes occurring in the obese mouse liver in this transition period. The change in hepatic PPRibP/mg DNA in the obese mice is positively correlated with age (up to 4 months, body weight 60 g) and with parameters linked to the activity of the pentose phosphate pathway. There is no apparent correlation between PPRibP concentration and inorganic phosphate, the energy status of the cell, or the hepatic PPRibP synthetase (EC 2.7.6.1.) activity. The increase in the bioavailability of PPRibP, which is both a substrate and activator of the de novo and salvage pathways of purine and pyrimidine synthesis, is considered in relation to the increased nucleotide requirement associated with the rise in total hepatic RNA, DNA, and adenine nucleotide in the obese mouse.
The lens has a very high content of UDP sugars. These are required for glycoprotein and proteoglycan synthesis, as components of fiber cell membranes and the capsule. In diabetes, changes in these sugar nucleotides are related to pathological changes in the basement membranes of cells from non-insulin-requiring tissues. We have investigated whether this is the case in the lens in diabetes and we report here that UDP-sugar levels are, in contrast to the norm in other non-insulin-requiring tissues, decreased at 2 and 4 weeks of diabetes. This is despite an elevation in the precursors of their formation, both of the pyrimidine (PPRibP) and carbohydrate (glucose, glucose 6-phosphate) components. Also reported here is the observation that lens pyrimidine biosynthesis occurs primarily by the de novo route, and that orotate phosphoribosyltransferase and orotidine-5'-phosphate decarboxylase are unchanged in diabetes. We have measured the energy charge of the adenine and uridine nucleotide pools and report both to be compromised under the diabetic condition. The fall in ATP provision is proposed to be responsible for the fall in UTP and hence leads to the recorded decrease in the UDP sugars. These changes are discussed in relation to the change in capsular and fiber cell composition and the functional significance of this in cataract formation.
Treatment efficacy is typically evaluated by examining group means and pre-post change scores. Although informative, such analyses may obscure individual or subgroup differences in response (outcome profiles). The present study used two different methods to define treatment outcome profiles--rationally-derived criteria (Frank et al., Archives of General Psychiatry 48, 851-855, 1991) and dynamic clustering--to evaluate four treatments of unipolar depression: behaviour therapy, amitriptyline, psychodynamic psychotherapy and relaxation training (attention placebo). The profiling methods yielded similar results. Regardless of treatment, the majority of patients displayed either a recovery or nonremission outcome profile, with relatively few instances of remission followed by a recurrence of depression. These findings challenge the view that any of the treatments are associated with a strong tendency to relapse, at least over the 3-month follow-up period. To further characterize the major outcome profiles, discriminant analysis was performed. Results indicated that recovery and nonremission profiles differed in that the latter was associated with a longer and more severe index episode and greater neuroticism. A number of variables, including family history of depression and therapists' prediction of outcome, failed to distinguish recovered from unremitted patients.
Enzymes and metabolic intermediates of glycolysis, pentose phosphate pathway and the tricarboxylic acid cycle were measured in immature rat uterus after treatment with oestradiol. The flux of glucose through alternative pathways was examined. Fructose-2,6-bis-phosphate, the well known regulator of glycolytic pathway, increased after the injection of oestradiol and remained elevated. This increase was accompanied by raised levels of most of glycolytic intermediates and by increase in glycolytic flux. The key enzymes of glycolysis and all the enzymes of pentose phosphate pathway showed a gradual increase in the activity with administration of oestradiol up to 48 hours. Phosphoribosyl pyrophosphate, the metabolite required in nucleotide synthesis, was also elevated. Marked changes in the levels of key metabolic intermediates and the enzyme activities are correlated with the increased nucleic acid, protein and lipid synthesis occurring following oestradiol 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.
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.
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.
We describe a pararectus retroperitoneal approach for radical nephrectomy in a patient on chronic ambulatory peritoneal dialysis. This approach allows early ligation of the renal pedicle pre-operatively and immediate resumption of peritoneal dialysis post-operatively.
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.
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.
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.
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.
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.