Differences in easily recognised coronary risk factors by age at first myocardial infarction.
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Biomedical subjects
Publications and source records attributed to M C Robertson.
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The rat luteal 20alpha-hydroxysteroid dehydrogenase plays a key role at catabolizing progesterone and at decreasing the level of this steroid secreted by the ovaries. Throughout pregnancy and before parturition neither the mRNA nor the protein for this enzyme could be detected. In this investigation we set to examine whether PRL and PRL-like hormone from placental origin silence the expression of this gene and whether PRL action involves tyrosine kinase activity and/or de novo protein synthesis. The results revealed that PRL and PRL-like hormone from rat placental origin (rPL-1 and rPL-2), but not rat growth hormone, caused a rapid and profound inhibition of 20alpha-HSD mRNA expression in highly luteinized granulosa cells. Immunoprecipition and western blot analysis indicate that PRL-R associates with JAK2 and Stat5, and this association is increased within 30 seconds with PRL treatment. Although both JAK2 and Stat5 were phosphorylated on tyrosine upon PRL treatment, the PRL mediated inhibition of 20alpha-HSD was not reversed by either tyrosine kinase inhibitors, AG18 and genistein, but was largely reversed by the protein synthesis inhibitor cycloheximide. In summary, results of this investigation indicate that although PRL can activate the JAK2/Stat5 system in the corpus luteum, the down regulation of 20alpha-HSD mRNA by PRL does not appear to involve tyrosine kinase activity but depends on de novo synthesis of protein(s).
OBJECTIVES: This study sought to compare the clinical features and outcome of a first myocardial infarction with onset of symptoms during or within 30 min of exercise, at rest and in bed. BACKGROUND: It is not known whether activity at onset influences outcome of acute myocardial infarction. METHODS: Information collected using a standard questionnaire was used to relate activity at the onset of symptoms to in-hospital outcome in 2,468 consecutive patients admitted to a coronary care unit with a first myocardial infarction between 1975 and 1993. RESULTS: Patients with exercise-related onset were more likely to be younger and male. Those with onset in bed were more likely to be older and have a history of stable or unstable angina. Compared with patients whose symptoms began at rest, those with exercise-related onset had a lower in-hospital mortality rate after adjusting for age, gender and year of admission (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.40 to 0.89), and patients with onset in bed had a higher mortality rate (OR 1.38, 95% CI 1.03 to 1.85). The incidence of cardiac failure requiring diuretic therapy was also lower for exercise-related onset (OR 0.83, 95% CI 0.67 to 1.04) and higher when onset was in bed (OR 1.36, 95% CI 1.11 to 1.66). CONCLUSIONS: There is an association between activity at onset and outcome of acute myocardial infarction. Differences in pathophysiology or in the population at risk could explain this observation.
BACKGROUND: There are conflicting reports about the effects of angiotensin converting enzyme inhibitors on insulin sensitivity and glycaemic control. In addition, the chronic effects of ACEI on insulin sensitivity in normotensive but insulin resistant individuals have been controversial. AIM: To determine the long-term effects of low-dose captopril or enalapril on insulin sensitivity and lipid parameters in normotensive non-insulin dependent diabetic volunteers. METHODS: Twenty-eight normotensive non-insulin dependent diabetes mellitus subjects on diet alone or diet plus oral hypoglycaemic agents were randomized in a single-blind cross-over study to receive either captopril (12.5 mg daily) or enalapril (5 mg daily). Initially, captopril was compared with enalapril for 28 days with a 28-day washout period between drug regimens. For the long-term study, the subjects then remained on the second ACEI for a further 11 months. Insulin sensitivity was measured using the isoglycaemic hyperinsulinaemic clamp (insulin infusion rate 20 mIU/kg/min) at the start and completion of each part of the cross-over study and then at 3, 6 and 12 months of drug therapy. Fasting glucose, insulin, HbA1, lipids and lipoproteins were measured at the start of each clamp. RESULTS: No first or second order carry-over effects were demonstrated between the ACEIs. No differences were detected between enalapril and captopril on insulin sensitivity at any of the time points. Statistically significant hypotension was avoided, and at doses used the ACEIs did not modify any parameters of glycaemic control over the 12-month study period. There were no significant alterations in plasma cholesterol, triglycerides, HDL cholesterol or Apo A1 levels during the study. CONCLUSIONS: Long-term low-dose ACEIs (captopril/enalapril) do not modify insulin sensitivity, glycaemic control or lipids in normotensive non-insulin dependent diabetic subjects.
OBJECTIVE: To determine the current prevalence of hyperuricaemia and gout in New Zealand Maori and Europeans for comparison with previous studies. METHODS: 342 Maori and 315 European men and women aged 15 years and older were studied by personal interview and a musculoskeletal system examination. The 1977 ARA criteria for gout in a survey setting were used and serum uric acid was determined by a uricase method. The data were compared with those of previous New Zealand studies. RESULTS: Gout was significantly more common in Maori (6.4%) than Europeans (2.9%) (delta = 3.6%, 95% confidence interval 0.4 to 6.8) and in Maori men (13.9%) than in European men (5.8%) (delta = 8.1%, 95% CI 1.0 to 15.2). Hyperuricaemia was significantly more common in Maori men (27.1%) than in European men (9.4%) (delta = 17.7%, 95% CI 8.3 to 27.1) and in Maori women (26.6%) than in European women (10.5%) (delta = 16.1%, 95% CI 8.5 to 23.7). At least 14% of hyperuricaemic individuals were receiving diuretics, of whom 78% were women. Comparison with previous studies shows that the prevalence of gout has increased in both Maori and Europeans, particularly in men. In Maori men the prevalence of gout has risen from 4.5-10.4% previously to 13.9%, and in European men from 0.7%-2.0% previously to 5.8%. Clinical differences included a stronger family history, earlier age at onset, and a higher frequency of tophi and polyarticular gout in Maori than Europeans. Of those with gout, 62% of Maori and 63% of Europeans were hyperuricaemic on the day surveyed and six (19.4%) were on diuretics. Treatment of gout was inadequate in most cases. CONCLUSIONS: Hyperuricaemia and gout remain common among Maori. Of concern is that the prevalence of gout appears to be on the increase, not only in Maori but also in Europeans in New Zealand.
Adult virgin female rats display maternal behavior when continuously exposed to foster young for 5-6 days. Central infusions of PRL or placental lactogens (PLs) together with systemic treatment of progesterone (P) and estradiol (E2) stimulate maternal behavior in 1-2 days. In the present set of studies, it was asked whether the actions of lactogenic hormones are dependent upon both E2 and P and specific to lactogenic molecules. Moreover, we wanted to know whether central infusions of rat (r) PRL and PLs were equally effective in inducing maternal behavior. In the first study, adult virgin rats were ovariectomized (ovx) and stereotaxically fitted with bilateral cannulas directed at the medial preoptic area (MPOA). Rats were then assigned to one of four groups: P plus E2, blank (B) plus E2, P plus B, and B plus B. P-filled or B capsules were implanted sc on treatment day 1 and removed on day 11, whereas E2 or B capsules were implanted on day 11. All groups were infused with rPRL (40 ng/side) five times from days 11-13 and injected with bromocriptine (CB-154) sc (days 11-17) to suppress endogenous PRL release. Behavioral testing was conducted daily from days 12-17. It was found that exposure to both P and E2 was necessary to induce a fast onset of maternal behavior in PRL-infused females; priming with P or E2 alone in PRL-treated rats failed to stimulate a fast onset of behavior relative to that in nonsteroid-treated controls. In the second experiment to determine the biochemical specificity of PRL's action, adult nulliparous rats were ovx, implanted with bilateral cannulas directed at the MPOA, treated with both P and E2, injected with CB-154, and infused centrally (five times) with 40 ng (per side) of bovine GH, ovine LH, or vehicle. Central infusions of either bovine GH or ovine LH failed to stimulate maternal behavior, suggesting that the stimulatory actions of PRL are related to its lactogenic properties. In the final study, rats were ovx, fitted with bilateral cannulas directed at the MPOA; treated with P, E2, and CB-154; and given a single set of bilateral infusions of rPL-I or rPRL (40 ng/side.infusion) on day 11, three sets of infusions of rPL-I or rPRL (days 11 and 12), or vehicle infusions. Rats given three infusions of rPL-I and rPRL responded faster than controls, although the effect was not as robust as that in animals given five infusions in the initial study. rPL-I and rPRL groups did not differ from one another. Together these studies indicate that 1) both P and E2 are required for lactogenic stimulation of maternal behavior; 2) the stimulatory actions of PRL and rPLs on maternal behavior are related to their lactogenic properties; 3) extended treatment of females with lactogenic hormones is more effective in stimulating the onset of maternal behavior; and 4) the neural potencies of rPRL and rPL-I are similar. These findings provide support for the idea that the induction of maternal behavior is stimulated by the central actions of lactogenic hormones.
Use of the term "old age' in notifying deaths of residents in Oxfordshire nursing homes between 1984 and 1994 was matched with recorded age. 2264 records covering 44 registered nursing homes were looked at. The oldest person referred to as dying from old age was 106, the youngest 69 years. The most general starting point for a diagnosis of old age was 77 though the years from the mid-eighties through the early nineties were taken by the majority of notifiers as fitting this description.
The object of the study was to determine whether the increased mortality associated with low blood pressure in elderly people arises because of the adverse effects of hypotension or because of confounding variables. A community sample of 782 people aged 70 years and older was followed for 3 years. Blood pressure measurements were taken on initial assessment and hypotension was defined separately for systolic and diastolic pressures as a pressure less than the tenth percentile for the sample (systolic < or = 122 mmHg, diastolic < or = 68 mmHg). After 3 years 135 participants had died and of these 31 had low systolic or diastolic blood pressure at baseline. Low diastolic pressure was associated with an increased mortality over the 3 years (hazard ratio 1.85, 95% Confidence Interval 1.18-2.91). This increase in risk was explained by confounding variables. Low systolic pressure was not associated with increased mortality. The increased mortality of those with low blood pressure is explained by concurrent illness.
The possible role of the conceptus in stimulating the onset of maternal behavior through its secretion of placental lactogens and their passage into the brain was investigated in female rats. In the first study, significant mitogenic activity in the Nb2 lymphoma cell bioassay was detected in cerebrospinal fluid (CSF) samples collected by push-pull perfusion from rats on days 12-21 of pregnancy, coincident with the establishment of placental function. In contrast, mitogenic activity was absent from CSF in lactating and gonadectomized, virgin females. In a second study the mitogenic activity in day 12 pregnant samples was neutralized 71% with antibodies to rat placental lactogen-I (rPL-I) and > 90% with a combination of antibodies to rPL-I plus rPL-II. In contrast, activity on day 21 of pregnancy, 1 day prepartum, was reduced by antibodies to rPL-II (> 85%), but not by antibodies to rPL-I, indicating that the predominant lactogen in the CSF prepartum is rPL-II. The behavioral actions of placental secretions were assessed in the third experiment by infusing recombinant rPL-I and purified rPL-II directly into the medial preoptic area of the brain of steroid-primed, nulliparous rats. Latencies to respond maternally to foster young were significantly reduced in rPL-I- and rPL-II-treated rats (2- to 3-day latencies) when compared with latencies in control females (5- to 6-day latencies). Thus, the conceptus through its secretion of rPLs which apparently gain access to the CSF helps to prime the pregnant female's brain to respond maternally at the end of gestation. This endocrine communication between the developing conceptus and pregnant female appears to be an important part of the biological system which helps to establish successful maternal care.
The rat placenta expresses two rat placental lactogen-I (rPL-I) proteins: the normal rPL-I in the first half of pregnancy and a variant (rPL-Iv) in the second half of pregnancy. They are 70% identical at the amino acid level but arise from different cell types: rPL-I from giant cells and rPL-Iv from cytotrophoblasts. To assess whether rPL-Iv originates from alternative splicing of the rPL-I gene or is the product of a separate gene, genomic clones of rPL-I and rPL-Iv were isolated from a lambda EMBL-3 rat genomic library. Restriction enzyme analysis of the 14-kilobase full-length genomic clones of rPL-I and rPL-Iv indicated that the two genes are distinct. To assess the biological activity of the variant protein relative to other members of the rat PL/PRL/GH family, two expression systems were chosen to obtain the purified recombinant protein: 1) a secreted form of rPL-Iv was obtained from Chinese hamster ovary (CHO) cells transfected with rPL-Iv-complementary DNA; and 2) a rPL-Iv fusion protein (Bac-rPL-Iv) was obtained from Spodoptera frugiperda (Sf9) insect cells that had been infected with a recombinant baculovirus generated from rPL-Iv complementary DNA. An antibody was generated to the purified Bac-rPL-Iv fusion protein and used for affinity chromatography to purify recombinant rPL-Iv from the CHO cell media. The mitogenic activity of rPL-Iv was monitored in the Nb2 lymphoma cell bioassay. The relative potency of rPL-Iv compared with other members of the PL/PRL/GH family follows: ovine PRL 100, rPL-I 200, rPL-II 160, rPRL 40, CHO-rPL-Iv 0.7, and Bac rPL-Iv 0.4. Iodinated CHO-rPL-Iv showed minimal binding to Nb2 lymphoma cells, but at a 500-fold protein concentration rPL-I was able to displace [125I]rPL-I from the lymphoma cell PRL receptor. Using recombinant CHO-derived rPL-Iv as standard and antisera against the Bac-rPL-Iv fusion protein, a RIA was developed for rPL-Iv. In pregnant rats rPL-Iv appeared in the serum at day 14, rising to a peak of 2080 +/- 440 ng/ml at day 18, followed by a slight decline. These values reflect the levels of messenger RNA for rPL-Iv in rat placenta noted previously. In summary, rPL-Iv arises from a gene different from rPL-I and the rPL-I protein displays minimal binding and mitogenic activity in the Nb2 lymphoma cells.
Rat placental lactogen-I (rPL-I), expressed in rat uteri at midpregnancy, belongs to the GH/PRL/cytokine family of hormones (Wallis, 1992), all members of which exhibit a similar mechanism of receptor activation. Lactogenic activity of rPL-I as determined by Nb2 lymphoma cell bioassay was slightly higher than that of hGH. rPL-I was capable also of stimulating beta-casein production in mouse HC-11 cells. Competitive binding experiments using [125I]hGH or [125I]bPL and purified prolactin receptor extracellular domains (PRLR-ECDs) from rat (r), rabbit (rb), and bovine (b) showed rPL-I to be 12, 40, and 7-fold, respectively, less effective than hGH when competing with [125I]hGH. Displacement of [125I]bPL by rPL-I from rPRLR-ECD and rbPRLR-ECD was also 4-, and 30-fold less effective, respectively, than that by bPL. rPL-I did not compete at all with [125I]bPL for binding to bPRLR-ECD. In contrast, competitive binding experiments with [125I]hGH to a microsomal fraction of Nb2 cells showed rPL-I to be slightly more active than hGH. The stoichiometries of the complexes formed by rPL-I with rbPRLR-ECD, rPRLR-ECD, and bPRLR-ECD were studied by gel filtration. Whereas a 1:1 complex was formed between rPL-I and rPRLR-ECD and rbPRLR-ECD, no complex could be detected between rPL-I and bPRLR-ECD. The present results support the hypothesis that transient forms of a homodimer complex may be sufficient to initiate the biological signal, despite its short half-life.
Peroxidation of low density lipoproteins (LDL) may be involved in the development of atherosclerosis which is prevalent in patients with chronic renal failure and renal transplant recipients. We determined the copper ion catalyzed oxidation in vitro, vitamin E content, and chemical and fatty acid composition of LDL isolated from 38 patients with renal disease and 15 healthy subjects. Also the acute effect of hemodialysis treatment on LDL oxidation variables was tested. The lag time in conjugated diene formation during oxidation was significantly (P = 0.011) shorter in LDL from renal transplant recipients (66 min, N = 18) mainly due to significantly (P < 0.05) shorter times in women (47 min, N = 7), compared with healthy subjects (83 min, N = 15), patients on hemodialysis (91 min, N = 13) and patients treated by continuous ambulatory peritoneal dialysis (CAPD) (82 min, N = 7). The maximum rate and the extent of LDL oxidation were significantly (P < 0.01) lower in all patients with renal disease compared with healthy subjects. The triglyceride content of LDL was significantly (P < 0.001) higher in women with kidney grafts (7.3%) compared with levels in the corresponding men (5.3%) and healthy women (5.0%), and was correlated significantly with the lag time in LDL oxidation in renal transplant recipients (Spearmans r = -0.502, P = 0.034). The percentage oleic acid in LDL was significantly higher (P = 0.002) and the percentage linoleic acid was significantly lower (P = 0.046) in patients with renal disease, and may largely account for their lower rates and extent of LDL oxidation. Levels of the LDL oxidation variables and organic lipid peroxide content of LDL were not significantly different before and after hemodialysis and 24 hours later. These results suggest that LDL from women with renal transplants may be abnormally susceptible to oxidation possibly due to increased triglyceride content.
In a cross-sectional study of a total population aged 70 years and over in a rural New Zealand township (sample size 682) we investigated factors which characterize those who felt they had a great deal of control and those who felt they had little or no control over future health. In a significant logistic regression model those with a feeling of a great deal of control over future health had a lower prevalence of chronic obstructive lung disease, higher prevalence of diabetes, took less alcohol, were more likely to be satisfied with bowel function, had a lower protein intake, were more likely to participate in strenuous to moderate activity and were less likely to have features of depression. Different perceptions of control were associated with significant differences in health practices and health status.
BACKGROUND: There are conflicting reports about the effects of ACE inhibitors (ACEI) on insulin sensitivity and glycaemic control. Most studies have used a standard high dose of an ACEI but there have been no studies reported to establish whether any changes in glycaemic control or insulin sensitivity associated with ACEI are dose-related. AIM: To examine the effect of increasing doses of enalapril on insulin sensitivity in normotensive non-insulin dependent diabetic subjects. METHODS: The effects of increasing doses of enalapril on insulin sensitivity in ten normotensive non-insulin dependent diabetic subjects were measured, using the hyperinsulinaemic isoglycaemic clamp technique. Following a baseline study, enalapril was commenced at 5 mg daily and increased to 10 mg daily then 20 mg daily at 14 day intervals. Repeat studies were undertaken after 14 days at each dosage. RESULTS: There was a significant dose-related reduction of systolic blood pressure with enalapril. In contrast enalapril at 5-20 mg daily produced no significant changes in insulin mediated glucose uptake (M-value) or insulin sensitivity index (ISI). CONCLUSIONS: These findings indicate that in this insulin resistant population of normotensive non-insulin dependent diabetics, angiotensin converting enzyme inhibition with enalapril has no significant effect on insulin mediated glucose uptake.
The secretion of peptide 23 by rat pituitary cells is stimulated by growth hormone-releasing hormone and inhibited by somatostatin. Recent cloning of the cognate cDNA for peptide 23 revealed that it is identical to pancreatitis-associated protein (PAP). In the present study, the clearance and tissue uptake of recombinant peptide 23/PAP in normal adult male rats was assessed. The plasma half-life of recombinant peptide 23/PAP was 4.8 +/- 1.4 (S.D.) min. Maximal accumulation of radio-labelled peptide 23/PAP was observed in the kidney, stomach, small intestine and pancreas whereas negligible uptake was seen in the liver, lung or heart. Peptide 23/PAP was detected in a variety of tissue extracts using a radioimmunoassay. Extracts of ileum contained the highest concentrations of peptide 23/PAP. In situ hybridization analysis showed that peptide 23/PAP mRNA was highly expressed in the columnar epithelial cells of ileum, jejunum and duodenum. These observations demonstrate that peptide 23/PAP, a protein previously thought to be of pituitary origin, is widely expressed in the gastrointestinal tract and that it is rapidly removed from the circulation by the kidney and by tissues which express peptide 23/PAP.
Plasma lathosterol concentration which is an index of cholesterol synthesis rate was measured in 36 patients with chronic renal failure (CRF) including 13 who were dialysis independent, 12 receiving hemodialysis and 11 on continuous ambulatory peritoneal dialysis (CAPD), 17 renal transplant recipients and 27 healthy control subjects. Concentrations of plasma lathosterol were significantly (ANOVA p = 0.03) lower in all categories of renal patients excepting those treated by CAPD, compared with control values. In normolipidemic subjects (cholesterol < or = 6.50 mmol/l and triglycerides < or = 2.0 mmol/l) plasma lathosterol levels in hemodialysis patients and renal transplant recipients were still significantly (ANOVA p = 0.02) lower than control values. In transplant recipients, the plasma lathosterol/cholesterol ratio was significantly (p = 0.02) lower than those treated with azathioprine and prednisone compared with those treated with these drugs and cyclosporin. Significant (p < 0.001) positive correlations were recorded between plasma lathosterol concentration and plasma levels of apolipoprotein B (apoB) and very low density lipoprotein (VLDL) lipids in the renal patients. These data suggest that the rate of cholesterol synthesis may be low in undialysed and hemodialysed patients with CRF and in renal transplant recipients, particularly those treated with double therapy, and may be linked to the metabolism of apoB and VLDL.
Accumulation and distribution of cell cholesterol in plasma lipoproteins of incubated blood was examined in 36 patients with chronic renal failure including 13 who were dialysis-independent, 12 on haemodialysis, and 11 on continuous ambulatory peritoneal dialysis (CAPD), 17 renal transplant recipients, and 8 healthy controls. In addition, transport of cholesterol between red blood cells and high-density lipoprotein subfraction 3 (HDL3) isolated from a subgroup of patients with chronic renal failure was determined. Significantly less cell cholesterol appeared in plasma (P < 0.002) and HDL (P = 0.03), the main recipient of cell cholesterol, in patients with chronic renal failure compared with healthy subjects. Corresponding values in blood from renal transplant recipients were similar to controls. In patients with chronic renal failure, plasma HDL3 cholesterol levels (P < 0.02), HDL3 phospholipid content (P < 0.001) and net transport of red cell cholesterol to isolated HDL3 (P < 0.001) were significantly lower compared with controls. The data suggest that in patients with chronic renal failure, low levels of plasma HDL3 of abnormal composition may restrict the incorporation of cell cholesterol into the antiatherogenic HDL fraction potentially leading to inefficient transport of cholesterol from peripheral tissues and the development of atherosclerosis. These abnormalities appear to be reversed by renal transplantation.
OBJECTIVE: The aim of the study was to compare red blood cell (RBC) fatty acid composition, plasma lipids and lipoproteins and dietary intake between urban and rural Melanesian Fijians. DESIGN: A cross-sectional study was performed in a random subsample (n = 154) from a total survey population of 589 subjects. SETTING: Melanesian Fijians living in the relatively urban settlement of Nabua, Suva and On the remote island of Qamea (rural) were studied. RESULTS: The proportions of myristic acid (1.4% versus 0.3%, P < 0.001) and arachidonic acid (10.1% versus 11.4%, P < 0.01) were significantly higher and proportions of oleic acid (14.4% versus 13.2%, P < 0.05) and linoleic acid (11.9% versus 8.1%, P < 0.001) were significantly lower in RBC from rural compared with urban men, and a similar pattern was seen in women. Plasma cholesterol levels were significantly (P < 0.05) higher in the rural subjects. Urban/rural differences in plasma cholesterol levels were not significant when the proportion of RBC myristate was taken into account. CONCLUSIONS: The results suggest that consumption of myristic acid from coconut fat is greater and the intake of linoleic acid is less in Fijians living on a remote island and may contribute to their higher plasma cholesterol levels compared with their urban counterparts.