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K MacLeod

Publications and source records attributed to K MacLeod.

At least 19 recordsLinked to original sources
PubMed2005

Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.

AIMS: Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In the first DIGAMI study, an insulin-based glucose management improved survival. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin-glucose infusion followed by insulin-based long-term glucose control; group 2, insulin-glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice. METHODS AND RESULTS: DIGAMI 2 recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction randomly assigned to groups 1 (n=474), 2 (n=473), and 3 (n=306). The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2.1 (interquartile range 1.03-3.00) years. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively, whereas blood glucose was 12.8, 12.5, and 12.9 mmol/L, respectively. Blood glucose was significantly reduced after 24 h in all groups, more in groups 1 and 2 (9.1 and 9.1 mmol/L) receiving insulin-glucose infusion than in group 3 (10.0 mmol/L). Long-term glucose-lowering treatment differed between groups with multidose insulin (> or =3 doses/day) given to 15 and 13% of patients in groups 2 and 3, respectively compared with 42% in group 1 at hospital discharge. By the end of follow-up, HbA1c did not differ significantly among groups 1-3 ( approximately 6.8%). The corresponding values for fasting blood glucose were 8.0, 8.3, and 8.6 mmol/L. Hence, the target fasting blood glucose for patients in group 1 of 5-7 mmol/L was never reached. The study mortality (groups 1-3 combined) was 18.4%. Mortality between groups 1 (23.4%) and 2 (22.6%; primary endpoint) did not differ significantly (HR 1.03; 95% CI 0.79-1.34; P=0.831), nor did mortality between groups 2 (22.6%) and 3 (19.3%; secondary endpoint) (HR 1.23; CI 0.89-1.69; P=0.203). There were no significant differences in morbidity expressed as non-fatal reinfarctions and strokes among the three groups. CONCLUSION: DIGAMI 2 did not support the fact that an acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction when compared with a conventional management at similar levels of glucose control or that insulin-based treatment lowers the number of non-fatal myocardial reinfarctions and strokes. However, an epidemiological analysis confirms that the glucose level is a strong, independent predictor of long-term mortality in this patient category, underlining that glucose control seems to be an important part of their management.

Aged↗
PubMed2002

Insulin-treated diabetes and driving in the UK.

Diabetes, and particularly insulin-treated diabetes, has important implications for motor vehicle driving, largely because of its association with potential hypoglycaemia. For this reason, most countries operate some driving restrictions on insulin-treated diabetic patients, as well as systems of intermittent reassessment of hypoglycaemic risk. In the UK, regulations are operated by the Driver and Vehicle Licensing Agency (DVLA), which is an agency of the Department of the Environment, Transport and the Regions (DETR). They are supported by an Expert Panel which advises the Secretary of State on diabetes-related issues relating to fitness to drive. The patient organization Diabetes UK is also concerned with diabetes and driving issues, largely from a position of lobbying policy-influencers and supporting individual cases. All parties involved with diabetes and driving issues recognize the need for more research on the subject, as the current literature is flawed in design, though no convincing excess of accidents amongst diabetic drivers has been conclusively demonstrated. Currently in the UK, Class 2 vehicles (large trucks and passenger vehicles) are barred to diabetic drivers on insulin. European law has recently extended this to so-called C1 (large vans and small lorries) and D1 (minibuses) vehicles, though the law has recently been revised to allow individual consideration for potential diabetic C1 drivers on insulin treatment. Diabetes and insulin-treated diabetes is an emotive and difficult issue, for which a stronger evidence base is urgently needed.

Automobile Driving↗
PubMed2001

Multiple lysosomal trafficking phenotypes in metastatic mouse mammary tumor cell lines.

Although altered synthesis and trafficking of lysosomal proteins and their receptors are associated with a wide range of human and rodent malignancies, the basis for their involvement remains obscure. Here we describe findings on a set of mouse mammary tumor cell lines that we are using as a model to study the role of these proteins in oncogenesis and tumor progression. Three distinct proteinase-secreting phenotypes were identified among the metastatic cell lines of the set. Two phenotypes displayed a high level of secretion of cathepsin L and the third was characterized by elevated secretion of matrix metalloproteinase 9 (MMP-9). The two cathepsin L-secreting phenotypes were distinct in that they displayed differences in cathepsin trafficking, expression of mannose 6-phosphate/insulin-like growth factor receptor and expression of proliferin, a mannose-phosphorylated angiogenic factor. Although cells representing all three phenotypes are capable of dissemination to distant organs when implanted into mouse mammary glands, only cells with the MMP-9 phenotype were found to be capable of direct intravasation. These findings indicate that multiple proteinase-secreting phenotypes can arise from the same tumor and suggest that cathepsin L and other lysosomal proteins may play a role in dissemination of tumor cells via the lymphatic system.

Animals↗
PubMed2000

The Oort crowd

Explore the source record for details and available documents.

Journal Article↗
PubMed2000

Plant-derived estrogens relax coronary arteries in vitro by a calcium antagonistic mechanism.

OBJECTIVES: To investigate the potential for plant derived estrogens (phytoestrogens) genistein, phloretin, biochanin A and zearalanone to relax rabbit coronary arteries in vitro and to determine the mechanism(s) of such relaxation. BACKGROUND: Epidemiological data suggests a reduction in the incidence of coronary heart disease in humans who have a high intake of phytoestrogens. METHODS: Isolated rabbit coronary artery rings were suspended in individual organ baths, precontracted with potassium chloride (30 mM), and the relaxing effects and mechanisms of relaxation to genistein, phloretin, biochanin A and zearalanone were determined by measurement of isometric tension. RESULTS: Genistein, phloretin and biochanin A induced significant gender-independent relaxation in rings with and without endothelium. Inhibition of nitric oxide and prostaglandin synthesis with L-NAME and indomethacin had no effect on genistein-induced relaxation. Relaxation was unaffected by the specific estrogen receptor antagonist ICI 182,780, the ATP-sensitive potassium channel inhibitor glibenclamide and the potassium channel inhibitor, barium chloride. Calcium concentration-dependent contraction curves in high potassium depolarization medium were significantly shifted to the right and downward after incubation with genistein and zearalanone. An inhibitory effect of genistein (2 microM) on L-type calcium current in guinea-pig ventricular myocytes confirmed a calcium antagonist relaxing mechanism of action. In healthy volunteers, plasma genistein levels of approximately 2 microM are achieved after ingestion of a commercially available soy protein drink (Supro) containing 37 mg genistein. CONCLUSIONS: This study demonstrates that phytoestrogens induce endothelium-independent relaxation of coronary arteries; the mechanism involves calcium antagonism. These mechanisms may contribute to the potential long-term cardiovascular protective effect of these substances.

Adult↗
PubMed1999

Mucosal immunity in extrinsic allergic alveolitis: salivary immunoglobulins and antibody against inhaled avian antigens among pigeon breeders.

BACKGROUND: Inhaled antigens from pigeons can cause extrinsic allergic alveolitis (EAA); a model disease of pulmonary inflammation. Among pigeon breeders, serum antibody and sensitized lymphocytes specific for these antigens have been described primarily, but not always, with disease. Antibody activity within the lung may have a closer association with disease, however, sampling by alveolar lavage at bronchoscopy is impractical for screening, therefore we used saliva to quantify the mucosal antibody response. OBJECTIVE: To establish: (a) if antibody activity against inhaled avian antigens was detectable in the saliva of pigeon breeders, (b) if the distribution of saliva antibody and total immunoglobulin levels were quantitatively or qualitatively different from serum, and (c) whether the hypersensitivity symptoms of EAA were associated more with the mucosal or the systemic humoral immune response. MEASURES: Saliva and serum total and avian antigen-specific IgG, IgA (IgA1 and IgA2) antibody activity in 87 pigeon breeders and 24 control subjects with no avian exposure. Albumin levels were used as a protein reference and cotinine levels confirmed smoking status. Specific hypersensitivity symptoms and various exposure indices to pigeons were established by interview. RESULTS: Absolute levels and relative proportions (vs albumin) of IgG, IgA and IgA1 in saliva, and IgG in serum, were significantly higher in pigeon breeders compared with controls, suggesting mucosal inflammation. Avian antigen-specific antibody of all isotypes was readily demonstrable in saliva (predominantly IgA) and serum (predominantly IgG) from pigeon breeders, and there were no significant titres in controls. The levels of IgG antibody in saliva and in serum correlated significantly (r = 0.52, P < 0.001), and both correlated with the raised immunoglobulin levels. In both saliva and serum the IgG rather than the IgA antibody activity was associated with symptoms of EAA. CONCLUSIONS: Antibody activity in saliva and serum, representing the mucosal and systemic responses, respectively, were both strongly stimulated by inhaled antigens. The IgG antibody titres of saliva and serum correlated significantly and were a useful index of inflammation, as measured by the raised total immunoglobulin levels, and symptoms. This suggests that IgG antibody in serum may reflect clinical and immunological sensitization of the lung mucosa. Collecting saliva is noninvasive, and saliva antibody measurement is a convenient method for monitoring EAA, especially in children, and will facilitate sampling for example in epidemiological studies of antibody prevalence.

Albumins↗
PubMed1998

Who reads temporal information contained across synchronized and oscillatory spike trains?

Our inferences about brain mechanisms underlying perception rely on whether it is possible for the brain to 'reconstruct' a stimulus from the information contained in the spike trains from many neurons. How the brain actually accomplishes this reconstruction remains largely unknown. Oscillatory and synchronized activities in the brain of mammals have been correlated with distinct behavioural states or the execution of complex cognitive tasks and are proposed to participate in the 'binding' of individual features into more complex percepts. But if synchronization is indeed relevant, what senses it? In insects, oscillatory synchronized activity in the early olfactory system seems to be necessary for fine odour discrimination and enables the encoding of information about a stimulus in spike times relative to the oscillatory 'clock. Here we study the decoding of these coherent oscillatory signals. We identify a population of neurons downstream from the odour-activated, synchronized neuronal assemblies. These downstream neurons show odour responses whose specificity is degraded when their inputs are desynchronized. This degradation of selectivity consists of the appearance of responses to new odours and a loss of discrimination of spike trains evoked by different odours. Such loss of information is never observed in the upstream neurons whose activity is desynchronized. These results indicate that information encoded in time across ensembles of neurons converges onto single neurons downstream in the pathway.

Animals↗
PubMed1998

Biomarkers of oxidative stress are significantly elevated in Down syndrome.

There is convincing epidemiological and in vitro evidence of chronic oxidative stress in individuals with Down syndrome (DS). These individuals develop Alzheimer like changes in the brain in their 30s and 40s. The incidence of autoimmune diseases and cataracts is significantly increased, and the overall ageing process is accelerated. In vitro studies show that impaired viability of DS neurons may be amended by simple chemical antioxidants, such as vitamin E, BHT and propyl gallate, clearly indicative of oxyl radical involvement. However, because of the lack of in vivo experiments, the role of oxidative stress in DS remains controversial. We report here on the results of the chemical analyses of urine samples of 166 individuals, where DS subjects were matched by their siblings. The levels of 8-hydroxy-2'-deoxyguanosine (2.35 +/- 1.69 in DS vs. 1.35 +/- 1.04 in controls, P = 0.00011), a biomarker of oxidative damage to DNA, and malondialdehyde (0.255 +/- 0.158 in DS vs. 0.204 +/- 0.128 in controls, P = 0.033), a biomarker of lipid peroxidation, are significantly elevated in individuals with DS. Dietary influences failed to show any significant correlation with the oxidative stress biomarkers. These results provide direct evidence for increased oxidative stress in individuals with DS.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Comparison of alternative buffers for use with a new live oral cholera vaccine, Peru-15, in outpatient volunteers.

During development of Peru-15, a new live oral vaccine for cholera, the role of buffer needed to be evaluated. Generally, oral bacterial vaccines are acid labile and need to be administered by using a formulation which protects them from gastric acid. We compared three different buffers for use with Peru-15, including a standard bicarbonate-ascorbic acid buffer, Alka-Seltzer, and a new electrolyte-rice buffer, CeraVacx. Saline served as the control. Thirty-nine healthy adult volunteers received Peru-15 (10(8) CFU) with one of the three buffers or saline in a double-masked study. The volunteers were monitored for symptoms for 7 days after the dose, serum was tested for antibody responses by vibriocidal antibody and immunoglobulin G antitoxin enzyme-linked immunosorbent assays, and stool samples were tested for excretion of the vaccine strain. Side effects were minimal in all groups. All 30 volunteers who took Peru-15 with a buffer showed significant rises in vibriocidal antibody titer. The magnitude of the rises was higher in the CeraVacx group than in the other two buffer groups. Four of nine volunteers who took the vaccine with saline also showed increased titers, but they were lower than those in any of the three buffer groups. Excretion of the vaccine strain was similar in the buffer groups, but excretion was not associated with the magnitude of the vibriocidal responses. Excretion of Peru-15 was not detected in the saline group. We conclude that buffer does amplify the serological response to Peru-15 and that CeraVacx may provide benefits not provided by other buffers.

Administration, Oral↗
PubMed1996

Distinct mechanisms for synchronization and temporal patterning of odor-encoding neural assemblies.

Stimulus-evoked oscillatory synchronization of neural assemblies and temporal patterns of neuronal activity have been observed in many sensory systems, such as the visual and auditory cortices of mammals or the olfactory system of insects. In the locust olfactory system, single odor puffs cause the immediate formation of odor-specific neural assemblies, defined both by their transient synchronized firing and their progressive transformation over the course of a response. The application of an antagonist of ionotropic gamma-aminobutyric acid (GABA) receptors to the first olfactory relay neuropil selectively blocked the fast inhibitory synapse between local and projection neurons. This manipulation abolished the synchronization of the odor-coding neural ensembles but did not affect each neuron's temporal response patterns to odors, even when these patterns contained periods of inhibition. Fast GABA-mediated inhibition, therefore, appears to underlie neuronal synchronization but not response tuning in this olfactory system. The selective desynchronization of stimulus-evoked oscillating neural assemblies in vivo is now possible, enabling direct functional tests of their significance for sensation and perception.

Animals↗
PubMed1996

Isolation, excessive time demands and sexism face female MDs, CMA workshop told.

Networking plays a critical role in the professional development of female physicians and meetings such as a recent CMA-sponsored workshop help encourage it, physicians attending the workshop were told. Janet Bickel told the female doctors hat one of the key problems they face is overcoming structural inflexibility that does not allow a balance between personal and professional concerns: "Meetings like this one help you realize your own strengths, and get a new perspective on your expertise and values.

Canada↗
PubMed1994

The response of bone to external loading regimens.

The results of Hert et al. have been re-examined using an external pin fixation technique involving New Zealand White rabbits. New bone formation was assessed with tetracycline epifluorescence in 49 animals. The animals were operated upon using inhalational anaesthesia, and pins were placed at opposite ends of the tibia of both hind limbs. Following recovery, oxytetracycline was given at a dosage of 25 mg kg-1 body weight intraperitoneally on the day of loading and on the fourteenth day of the loading regimen. The bones were loaded for 45 min per 24 h. Undemineralized specimens were sectioned and standardized photographs produced. The area of new bone was determined by a planimeter and by digitization. In dynamic loading the shape of the force/time curve is of little significance; the response is frequency dependent and for higher frequencies the response is greater than that from continuous loading; there was no statistical significance between the rapid relief loading regimens. For continuous loading the response is a function of the load value. In all cases more bone is laid down in immature subjects than in adults. With regard to osteoclastic activity, all loading increased the areas of resorption irrespective of character, in all adult animals intermittent loads produced a greater area of ostoeclastic resorption than static loads and produced a greater change as the number of load cycles per minute increased. The adult control animals had more resorptive activity than the immature animals although there was no statistical significance. Loading, irrespective of its character, led to a net increase of bone, the osteoblastic effects thus outweighing the osteoclastic effects.

Aging↗
PubMed1994

Pax-QNR/Pax-6, a paired- and homeobox-containing protein, recognizes Ets binding sites and can alter the transactivating properties of Ets transcription factors.

We have previously isolated a cDNA clone encoding a protein with a paired- and homeodomain from MC29-transformed quail neuroretina cells that we have termed Pax-QNR. Pax-QNR is homologous to the murine Pax-6, which is mutated in the autosomal dominant mutation small eye (Sey) of the mouse and aniridia in man. The 46 kDa Pax-QNR protein binds specifically to the e5 DNA recognition sequence present upstream of the Drosophila even-skipped gene. The Pax-QNR paired and homeobox domains expressed separately in bacteria are both able to recognize this sequence. The core sequence recognized by the paired domain of Pax genes is TTCC (GGAA), and this sequence is also present in the core recognition site bound specifically by Ets family-encoded proteins. Ets proteins are a family of transcription factors sharing a highly conserved 85 amino acid DNA binding domain. In this article we demonstrate that Pax-QNR/Pax-6 expressed in reticulocyte lysate is able to specifically recognize several Ets binding sites. In addition, we found that the transactivation mediated by the p68c-ets-1 pr p55erg through the Polyomavirus enhancer sequence is specifically inhibited by the p46kDaPax-QNR in transient transfection assay.

Animals↗
PubMed1988

Regulation of erythroid cell-specific gene expression during erythropoiesis.

The aim of our group's work over the past few years has been to investigate the molecular mechanisms regulating erythroid cell-specific gene expression during erythroid cell differentiation. In addition to the alpha-globin gene, we have focussed on two non-globin genes of interest encoding the rabbit red cell-specific lipoxygenase (LOX) and the mouse glutathione peroxidase (GSHPX), an important seleno-enzyme responsible for protection against peroxide-damage. Characterisation of the GSHPX gene showed that the seleno-cysteine residue in the active site of the enzyme is encoded by UGA, which usually functions as a translation-termination codon. This novel finding has important implications regarding mRNA sequence context effects affecting codon recognition. The regulation of the GSHPX and red cell LOX genes has been investigated by functional transfection experiments. The 700 bp upstream of the GSHPX promoter seems to function equally well when linked to the bacterial chloramphenicol acetyl transferase (CAT) gene and transfected into mouse erythroid or fibroblast cell lines. However, the presence of tissue-specific DNase I hypersensitive sites (DHSS) in the 3' flanking region of the GSHPX gene suggests that such sites may be important in its regulation in the various cell types in which it is highly expressed, i.e., erythroid cells, liver and kidney. The transcription unit of the RBC LOX gene has also been defined and 5' and 3' flanking regions are being investigated for erythroid-specific regulatory elements: a region upstream of the LOX gene gives increased expression of a linked CAT gene when transfected into mouse erythroid cell lines compared to non-erythroid cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1987

A double blind placebo controlled comparison of verapamil, atenolol, and their combination in patients with chronic stable angina pectoris.

The efficacy and effect on cardiac function of verapamil 120 mg three times a day and atenolol 100 mg once a day, singly and in combination, were evaluated in 15 patients with angina pectoris. While they were on the combination treatment four patients withdrew from the study. Episodes of angina pectoris and glyceryl trinitrate consumption were significantly reduced only on the combination. On the combination only four patients developed evidence of ischaemia during exercise compared with seven on verapamil and ten on atenolol. ST segment depression at peak exercise, assessed by 16 point precordial mapping, was reduced by all active treatments from 7.1 on placebo to 2.7, 0.9, and 0.6 mm on atenolol, verapamil, and the combination respectively. Mean left ventricular ejection fraction fell significantly from 60% on placebo to 53% on the combination but was unchanged on verapamil and atenolol. Verapamil was an effective alternative to atenolol; the combination was the most effective treatment but was associated with a significant morbidity.

Aged↗