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Biomedical subjects

M K Walker

Publications and source records attributed to M K Walker.

At least 19 recordsLinked to original sources
PubMed2005

Toxicogenomic profile of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the murine fetal heart: modulation of cell cycle and extracellular matrix genes.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and similar environmental contaminants have been demonstrated to be potent cardiovascular teratogens in developing piscine and avian species. In the present study, we investigated the effects of TCDD on gene expression during murine cardiovascular development. C57Bl6N pregnant mice were dosed with 1.5, 3.0, or 6.0 microg TCDD/kg on gestational day (GD) 14.5, and microarray analysis was used to characterize the global changes in fetal cardiac gene expression on GD 17.5. TCDD significantly altered expression of a number of genes involved in xenobiotic metabolism, cardiac homeostasis, extracellular matrix production/remodeling, and cell cycle regulation. Interestingly, while the AhR-responsive genes Cyp1A1, Cyp1B1, Ugt1a6, and Ahrr, were all induced by TCDD in the fetal murine heart, other AhR-responsive genes, Cyp1a2, Nqo1, and Gsta1, were not. Quantitative real-time polymerase chain reactions confirmed the changes in expression of several G1/S-type cyclins and extracellular matrix-related genes. These results demonstrate the global changes in cardiac gene expression that result from TCDD exposure of the fetal murine heart and implicate genes involved in cell cycle and extracellular matrix regulation in TCDD-induced cardiac teratogenicity and functional deficits.

Animals↗
PubMed2005

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on murine heart development: alteration in fetal and postnatal cardiac growth, and postnatal cardiac chronotropy.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related chemicals are potent cardiovascular teratogens in developing piscine and avian species. In the present study we investigated the effects of TCDD on murine cardiovascular development. Pregnant mice (C57Bl6N) were dosed with 1.5-24 microg TCDD/kg on gestation day (GD) 14.5. At GD 17.5, fetal mice exhibited a dose-related decrease in heart-to-body weight ratio that was significantly reduced at a maternal dose as low as 3.0 microg TCDD/kg. In addition, cardiocyte proliferation was reduced in GD 17.5 fetal hearts at the 6.0-microg TCDD/kg maternal dose. To determine if this reduction in cardiac weight was transient, or if it continued after birth, dams treated with control or 6.0 microg TCDD/kg were allowed to deliver, and heart weight of offspring was determined on postnatal days (P) 7 and 21. While no difference was seen on P 7, on P 21 pups from TCDD-treated litters showed an increase in heart-to-body weight ratio and in expression of the cardiac hypertrophy marker atrial natriuretic factor. Additionally, electrocardiograms of P 21 offspring showed that the combination of in utero and lactational TCDD exposure reduced postnatal heart rate but did not alter cardiac responsiveness to isoproterenol stimulation of heart rate. These results demonstrate that the fetal murine heart is a sensitive target of TCDD-induced teratogenicity, resembling many of TCDD-induced effects observed in fish and avian embryos, including reduced cardiocyte proliferation and altered fetal heart size. Furthermore, the combination of in utero and lactational TCDD exposure can induce cardiac hypertrophy and bradycardia postnatally, which could increase the risk of cardiovascular disease development.

Animals↗
PubMed2005

Prevalence of undiagnosed Type 2 diabetes and impaired fasting glucose in older British men and women.

AIM: To estimate the prevalence of undiagnosed diabetes and impaired fasting glucose in older British men and women, using the 1999 World Health Organization (WHO) thresholds based on fasting glucose measurements. METHODS: Participants in the British Regional Heart Study and the British Women's Heart and Health Study were selected from one socially representative general practice in 24 British towns. Included in this analysis were 3736 men and 3642 women aged 60-79 years (predominantly white), who provided a single fasting blood sample at a clinical examination between 1998 and 2001, and who had no previous diagnosis of diabetes. RESULTS: Two hundred and eleven men (5.7%) and 190 women (5.2%) had a fasting blood glucose level consistent with the WHO threshold for a diagnosis of diabetes (> or = 7.0 mmol/l), whilst a further 667 men (17.9%) and 642 women (17.6%) had impaired fasting glucose levels (6.1 < or = 7 mmol/l). When analyses were restricted to subjects who had fasted for at least 8 h, and whose blood sample was taken before 12.00 h, the predicted prevalence of undiagnosed diabetes (based on two separate measurements) was 6.7% in men and 6.0% in women. The predicted prevalence of impaired fasting glucose (based on two separate measurements) was approximately 20% in both sexes. CONCLUSIONS: More than one-fifth of older white British men and women have either undiagnosed diabetes or impaired fasting glucose according to new WHO criteria. Strategies for the primary and secondary prevention of Type 2 diabetes among older individuals are urgently needed.

Aged↗
PubMed2003

Insulin regulation in AhR-null mice: embryonic cardiac enlargement, neonatal macrosomia, and altered insulin regulation and response in pregnant and aging AhR-null females.

The aryl hydrocarbon receptor (AhR) was originally characterized because of its high affinity binding of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. However, studies using AhR-null mice have demonstrated the importance of this protein in normal physiology and development. Here we demonstrate that AhR-null embryos develop cardiac enlargement, and that this phenotype is dependent, at least in part, on the maternal genotype. Neonates born to AhR-null females had increased heart weights regardless of the neonatal genotype, an outcome also observed in gestational diabetes. The cardiac hypertrophy markers, beta-myosin heavy chain and atrial natriuretic factor, and the cardiac proliferative index were increased in AhR-null embryos, indicating that the cardiac enlargement is associated with myocyte hypertrophy and hyperplasia, which begin prior to birth. Importantly, two- to three-month-old pregnant and seven-month-old nonpregnant females, but not nonpregnant three-month-old AhR-null females had significantly decreased fasting plasma insulin levels and a reduced ability to respond to exogenous insulin compared to controls. Despite these alterations in insulin regulation and responsiveness, pregnant AhR females did not have abnormal glucose tolerance tests and did not develop hyperglycemia, classic characteristics of gestational diabetes. However, twenty-three percent of seven-month-old AhR-null females did have altered glucose tolerance tests, but did not show hyperglycemia or increased hemoglobin A1C concentration under normal feeding conditions. While the ultimate cause of the neonatal phenotype remains unclear, these studies establish that the AhR is required for normal insulin regulation in pregnant and older mice and for cardiac development in embryonic mice.

Age Factors↗
PubMed2002

Aryl hydrocarbon receptor null mice develop cardiac hypertrophy and increased hypoxia-inducible factor-1alpha in the absence of cardiac hypoxia.

The aryl hydrocarbon receptor (AhR) is a member of the basic helix loop helix PAS (Per-ARNT-SIM) transcription family, which also includes hypoxiainducible factor-1alpha (HIF-1alpha) and its common dimerization partner AhR nuclear translocator (ARNT). Following ligand activation or hypoxia, AhR or HIF-1alpha, respectively, translocate into the nucleus, dimerize with ARNT, and regulate gene expression. Mice lacking the AhR have been shown previously to develop cardiac enlargement. In cardiac hypertrophy, it has been suggested that the myocardium becomes hypoxic, increasing HIF-1alpha stabilization and inducing coronary neovascularization, however, this mechanism has not been demonstrated in vivo. The purpose of this study was to investigate the cardiac enlargement reported in AhR(-/-) mice and to determine if it was associated with myocardial hypoxia and subsequent activation of the HIF-1alpha pathway. We found that AhR(-/-) mice develop significant cardiac hypertrophy at 5 mo. However, this cardiac hypertrophy was not associated with myocardial hypoxia. Despite this finding, cardiac hypertrophy in AhR(-/-) mice was associated with increased cardiac HIF-1alpha protein expression and increased mRNA expression of the neovascularization factor vascular endothelial growth factor (VEGF). These data demonstrate that the development of cardiac hypertrophy in AhR(-/-) mice not associated with myocardial hypoxia, but is correlated with increased cardiac HIF-1alpha protein and VEGF mRNA expression.

Age Factors↗
PubMed2001

Hypoxia regulates avian cardiac Arnt and HIF-1alpha mRNA expression.

The aryl hydrocarbon receptor nuclear translocator (Arnt) and hypoxia-inducible factor (HIF)-1alpha mediate cellular responses to hypoxia. We investigated the ability of hypoxia to regulate Arnt and HIF-1alpha mRNA in the heart in vivo. We cloned avian Arnt, developed an in vivo model of chronic cardiac hypoxia, and measured expression of cardiac Arnt and HIF-1alpha mRNA by quantitative RT-PCR. Chronic hypoxic exposure (24 h to 15% O(2)) of day 9 chick embryos resulted in a 30-fold increase in covalent binding of (3)H-misonidazole, a hypoxic tissue marker, to cardiac tissue, and a 2-fold induction of cardiac inducible nitric oxide synthase mRNA, compared to normoxic controls. In this same model, cardiac Arnt mRNA expression decreased by 35%, while HIF-1alpha mRNA expression increased 400%. These data suggest that regulation of Arnt and HIF-1alpha mRNA expression may contribute to the physiological responses of the heart during prolonged hypoxia.

Amino Acid Sequence↗
PubMed2001

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibition of coronary development is preceded by a decrease in myocyte proliferation and an increase in cardiac apoptosis.

BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes cardiovascular toxicity, culminating in edema, hemorrhage, and mortality in piscine, avian, and mammalian embryos. To elucidate the mechanism of the cardiovascular teratogenicity of TCDD, we used a chick embryo model to determine whether TCDD alters coronary artery development and whether this alteration was associated with apoptosis and/or changes in myocyte proliferation. METHODS: Fertile chicken eggs were injected with corn oil (control), 0.24, or 0.40 pmol TCDD/g in corn oil before incubation. To evaluate effects of TCDD on differentiation of coronary arteries, chick embryo hearts from incubation days 8 (D8), D10, and D12 were stained with anti-alpha-smooth muscle actin. Myocyte proliferation was measured by BrdU incorporation on D6, 8, 10, and 12 after TCDD treatment. In addition, temporal and spatial patterns of apoptosis were detected by TUNEL on D3, D5, D6, D8, and D10, and immunohistochemistry was used to identify the origin of apoptotic cells on D6. RESULTS: TCDD increased apoptosis in structures where cell death normally occurs, including the outflow tract, endocardial cushion of the atrioventricular canal, and dorsal mesocardium, peaking in intensity on D6. Immunohistochemistry revealed that cells undergoing TCDD-induced apoptosis in the dorsal mesocardium were not neural or epicardial in origin. On D8 and D10 TCDD reduced myocyte proliferation. On D10, TCDD reduced coronary artery size and on D10 and D12 TCDD induced a dose-dependent decrease in coronary artery number. CONCLUSIONS: The reduction of myocyte proliferation by TCDD preceded the reduction in coronary artery number and size, suggesting that changes in coronary development may be a consequence of reduced myocyte proliferation and a thinner ventricle wall. The peak of TCDD-induced increase in apoptosis occurred even earlier in embryo development and thus may contribute to changes in myocyte proliferation, coronary development, and cardiac structural malformations; however, a cause-and-effect relationship between apoptosis and these other events has yet to be established.

Actins↗
PubMed2001

Correlation of cardiotoxicity mediated by halogenated aromatic hydrocarbons to aryl hydrocarbon receptor activation.

In mammals, the toxicity of halogenated aromatic hydrocarbons (HAH) correlates with their ability to activate the aryl hydrocarbon receptor (AHR). To test this correlation in an avian model, we selected six HAHs based on their affinity for the mammalian AHR, including: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PCDD); 2,3,7,8-tetrachlorodibenzofuran (TCDF); 2,3,4,7,8-pentachlorodibenzofuran (PCDF); 3,3',4,4'-tetrachlorobiphenyl (PCB 77); and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153). We determined the ability of these compounds to induce cardiotoxicity, as measured by an increase in heart wet weight on incubation day 10 in the chick embryo (Gallus gallus) and formation of the avian AHR/ARNT/DNA binding complex in chicken hepatoma cells. Relative potency values (RPs) were calculated by dividing the TCDD EC(50) (AHR/ARNT/DNA binding) or ED(50) (15% increase in day-10 heart wet weight) by the HAH congeners EC(50) or ED(50), respectively. The rank order of potencies for inducing cardiotoxicity were TCDD > PCDD = PCDF = TCDF > PCDF > PCB77, PCB 153, no effect. The RP values for inducing AHR/ARNT DNA binding were then correlated with those for inducing cardiotoxicity (the RP values of PCDD were determined to be statistical outliers). This correlation was found to be highly significant (r = 0.94, p = 0.017). The ability of PCDD to act as an AHR agonist was verified using luciferase reporter assays and analysis of cytochrome P4501A1 protein levels. These results indicate that the ability of HAHs to activate the avian AHR signaling pathway, in general, correlates with their ability to mediate cardiotoxicity in the chick embryo.

Animals↗
PubMed2001

Does the body image exist in three dimensions? The study of visual mental representation of a body and a nonbody object.

Do the mental images of 3-dimensional objects recreate the depth characteristics of the original objects? This investigation of the characteristics of mental images utilized a novel boundary-detection task that required participants to relate a pair of crosses to the boundary of an image mentally projected onto a computer screen. 48 female participants with body attitudes within expected normal range were asked to image their own body and a familiar object from the front and the side. When the visual mental image was derived purely from long-term memory, accuracy was better than chance for the front (64%) and side (63%) of the body and also for the front (55%) and side (68%) of the familiar nonbody object. This suggests that mental images containing depth and spatial information may be generated from information held in long-term memory. Pictorial exposure to views of the front or side of the objects was used to investigate the representations from which this 3-dimensional shape and size information is derived. The results are discussed in terms of three possible representational formats and argue that a front-view 2 1/2-dimensional representation mediates the transfer of information from long-term memory when depth information about the body is required.

Adolescent↗
PubMed2000

Hemodynamic dysfunction and cytochrome P4501A mRNA expression induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin during embryonic stages of lake trout development.

Lake trout embryos exposed to [(3)H]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) manifest toxicity after hatching by subcutaneous edema of the yolk sac, pericardial edema, meningeal edema, subcutaneous hemorrhages, and a marked congestion of blood flow in various vascular beds culminating in death. Our objective was to determine if this syndrome was associated temporally with morphologic lesions in the vascular endothelium, increased vascular permeability, and cytochrome P4501A (CYP1A) mRNA induction. Lake trout embryos exposed as fertilized eggs to TCDD were found to exhibit marked reductions in perfusion of the peripheral vasculature during the early sac fry stage of development (stage F(1)9), which consistently preceded other gross lesions and mortality observed later in sac fry development (stage F(2)10). This reduction in blood flow was manifested as severe capillary congestion and hemoconcentration in certain vascular beds. Transmission electron microscopic (TEM) examination of endothelial cells in these vascular beds failed to reveal cellular necrosis at hatching (stage E(5)8) and throughout sac fry development (stages F(1)9-F(2)10). Rather, only subtle ultrastructural changes in endothelial cells were found consisting of increased vacuolation, separation of intercellular junctions, and cytoplasmic blebbing, consistent with the TCDD dose and time course for developmental cardiovascular toxicity, which began to manifest itself in some embryos approximately 1 week prior to hatching (E(5)8). To assess permeability of yolk sac vasculature to certain constituents in blood, sac fry (stage F(2)10) were analyzed for the presence of plasma proteins, granulocytes, and serum creatine kinase activity in yolk sac subcutaneous edema fluid from control and TCDD-exposed treatment groups. TCDD dose- and time-related increases in yolk sac edema volume, plasma protein content of edema fluid, granulocyte concentration, and creatine kinase activity in the fluid were observed in midstage and late stage of sac fry development (stage F(2)10). Thus, yolk sac subcutaneous edema fluid is an ultrafiltrate of blood and results from increased vascular permeability. In contrast to the changes in vascular blood flow and permeability induced by TCDD during stages F(1)9 and F(2)10 of sac fry development, respectively, CYP1A mRNA levels were induced by TCDD as early as the 10-somite embryo (stage E(2)5). TCDD also caused a dose-related increase in CYP1A mRNA levels in sac fry at hatching (stage E(5)8) and throughout sac fry development (stages F(1)9-F(2)10). We conclude that subtle, ultrastructural changes in vascular endothelial cells consistently precede increases in vascular permeability and sac fry mortality; however, induction of CYP1A mRNA occurs prior to any observable morphological lesions, changes in vascular permeability, or sac fry mortality.

Animals↗
PubMed2000

Characterization of cardiotoxicity induced by 2,3,7, 8-tetrachlorodibenzo-p-dioxin and related chemicals during early chick embryo development.

Cardiotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was studied in White Leghorn-Babcock (WLB) and Plymouth Rock-Barred (PRB) chick embryos. TCDD, injected on day 0 (D0), induced a dose-related increase in heart weight in both strains in the absence of pericardial edema on D10. PRB embryos were four to five times more sensitive to this cardiotoxicity than WLB. To determine if another aryl hydrocarbon receptor agonist produced a similar response, graded doses of TCDD; 3,3',4,4',5-pentachlorobiphenyl (PeCB 126); or 2,2',4,4',5,5'-hexachlorobiphenyl (HxCB 153) were injected into WLB eggs. TCDD and PeCB 126 induced a dose-related increase in heart weight without pericardial edema, while HxCB 153 had no effect. We then hypothesized that TCDD-induced cardiotoxicity progressed to heart failure and edema. In PRB, morphometric analysis revealed that TCDD (0.06-0.45 pmol/g) induced a dose-related increase in left and right ventricle cavity area without wall hypertrophy on D10, consistent with dilated cardiomyopathy. A time course showed that 0.24 pmol/g did not alter heart morphology on D8 but induced cardiac dilation on D10 and D12. The 0.24 pmol/g dose also induced changes associated with progression of cardiomyopathy toward heart failure, including increased cardiac atrial natriuretic factor mRNA expression and decreased cardiac responsiveness to isoproterenol-induced positive chronotropy, on D10 and D12. Finally, 0.24 pmol/g induced a significantly higher incidence of subcutaneous and peritoneal edema, indicative of overt heart failure, on D12 (75%, 15/20) compared to D10 (14%, 3/22). In conclusion, TCDD induced a phenotype of dilated cardiomyopathy and symptoms associated with the development of congestive heart failure.

Actins↗
PubMed2000

Molecular characterization and developmental expression of the aryl hydrocarbon receptor from the chick embryo.

The aryl hydrocarbon receptor (AhR) was cloned from the chick embryo and its function and developmental expression characterized. Chicken AhR cDNA coded for 858 amino acid protein and 396 bp of 3' UTR. The basic helix loop helix domain exhibited 87-100% amino acid identity to avian, mammalian, and amphibian AhR, and 69-74% to piscine AhR. The PAS (Per-ARNT-Sim) region was slightly less well conserved with (a) 97% identity to other avian sequences, (b) 81-86% to amphibian and mammalian AhR, and (c) 64-69% with piscine AhR. The carboxy terminus diverged the most among species with less than 53% amino acid identity between chicken and any available mammalian and piscine AhR sequences. The chicken AhR RNA and protein were 6.1 kb and 103 kDa, respectively. Chicken AhR dimerized with human AhR nuclear translocator and bound the mammalian dioxin-response element in a ligand-dependent manner. AhR protein was detected in neural ganglia; smooth, cardiac, and skeletal muscle; and epithelium involved in epithelial-to-mesenchymal transformations, such as pituitary, gastrointestinal tract, limb apical-ectodermal ridge, and kidney collecting ducts. AhR mRNA was detected in all tissues expressing protein, except myocardium. Cytochrome P4501A4 mRNA was highly induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a subset of tissues expressing AhR, including small intestine, liver, kidney, blood vessels, and outflow tract myocardium. In conclusion, the AhR sequence and function is highly conserved between birds and mammals, and although many tissues express AhR during chick embryo development, only a subset are responsive to TCDD induction of CYP1A4.

Amino Acid Sequence↗
PubMed2000

Focal microinjection of carbachol into the periaqueductal gray induces seizures in the forebrain of the rat.

Previous studies have reported that the repetition of running-bouncing and tonic-clonic seizures mediated by brainstem structures eventually elicits seizure activity in the forebrain. The purpose of the present study was to determine if the periaqueductal gray (PAG) region is a component of the neural network through which brainstem seizures elicit forebrain seizures. Bilateral microinjection of 40 nmol carbachol into the PAG region of rats induced arrested, staring behavior accompanied by epileptiform electrocorticogram (ECoG) afterdischarge recorded from the parietal cortex. In two animals limbic seizure activity similar to kindled amygdala seizures was also induced. The carbachol effect was dose-related as the 40 nmol dose induced a significantly greater duration of ECoG afterdischarge than a 20 nmol dose. The carbachol effect was mediated by muscarinic receptors as bilateral 50 nmol atropine microinjection 1 min prior to 40 nmol carbachol microinjection inhibited all seizure activity. Immunohistochemical detection of the proto-oncogene c-fos was used to verify that seizure activity was induced in forebrain regions. Rats with seizures induced by PAG carbachol microinjections exhibited dense c-fos-like immunoreactivity in the dentate gyrus but not the CA(1) or CA(3) regions, amygdala, piriform cortex, perirhinal cortex or hypothalamus. In addition, PAG microinjection of 10 nmol N-methyl-D-aspartic acid (NMDA) induced wild-running convulsions while 400 pmol bicuculline induced clonic spasms, myoclonic activity or limbic seizures. These results indicate that stimulation of the PAG, a brainstem structure, is sufficient to induce forebrain seizures. Since the forebrain seizures were induced by a single carbachol administration, it is proposed that the PAG serves as a pathway for caudal-rostral seizure generalization.

Animals↗
PubMed1998

Eating disorders revisited. II: Bulimia nervosa and related syndromes.

Bulimia nervosa and related syndromes are common, and occur in up to 5% of women who attend general practitioners. Young women in First World countries, particularly those who "diet", are at increased risk. Behaviours, such as binge eating and induced vomiting, are typically kept well hidden. Only a minority of those with these disorders present for treatment. General practitioners play a key role in primary and secondary prevention. Effective treatments include psychotherapies that focus on the patient's attitudes and relationships, not just the binge eating behaviour. About 50% of patients make a complete recovery, but the long term outcome is unknown.

Bulimia↗
PubMed1998

Eating disorders revisited. I: Anorexia nervosa.

Anorexia nervosa is a serious psychiatric illness with a high morbidity and a significant lifetime mortality. Recurring themes in such patients centre on issues of self-worth and control. Treatment is difficult and prolonged, and may require hospitalisation. Therapy focuses on altering the misperceptions that patients have of themselves, both psychologically and physically. A multi-disciplinary team based in a specialised unit provides the treatment of choice, but if this is not available, a consistent, supportive relationship with an individual therapist familiar with the condition will be beneficial. Successful outcome should be based not simply on body weight but also on the resolution of anorexic thinking.

Anorexia Nervosa↗
PubMed1998

Validation of patient recall of doctor-diagnosed heart attack and stroke: a postal questionnaire and record review comparison.

Few studies have assessed the accuracy of patient recall of doctor-diagnosed heart attack and stroke on postal questionnaire, yet such data are widely used in epidemiologic studies. In the national prospective British Regional Heart Study of 7,735 men aged 40-59 years, based in general practice and followed up for a mean 13.8 years, a mailed questionnaire was sent to all available survivors in 1992. Patient recall of doctor-diagnosed heart attack and stroke was compared with the 316 new general practice-reported heart attacks and 102 new general practice-reported strokes from the medical record reviews. Both study and general practice records were checked for all discordant findings, and corrections were made to the study database. Patients tended to overrecall major cardiovascular events more than they underrecalled them, 33% versus 6% for heart attacks and 25% versus 11% for strokes. Among overrecalled heart attacks, other circulatory problems were present in 78% of the subjects; transient ischemic attacks accounted for 57% of overrecalled strokes. In contrast, the general practice record review system tended to underreport events rather than to overreport them, 3% versus 0.3% for heart attacks and 23% versus 5% for strokes. Patient recall of doctor-diagnosed heart attack and stroke provides a useful method for estimating prevalence rates and resource needs, but the tendency to overestimation needs to be recognized. In etiologic studies when strict diagnostic case criteria are essential, patient recall should be used to complement rather than to supplant medical record data.

Adult↗
PubMed1998

Antioxidant properties of indapamide, 5-OH indapamide and hydrochlorothiazide evaluated by oxygen-radical absorbing capacity and electron paramagnetic resonance.

The aim of these experiments was to investigate the radical scavenging properties of three diuretics: indapamide (IND) and its major metabolite, 5-OH indapamide (5-OH IND), compared to a reference diuretic, hydrochlorothiazide (HTZ). Electron Paramagnetic Resonance (EPR) was used to determine the scavenging abilities of these compounds on enzymatically produced superoxide radical anion, with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) used as a spin-trap. These experiments revealed that IND and specially 5-OH IND were effective superoxide radical anion scavengers at 0.2 mg/ml. In the second part of these studies, allophycocyanin was used as an indicator of free radical mediated protein damage. In the assay, 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH) was used as a peroxyl radical generator, Trolox (a water-soluble analogue of vitamin E) as a control standard, and the loss of allophycocyanin fluorescence was monitored. The antioxidant effects of the diuretics were expressed in oxygen-radical absorbing capacity (ORAC), where one ORAC unit equals the net protection produced by 1 microM Trolox. HTZ showed no protection up to 100 microM final concentration, whereas IND and 5-OH IND showed linear correlation with respect to concentration when expressed in ORAC units: 5-OH IND induced the highest protection against peroxyl radical. The above observations suggested that IND and 5-OH IND are potent radical scavengers, with the metabolite 5-OH IND having a superior antioxidant potency than IND. By contrast, HTZ had no effect. These radical scavenging properties of 5-OH IND may be of clinical interest for vascular protection and may help to protect the heart from oxidative injury.

Antioxidants↗