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Biomedical subjects

G R Norton

Publications and source records attributed to G R Norton.

At least 19 recordsLinked to original sources
PubMed2006

Impact of beta2-adrenoreceptor gene variants on cardiac cavity size and systolic function in idiopathic dilated cardiomyopathy.

In heart failure, the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenoreceptor (beta2-AR) gene are associated with exercise-capacity, clinical outcomes and response to beta-AR blocker therapy. Whether beta2-AR gene variants mediate these effects in-part through an impact on cardiac structural remodeling and pump function independent of the effects of beta-blockers is uncertain. We evaluated whether the Arg16Gly and Gln27Glu variants of the beta2-AR gene predict left ventricular ejection fraction (LVEF) and LV end diastolic diameter (LVEDD) in patients with idiopathic dilated cardiomyopathy (IDC) before and 6 months after receiving standard medical therapy other than beta-AR blockers. In all, 394 patients with IDC and 393 age and gender-matched controls were genotyped for the beta2-AR gene variants using restriction-fragment length polymorphism-based techniques. LVEF and dimensions were determined in 132 patients (of whom 71 were newly diagnosed) both at baseline and after 6 months. Genotype of neither variant was associated with the presence of IDC. Moreover, beta2-AR genotype did not determine LVEF or LV dimensions prior to initiating therapy. After 6 months of therapy, LVEF increased by 7.1+/-1.0 absolute units (P<0.0001) and LVEDD decreased by 0.27+/-0.06 cm (P<0.02). Adjusting for baseline values as well as gender, age, and type of angiotensin-converting enzyme inhibitor therapy received, genotype was associated with neither final LVEF and LVEDD, nor change in LVEF and LVEDD. In conclusion, these data suggest that in heart failure, the functional Arg16Gly and Gln27Glu variants of the beta2-AR gene have no independent effect on adverse structural remodeling and pump function.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Reduction in myocardial collagen cross-linking parallels left ventricular dilatation in rat models of systolic chamber dysfunction.

BACKGROUND: The transition from compensated left ventricular hypertrophy (LVH) to heart failure is associated with alterations in the myocardial interstitium. We hypothesized that LV dilatation is associated with modifications in collagen cross-linking. METHODS AND RESULTS: We studied 2 rat models of LV dilatation: (1) pressure-overload hypertrophy with heart failure (POH-F) induced by suprarenal abdominal aortic banding and (2) LVH induced by 7 months of isoproterenol (ISO, 0.04 mg x kg(-1) x d(-1)) administration. In POH-F rats and in rats receiving ISO, LV dilatation and a reduced systolic chamber performance were noted. Myocardial hydroxyproline concentrations ([HPRO]) were increased in the POH-F rats, whereas in rats receiving ISO, [HPRO] was decreased. In POH-F rats, the ratio of myocardial collagen type I to type III was increased, but in rats receiving ISO, myocardial collagen I/III was unchanged. In contrast to the diverse changes in myocardial collagen concentrations and phenotypes observed in the 2 models of LV dilatation, the ratio of myocardial insoluble to soluble (relationship between cross-linked and non-cross-linked) collagen was decreased in both the POH-F and ISO groups. Moreover, administration of captopril (0.22 mmol x kg(-1) x d(-1)), which inhibited the ISO-induced reduction in myocardial insoluble/soluble collagen but not the reduction in [HPRO], prevented the ISO-induced alterations in LV dimensions and performance. CONCLUSIONS: Because decreases in the ratio of myocardial insoluble to soluble collagen parallel LV dilatation in rats, reductions in myocardial collagen cross-linking may be an important mechanism contributing to LV dilatation in heart disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Antiadrenergic effects of adenosine in pressure overload hypertrophy.

In the present study, we sought to evaluate whether the antiadrenergic action of adenosine in the heart is altered in pressure overload hypertrophy produced in rats by suprarenal aortic banding. Epicardial and coronary effluent adenosine and inosine concentrations and release were significantly elevated in compensated pressure overload hypertrophy but not in hearts with left ventricular failure. In pressure overload hearts, the contractile response to beta-adrenergic stimulation was less inhibited by incremental concentrations of either adenosine or the selective A(1) receptor agonist chloro-N:(6)-cyclopentyl adenosine than in controls. Furthermore, the extent of desensitization to the antiadrenergic actions of adenosine in pressure overload hypertrophy appeared to be proportional to the extent of chamber dilation and dysfunction. A 60-minute infusion of adenosine produced a sustained antiadrenergic effect that lasted up to 45 minutes after the infusion was terminated in both controls and hearts with compensated hypertrophy. This effect was not observed in the decompensated left ventricular failure group. Subsequent infusion with adenosine of the A(2A) receptor antagonist 8-(3-chlorostyryl)-caffeine to counteract the proadrenergic effect of A(2A) receptor stimulation did not alter the decreased sensitivity to the antiadrenergic actions of adenosine in hypertrophied hearts. Finally, isolated myocytes from hypertrophied hearts demonstrated a decreased ability to suppress isoproterenol-elicited increases in [Ca(2+)](i) transients in the presence of adenosine and the A(2A) receptor antagonist compared with myocytes from control hearts. Myocardial adenosine concentrations increase during the compensated phase of pressure overload hypertrophy but then decrease when there is evidence of decompensation. The antiadrenergic actions of adenosine transduced via the myocardial A(1) receptor are diminished in pressure overload hypertrophied hearts. These factors may render these hearts more vulnerable to the detrimental effects of chronically increased sympathetic activity.

Adenosine↗
PubMed2001

Attenuation of cardiac failure, dilatation, damage, and detrimental interstitial remodeling without regression of hypertrophy in hypertensive rats.

Whether left ventricular (LV) hypertrophy is important in the development of LV failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling in hypertension has not been established. We examined the effect of an antihypertensive agent without the ability to regress LV hypertrophy on the development of LV changes in spontaneously hypertensive rats (SHR). Hydralazine given to SHR from 5.2 to 26 months of age returned systolic blood pressure to Wistar Kyoto (WKY) control values but failed to prevent the increase in LV mass noted in SHR (at 26 months of age: WKY, 0.99+/-0.02 g; untreated SHR, 1.40+/-0.02 g; treated SHR, 1.36+/-0.02 g; P<0.001 in SHR versus WKY). In comparison to both 16-month-old SHR and age-matched WKY, 26-month-old untreated SHR developed signs consistent with heart failure, LV dilatation (an increased LV internal radius), an eccentric LV geometry, advanced myocyte necrosis, an increase in myocardial collagen solubility (an index of decreases in myocardial collagen cross-linking), and marked increases in myocardial total, type III, and non-cross-linked myocardial collagen concentrations. Despite the inability of hydralazine to regress LV hypertrophy, treated SHR did not develop signs of heart failure, myocyte necrosis, decreases in myocardial collagen cross-linking, or increases in myocardial total, type III, and non-cross-linked collagen at 26 months of age. Moreover, treatment attenuated the development of LV dilatation and an eccentric LV geometry. In conclusion, antihypertensive therapy that does not attenuate LV hypertrophy but achieves normal blood pressure in SHR, is able to hinder the development of heart failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling.

Animals↗
PubMed2000

Attenuated beta-adrenoceptor-mediated cardiac contractile responses following androgenic steroid administration to sedentary rats.

Androgenic steroids administered in doses at pharmacological levels to sedentary animals have been shown to result in a reduced beta-adrenoceptor-mediated increase in systolic cardiac performance when assessed in vivo. Whether the attenuated adrenergic response occurs as a consequence of alterations in either cardiac loads, heart rate, modifications in left ventricular (LV) geometry, or a decrease in myocardial contractile performance has not been determined. In this study the effect of chronic administration (over 3 months) of an androgenic steroid (nandrolone decanoate, 5 mg. kg(-1) biweekly) on the response of load-insensitive indices of myocardial contractile function [the slope of the LV systolic stress-strain relationship (LV-E(n)(max), where E(n)(max) is systolic myocardial elastance)] to an adrenergic-inotropic stimulus was examined ex vivo in paced rat hearts. Systolic cardiac performance was assessed at 300 beats. min(-1) in isolated constant flow perfused heart preparations both before and during 10(-8.5) mol. l(-1) isoproterenol (ISO) infusion (approximate concentration of ISO eliciting 50% maximal inotropic response to ISO). Steroid administration resulted in left-shifted LV systolic and diastolic pressure-volume (P-V ) relationships. The leftshifted P-V relationships were attributed, in part, to increased slopes of these relationships. However, the steroid-mediated increment in the slope of the systolic P-V relationship (systolic chamber elastance, E(max)) was not associated with a similar change in LV E(n)(max) [control 19.2 (SEM 2.1) g. cm(-2), steroid 18.3 (SEM 2.4) g. cm(-2)] as determined in the absence of ISO. Isoproterenol infusion resulted in an increase in both E(max) and E(n)(max) in the control rats, without altering systolic performance in the steroid treated rats. Consequently, in the presence of ISO, the steroid treated rats exhibited a similar E(max), but a reduction in E(n)(max) compared to the control rats [control 25.6 (SEM 1.9) g. cm(-2), steroid 18.5 (SEM 1.5) g. cm(-2); P < 0.05]. In conclusion, these results would suggest that chronic high dose androgenic steroid administration produces a decrease in myocardial contractile reserve to beta-adrenoceptor stimulation.

Anabolic Agents↗
PubMed2000

Drinking away the hurt: the nature and prevalence of PTSD in substance abuse patients attending a community-based treatment program.

The prevalence of posttraumatic stress disorder (PTSD) was evaluated in 91 participants attending a community-based substance abuse program. The participants were classified as having PTSD, possible PTSD, or no PTSD using the modified PTSD symptom scale (MPSS; Falsetti, Resnick, H. S., Resnick, P. A. & Kilpatrick, 1993). These groups were then compared on measures of anxiety, depression, and fear using the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Anxiety Sensitivity Index (ASI), and the Fear Questionnaire (FQ). The results showed that 52.8% of participants had either PTSD (37.4%) or possible PTSD (15.4%). Findings also showed that those with PTSD experienced more potentially traumatic events (e.g., rape, being beaten-up) compared to the possible PTSD and no PTSD participants. The PTSD group also reported significantly greater scores on the ASI, BAI, and BDI than did the no PTSD group, and greater scores on the ASI and BAI than did the possible PTSD group. Further, when using a discriminant function analysis, self-report measures correctly classified 70% of the PTSD group and 80% of a composite group of possible PTSD and no PTSD participants. Implications of these results are discussed.

Adult↗
PubMed2000

Evidence of a disposition toward fearfulness and vulnerability to posttraumatic stress in dysfunctional pain patients.

Few investigations have addressed whether patient subgroups derived using the Multiaxial Assessment of Pain (MAP) [Turk, D. C., & Rudy, T. E. (1987). Towards a comprehensive assessment of chronic pain patients. Behaviour Research and Therapy, 25, 237-249; Turk, D. C., & Rudy, T. E. (1988). Toward an empirically derived taxonomy of chronic pain patients: integration of psychological assessment data. Journal of Consulting and Clinical Psychology, 56, 233-238.] differ with regard to fear and avoidance. It has, however, been reported that dysfunctional patients exhibit more pain-specific fear and avoidance than patients classified as interpersonally distressed or minimizers/adaptive copers [Asmundson, G. J. G., Norton, G. R., & Allerdings, M. D. (1997). Fear and avoidance in dysfunctional chronic back pain patients. Pain, 69, 231-236.]. We attempted to extend these findings by examining two fear constructs that are receiving increased attention in the chronic pain literature-anxiety sensitivity and PTSD. The sample comprised 115 patients with chronic pain. Of these, 14 (12.2%) were classified as dysfunctional, 21 (18.3%) as interpersonally distressed and 47 (40.8%) as minimizers/adaptive copers. Between-group differences were observed on the fear of cognitive and emotional dyscontrol dimension of anxiety sensitivity, total and symptom cluster scores on the PTSD measure, and depression. No differences were observed for the fear of somatic sensations dimension of anxiety sensitivity or agoraphobia, social phobia, and blood/injury fears. Dysfunctional patients generally exhibited elevated scores relative to one or both of the other MAP subgroups on fear of cognitive and emotional dyscontrol, depressed affect, PTSD symptom total score and PTSD symptom cluster scores. As well, a substantial proportion of dysfunctional and interpersonally distressed patients were classified as having PTSD (71.4 and 42.9%, respectively) when compared to minimizers/adaptive copers (21.3%). These results suggest that MAP subgroups differ with regard to their propensity to be(come) fearful and in their likelihood of having PTSD. Theoretical and clinical implications are discussed.

Adaptation, Psychological↗
PubMed2000

Alpha-adducin polymorphism in hypertensives of South African ancestry.

The alpha-adducin gene contributes significantly to hypertension in MHS rats (rats of the Milan hypertensive strain) and in some white and Japanese populations, causing a low renin, sodium, and diuretic-sensitive hypertension. No data are available from populations of African ancestry who have a high prevalence of low renin, sodium, and diuretic-sensitive hypertension. We studied the relationship between the 460-Trp variant of alpha-adducin gene with hypertension using a case-control study design in black South Africans. Surprisingly we found that the overall frequency of the 460-Trp allele was low (approximately 6%), but in spite of such relatively low frequency, the 460-Trp allele was 2.5-fold more frequent in hypertensives than normotensives (P = .028), with an odds ratio for hypertension associated to the state of carrier of at least one 460-Trp allele of 2.68. The finding of such low frequency of the 460-Trp allele in individuals of African ancestry points to the substantial ethnic variability of the genes that have been found to be associated with hypertension. On the other hand, it suggests an association of the 460-Trp allele with hypertension also in subjects of African origin.

Adult↗
PubMed2000

Effects of an androgenic steroid on exercise-induced cardiac remodeling in rats.

Habitual exercise results in a rightward shift in left ventricular end diastolic (LVED) pressure-volume or internal dimension (P-D) relationships [left ventricular (LV) remodeling]. However, exercise-mediated LV hypertrophy (LVH) produces an increased LV relative wall thickness [ratio (h/r) of wall thickness (h) to internal radius (r)] and hence a decrement in diastolic wall stress despite LV remodeling. In this study, the effect of chronic administration of an androgenic steroid on exercise-induced LV remodeling and h/r was examined in rats. Habitual exercise on voluntary running wheels resulted in LVH and a rightward shift in the LVED P-D relationships. However, LVH was sufficient to increase LVED h/r. Androgenic steroid administration to exercised rats, without influencing the development of exercise-induced LVH, produced a further rightward shift in the LVED P-D relationship associated with an increased diameter intercept. As a consequence, LVED h/r was reduced to control values. The steroid-mediated effects were not associated with alterations in either the quantity or quality of LV collagen. In conclusion, high-dose androgenic steroid administration alters exercise-induced LV remodeling and subsequently reduces the beneficial effect of physiological LVH on LV h/r.

Anabolic Agents↗
PubMed1999

Association of left ventricular systolic performance and cavity size with angiotensin-converting enzyme genotype in idiopathic dilated cardiomyopathy.

The insertion-deletion (ID) polymorphism of the angiotensin-converting enzyme (ACE) gene is a marker linked to differences in plasma and cardiac ACE activity as well as to an increased mortality in patients with idiopathic heart failure. We examined the possibility that ACE gene ID variants are associated with differences in left ventricular (LV) systolic performance or internal LV dimensions in a high-risk cohort of patients with idiopathic dilated cardiomyopathy (IDC). The ACE genotype was determined in 171 patients selected with IDC in New York Heart Association functional class II to III heart failure and with a LV ejection fraction of < or = 40%. Left ventricular performance and dimensions were assessed using echocardiography (n = 161) and radionuclide ventriculography (n = 169). The frequency of ACE gene ID alleles was not different in the study versus non-age-matched (n = 171; odds ratio 0.94) and age-matched (n = 106, odds ratio 0.88) control groups. Ejection fraction was found to be worse in patients with the DD genotype (echocardiography, DD = 23.5 +/- 0.70, ID + II = 26.8 +/- 0.8, p = 0.009; ventriculography, DD = 21.7 +/- 0.9, ID + II = 25.3 +/- 0.8, p = 0.003). LV end-systolic and end-diastolic diameters were increased in patients with the DD genotype. Multifactor regression analysis showed the ACE genotype to be an independent predictor of both ejection fraction (echocardiography, p <0.02; ventriculography, p <0.03) and end-diastolic diameter (p <0.02). In conclusion, the results of this study indicate that the DD genotype of the ACE gene is independently associated with both a reduced LV systolic performance and an increased LV cavity size in patients with IDC.

Aged↗
PubMed1999

A comparison of people with and without nocturnal panic attacks.

This study examined differences in frequency and severity of diurnal panic attacks between patients with (n = 22) and without (n = 21) a history of nocturnal panic attacks. Subjects were assessed with a modified version of the SCID, and completed daily panic attack diaries, the Anxiety Sensitivity Index, and the Fear Questionnaire. No differences were found between the groups in the actual number of expected or unexpected diurnal panic attacks experienced. Subjects in the nocturnal panic group experienced significantly more symptoms during diurnal panic attacks than did the diurnal only group. More specifically, the nocturnal panic group experienced more symptoms during expected diurnal panic attacks, but not during unexpected/spontaneous diurnal panic attacks. A greater proportion of the nocturnal panic subjects reported "chest pain" during diurnal panic attacks and a trend toward greater "fear of dying". Otherwise, the two groups were very similar. Implications of the findings are discussed in relation to the findings of other recent studies of nocturnal panic.

Adult↗
PubMed1999

Neurotic butterflies in my stomach: the role of anxiety, anxiety sensitivity and depression in functional gastrointestinal disorders.

This study examined the prevalence of functional gastrointestinal (FGI) disorders, and the association between FGI disorders and measures of affective distress, among a sample of 127 university students. Subjects completed a questionnaire battery including Research Diagnostic Questions for Functional Gastrointestinal Disorders, the Beck Anxiety Inventory, the Anxiety Sensitivity Index, the Beck Depression Inventory, and a medical utilization questionnaire. FGI disorders were diagnosed in 51.2% of the sample. Functional dyspepsia (22.8%), dyschezia (20.5%), functional heartburn (19.7%), functional chest pain (18.1%), and globus (12.6%) were the most frequently diagnosed disorders. Participants experiencing globus, functional dyspepsia, or functional heartburn showed significant differences in terms of anxiety, anxiety sensitivity, depression, and/or physician visits, when compared with participants without these disorders. Our results suggest that FGI disorders are strikingly prevalent among young adults, and specific FGI disorders are associated with affective distress. Implications of the observed association between psychological factors and FGI disorders are discussed.

Adolescent↗
PubMed1999

Beyond pain: the role of fear and avoidance in chronicity.

The purpose of the present article is to provide unification to a number of somewhat disparate themes in the chronic pain and phobia literature. First, we present a summary review of the early writings and current theoretical perspectives regarding the role of avoidance in the maintenance of chronic pain. Second, we present an integrative review of recent empirical investigations of fear and avoidance in patients with chronic musculoskeletal pain, relating the findings to existing cognitive-behavioral theoretical positions. We also discuss several new and emerging lines of investigation, specifically related to information processing and anxiety sensitivity, which appear to be closely linked to pain-related avoidance behavior. Finally, we discuss the implications of the recent empirical findings for the assessment and treatment of individuals who experience disabling chronic musculoskeletal pain and suggest possible avenues for future investigation.

Adaptation, Psychological↗
PubMed1999

Sustained antihypertensive actions of a dual angiotensin-converting enzyme neutral endopeptidase inhibitor, sampatrilat, in black hypertensive subjects.

Our objective was to evaluate the safety and antihypertensive efficacy of sampatrilat, a novel dual inhibitor of both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in subjects poorly responsive to ACE inhibitor monotherapy. The ability of sampatrilat (50 to 100 mg daily) (n = 28) to lower blood pressure was compared with that of the ACE inhibitor lisinopril (10 to 20 mg daily) (n = 30) using a double-blind, randomized, parallel group study design over a 56-day treatment period in black hypertensives. Changes in systolic (SBP) and diastolic (DBP) blood pressure were determined using repeated ambulatory blood pressure (ABP) monitoring. Both sampatrilat and lisinopril decreased plasma ACE concentrations after 28 and 56 days. The decrease in plasma ACE concentrations (U/L) was greater after lisinopril (-9.33 +/- 0.52) as compared with sampatrilat (-6.31 +/- 0.70) (P = .0001) therapy. Lisinopril, but not sampatrilat, increased plasma renin activity. Lisinopril produced a transient decrease in mean 24-h ABP (mm Hg) at 28 days (SBP = -9.0 +/- 2.3, DBP = -5.7 +/- 1.3; P < .01), which returned to pretreatment values by 56 days of therapy. Alternatively, sampatrilat produced a sustained decrease in mean ABP over the 56-day treatment period (day 28: SBP = -7.3 +/- 1.8, DBP = -5.2 +/- 1.2; P < .01: day 56: SBP = -7.8 +/- 1.5; DBP = -5.2 +/- 0.95; P < 0.01) with a greater treatment effect on DBP than that of lisinopril at day 56 (P = .05). Treatment-emergent adverse events were noted to be similar between both treatment groups. We conclude that the antihypertensive actions of ACE/NEP inhibitor monotherapy in black subjects offers a novel therapeutic approach to patients otherwise resistant to the sustained antihypertensive actions of ACE inhibitor monotherapy.

Adult↗
PubMed1999

Validation of the coping with health, injuries, and problems scale in a chronic pain sample.

OBJECTIVE: The Coping with Health, Injuries, and Problems (CHIP) Scale is a self-report instrument that is designed for diverse patient populations to provide measures of emotion-focused (e.g., emotional preoccupation) and task-oriented (e.g., palliative, instrumental, distraction) responses to injury. The present investigation assessed the factor structure, reliability, and validity of the measure in patients (n = 203) with chronic musculoskeletal pain. METHOD: Patients were administered questionnaires, including the CHIP Scale, and measures of pain coping strategies, adjustment, and personality. RESULTS: The factor structure, with one exception, was replicable, and the subscale reliabilities were acceptable. The subscales related in predictable ways to other similar questionnaires, to pain adjustment, and to personality. CONCLUSION: Overall, the CHIP Scale is both reliable and valid in assessing responses to chronic pain. Researchers and clinicians who want to use a psychometrically sound measure of response to illness that is applicable across diverse patient populations are encouraged to consider this measure.

Adaptation, Psychological↗