PubMed Health⌕ Search

Biomedical subjects

H A Verheul

Publications and source records attributed to H A Verheul.

At least 19 recordsLinked to original sources
PubMed2001

Tibolone: a compound with tissue specific inhibitory effects on sulfatase.

The aim was to test whether sulfatase activity is differently regulated by tibolone in human bone, endometrium and breast cells since selective inhibition of sulfatases in various tissues may contribute to the tissue-specificity of tibolone. Tibolone, its 3 alpha- and 3 beta-hydroxy metabolites and their 3-sulfated forms, and its Delta(4)-isomer strongly (70-90%) inhibited the sulfatase activity in human breast cell lines (two T-47D clones) and intermediately (8-43%) in human endometrial cells (HEC-1A). In contrast, they did not inhibit sulfatase in two human osteoblast-like cell lines (MG 63, HOS TE-85). The specific sulfatase inhibitor, EMATE, showed inhibition in all cell lines. Just as estrone sulfate, 3 alpha-sulfated tibolone was also converted by sulfatase to the unconjugated 3 alpha-hydroxy-tibolone intracellularly in all cell lines. The tissue specific inhibition pattern of sulfatase activity by tibolone and its metabolites suggest that tibolone could be protective against development of mammary carcinomas, whereas it retains favorable estrogenic effects on bone.

Animals↗
PubMed2000

Effects of estrogens and hormone replacement therapy on breast cancer risk and on efficacy of breast cancer therapies.

This review summarises preclinical and clinical data on effects of endogenous and exogenous estrogens on probability of breast cancer diagnosis, and on the course and efficacy of breast cancer therapies. The data indicate that higher endogenous estrogen exposure (e.g. pregnancy, early menarche and late menopause, estrogen levels in future breast cancer patients, obesity) or exogenous estrogens (oral contraceptives; hormone replacement therapies) may be associated with an increased probability of breast cancer diagnosis. However, there is little evidence that estrogens have deleterious effects on the course of breast cancer. Moreover, increased incidence of breast cancer diagnosis after prolonged hormone replacement therapy (HRT) use seems to be associated with clinically less advanced disease. In studies assessing both diagnosis and mortality, HRT is frequently associated with reduced mortality compared to never users. The interaction of progestagens and estrogens on the probability of breast cancer diagnosis is complex and dependent on type of progestagens and regimens employed. Efficacy of current treatment modalities for breast cancer (surgery, irradiation, adjuvant therapy or chemotherapy) is not negatively influenced by estrogens at concentrations considerably higher than those attained with current HRT preparations. Although it cannot be excluded that estrogens increase the probability of breast cancer diagnosis, available data fail to demonstrate that, once breast cancer has been diagnosed, estrogens worsen prognosis, accelerate the course of the disease, reduce survival or interfere with the management of breast cancer. It may therefore be concluded that the prevalent opinion that estrogens and estrogen treatment are deleterious for breast cancer, needs to be revisited. However, results of ongoing prospective, randomised clinical trials with different HRT regimens in healthy women or breast cancer survivors are needed to provide more definite conclusions about risks and benefits of HRT.

Breast Neoplasms↗
PubMed1999

To operate or not on elderly patients with aortic stenosis: the decision and its consequences.

OBJECTIVE: To evaluate the application of guidelines in the decision making process leading to medical or surgical treatment for aortic stenosis in elderly patients. DESIGN: Cohort analysis based on a prospective inclusive registry. SETTING: 205 consecutive patients (>/= 70 years) with clinically relevant isolated aortic stenosis and without serious comorbidity, seen for the first time in the Doppler-echocardiographic laboratories of three university hospitals in the Netherlands. RESULTS: The initial choice was surgery in 94 patients and medical treatment in 111. Only 59% of the patients who should have had valve replacement according to the practice guidelines were actually offered surgical treatment. These were mainly symptomatic patients under 80 years of age with a high gradient. Operative mortality (30 days) was only 2%. The three year survival was 80% in the surgical group (17 deaths among 94 patients) and 49% in the medical group (43/111). Multivariate analysis showed that only patients with a high baseline risk, mainly determined by impaired left ventricular function, had a significantly better three year survival with surgical treatment than with medical treatment. CONCLUSIONS: In daily practice, elderly patients with clinically relevant symptomatic aortic stenosis are often denied surgical treatment. This study indicates that a surgical approach, especially where there is impaired systolic left ventricular function, is associated with better survival.

Age Factors↗
PubMed1998

[Quality assessment indicators of cardiac surgeons' work; the validity of mortality rates].

OBJECTIVE: To determine the possibility of comparing the mortality rates of patients operated by different heart surgeons with each other. DESIGN: Retrospective cohort study. SETTING: Academic Medical Centre, Amsterdam, the Netherlands. PATIENTS AND METHODS: Clinical information, operation data and follow-up data on 783 patients who had undergone cardiac valve replacement, were collected from the clinical records. Aortic valve replacement had been performed in 446 patients (1979-1986) and mitral valve replacement in 337 patients (1980-1990). RESULTS: The one-year mortality rate was higher among patients operated on by heart surgeon A than among patients operated on by the other heart surgeons from the same team, viz. 16.4% and 9.5%, respectively, an absolute difference of 6.9%. The 95% confidence interval of the difference was 1.7-12.9. However, it was also found that the risk profiles of these patients of surgeon A differed from those of the other patients. After multivariate correction for this difference in risk profile, the difference in mortality was no longer statistically significant. CONCLUSION: The differences in mortality observed in our study could not be attributed to difference in quality of the heart surgeons, but were related with the risk profiles of the patients operated by one of them. Thorough analysis with correction for risks is necessary for the assessment of the quality of care, if the conclusions are not to be misleading.

Adult↗
PubMed1995

Analysis of risk factors for excess mortality after aortic valve replacement.

OBJECTIVES: This study sought to identify risk factors for both late observed and late "excess" mortality after aortic valve replacement and to examine the causes of late mortality. BACKGROUND: Because operative mortality after aortic valve replacement is very low, the timing of surgical intervention should focus on maximizing long-term survival. However, to judge the effect of valve replacement on long-term survival in an elderly population, it is important to separate mortality resulting from extraneous causes (background mortality) from disease-related mortality (excess mortality). Background mortality can be estimated by calculating expected mortality on the basis of age and gender. METHODS: From 1966 to 1986, 643 patients (mean age 59.6 years, 138 [21%] > or = 70 years old) underwent aortic valve replacement, 129 of whom also underwent coronary bypass grafting; 594 patients survived > or = 30 days after the procedure. The overall operative mortality rate for isolated aortic valve replacement decreased over time from 25.5% (1966 to 1972) to 2.6% (1980 to 1986). Cumulative total follow-up after discharge was 3,603 patient-years. Multivariate analysis was performed for both observed and excess mortality. RESULTS: Risk factors for both observed and excess mortality were previous myocardial infarction, coronary artery disease, heart failure and atrial fibrillation. Although age > or = 70 years was a risk factor for observed mortality (hazard rate ratio [HRR] 2.4, 95% confidence interval [CI] 1.6 to 3.7), it was not a risk factor for excess mortality. In contrast, isolated aortic regurgitation was an important risk factor for excess mortality only (HRR 3.8, 95% CI 1.3 to 11.2). Late mortality was valve related in 22% of patients, including sudden death in 7% and cerebral vascular accidents in 7%. Congestive heart failure was an important cause of death (21%) irrespective of the time elapsed since aortic valve replacement. In patients with aortic regurgitation, congestive heart failure was the main cause of death (38%); in patients with aortic regurgitation and preoperative heart failure or severe left ventricular dysfunction, heart failure was the cause of death in 44% and 63%, respectively. CONCLUSIONS: Analysis of excess mortality revealed that older age in itself is not a risk factor for late mortality after aortic valve replacement. Aortic regurgitation carries a high risk, probably associated with left ventricular dysfunction at the time of operation. Earlier operation may be warranted in such patients.

Age Factors↗
PubMed1995

Effects of ethinylestradiol on the course of spontaneous autoimmune disease in NZB/W and NOD mice.

Sex hormones affect (auto)immune responses in various ways. Investigations of the effects of estrogens have produced contradictory results. We studied the effects of gender, gonadectomy and of (supra)physiological doses of (the orally active) ethinylestradiol (EE) in two spontaneous autoimmune disease models: the NZB/NZW F1 and NOD mice. In both models we confirmed the female preponderance and the aggravating effects of gonadectomy in males but not in females. The accelerated mortality found in NZB/W mice treated with supraphysiological doses of EE was not associated with increased proteinuria, increased IgG-type anti-DNA levels or increased mononuclear cell infiltrations in the submandibular gland. In contrast, we found a severe reduction in body weight and in the weights of various organs (indications of toxicity), and a decrease rather than an increase in proteinuria and in mononuclear cell infiltrations (indications for autoimmunity). Physiological doses of EE did not significantly affect disease symptoms. In the NOD model a near-physiological, non-toxic dose of EE did not cause consistent changes on immunological disease symptoms either. Therefore, we conclude that the sexual dichotomy in spontaneous autoimmune models is due to protective effects of androgens and that the mortality by estrogens is due to toxic effects rather than accelerated autoimmunity.

Animals↗
PubMed1993

Effects of changes in management of active infective endocarditis on outcome in a 25-year period.

The clinical outcome and long-term follow-up of 130 consecutive patients (141 episodes) with active infective endocarditis who were treated between 1966 and 1991 were analyzed. There was a shift toward a higher proportion of referred patients (39 to 78%), patients aged > 60 years (11 to 41%) and urgent surgical treatment (11 to 44%). Medical treatment was administered in 98 patients (70%); 30-day mortality was 27%. Surgery was performed in 43 patients (30%), with an operative mortality of 26%; 9 of 14 patients (64%) who underwent operation within the first week of admission died. Patients with severe heart failure are at the highest risk for early mortality (relative risk = 21.1; 95% confidence interval 7.4-60.3). Referred patients were much more often treated surgically than were nonreferred patients (48 versus 14%) and had a lower operative mortality (24 vs 30%). Nonreferred patients were more often treated medically (86 vs 52%) and with lower mortality (19 vs 39%). The total follow-up time was 730 patient-years; only 1 patient was considered lost to follow-up. The overall cumulative 5-year and 10-year survival after hospital discharge for patients after urgent surgery were 84 +/- 7% and 53 +/- 7%, respectively, and for those after medical treatment 84 +/- 5% and 77 +/- 6%, respectively. The probability of remaining free of late events (recurrent endocarditis, late valve replacement or death) during 5 and 10 years for patients after urgent surgery was 84 +/- 7% and 53 +/- 15%, respectively, and for those after medical treatment 59 +/- 6% and 40 +/- 7%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Background mortality in clinical survival studies.

In long-term follow-up studies of survival after an initial event (eg, an operation) mortality from causes other than the one under study obscures the results, especially in elderly patients. In the traditional approach to the calculation of expected mortality a fictitious cohort is drawn from the general population, being matched for age, sex, and calendar time at the time of the initial event. The membership of this cohort is then kept constant from the initial event until the closing date of the study. The survival and mortality of this static cohort is then compared with that of the dynamic patient cohort to throw light on mortality from extraneous causes. This method can lead to severe bias if there is a strong correlation between the duration of observation of the patients and their age. The analysis can be improved by applying rate adjustment when calculating the background component of mortality. In this approach mortality rates from the general population are adjusted (weighted) so that the age, sex, and calendar year are at all times identical with those of each of the patients still alive and under observation. This is illustrated by means of a simplified example and a real-life one from a study at survival after aortic valve replacement. Estimation of rate-adjusted background mortality provides a framework that may put long-term survival, especially of elderly patients, in proper perspective.

Adult↗
PubMed1992

Value of exercise Doppler echocardiography in patients with prosthetic or bioprosthetic cardiac valves.

Doppler echocardiographic evaluation of the prosthetic valve function is usually performed at rest, although this situation is not representative for patients' daily activities. Therefore, a symptom-limited Master 2-step test was performed in 61 asymptomatic patients with normal left ventricular function. No adequate Doppler signals were obtained in 5 of 61 patients (8%) within 60 second after termination of exercise. In patients with aortic valve prostheses (n = 24), heart rate increased from 74 +/- 10 to 105 +/- 18 beats/min, the maximal instantaneous gradient from 44 (range 22 to 90) to 68 (range 28 to 165) mm Hg (r = 0.89) and the mean gradient from 24 (range 12 to 50) to 39 (range 18 to 100) mm Hg (r = 0.90). In 6 of 11 patients with a maximal flow velocity ratio between the left ventricular outflow tract and the aortic valve prosthesis less than or equal to 0.25, the mean gradient increased to a value greater than or equal to 50 mm Hg after exercise, whereas in patients with a ratio of greater than or equal to 0.25, this never occurred. In patients with mitral valve prostheses (n = 39), heart rate increased from 80 +/- 12 to 116 +/- 14 beats/min and mean gradient from 6 (range 3 to 10) to 14 (range 6 to 25) mm Hg (r = 0.59). The correlation of the mean diastolic pressure gradient after exercise with pressure half-time was 0.66. Systolic pulmonary artery pressure at rest and after exercise could be determined in 22 of 39 patients (56%) and increased from 34 (range 20 to 70) to 57 (range 35 to 110) mm Hg. It is concluded that the response to exercise can, to a large extent, be inferred from Doppler parameters at rest, particularly in patients with aortic valve prostheses. The clinical implication of the high gradients found in some asymptomatic patients in the present study should be elucidated by follow-up studies.

Adolescent↗
PubMed1992

Aortic valve regurgitation and the congenitally bicuspid aortic valve: a clinico-pathological correlation.

OBJECTIVE: To investigate the morphology of congenitally bicuspid aortic valves causing pure valve regurgitation. DESIGN: A case series collected over five years. SETTING: An academic hospital. PATIENTS AND METHODS: One hundred and forty eight excised congenitally bicuspid aortic valves. The morphological findings were correlated with sex, age, clinical history, and data on haemodynamic function before operation. Pure valve regurgitation was defined as grade 3-4/4 with a gradient less than 30 mm Hg. Aortic root dilatation was evaluated angiographically or echocardiographically or both. RESULTS: Three types were recognised: valves that were purely bicuspid (23%), bicuspid valves with a raphe (34%), and valves with an additional indentation of the free edge of the conjoined cusp (43%). In 14 cases pure valve regurgitation was present. Dilatation of the aortic root was present in 47 cases. The relative risk for regurgitation when the aortic root was dilated (compared with no dilatation) was 3.99. The relative risk for valve regurgitation when there was indentation of the conjoined cusp (compared with no indentation) was 4.95. The mean age at operation in patients with pure regurgitation was 56 years, which is significantly younger (p = 0.0008) than that of patients with a congenitally bicuspid valve with combined valve stenosis and regurgitation (64.7 years). CONCLUSIONS: Congenitally bicuspid aortic valves with a central indentation of the free edge of the conjoined cusp seem particularly likely to develop pure aortic valve regurgitation.

Adult↗
PubMed1991

Late results of 200 repeat coronary artery bypass operations.

To determine the clinical outcome and the long-term results of a second coronary artery bypass operation, we studied preoperative clinical status and catheterization data in 200 consecutive patients over a 9-year period (1979 to 1987) (mean follow up time 34 months, maximum 120). The study group included 169 men and 31 women (mean age 58.4 years [7% greater than 70 years]). Sixty-four percent of patients had severe angina (New York Heart Association class IV), 70% had 3-vessel coronary artery disease and 21% had poor left ventricular function. Reoperation was performed after a mean interval of 58 months after the first procedure. A mean of 3.3 distal anastomoses was placed. The operative mortality rate (30 days) was 7.5%, with additional cardiac morbidity (myocardial infarction, heart failure) in 11.5% of patients. Multivariate analysis showed an increased risk in women (risk ratio 3.6) and in patients with poor left ventricular function (risk ratio 3.1). The cumulative 5-year survival rate was estimated at 84%, with a rate of 77% for patients with poor left ventricular function (difference not significant). The probability of remaining free of a cardiac-related event (myocardial infarction, angioplasty, third operation, cardiac death) was 64% for 5 years. At the end of follow-up, 79% of the surviving patients were in New York Heart Association class I or II and nearly 50% of patients in the fifth year after the reoperation had good functional status. It is concluded that a reoperation is effective but carries an increased, immediate, operative risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Artery Bypass↗
PubMed1990

Effects of gender and sex steroids on the immune response.

Elevated immune responses and the higher incidence of autoimmune diseases in female (compared to male) humans and animals have been known for a long time. However, the scientific interest in this interrelationship has been limited both amongst immunologists and endocrinologists. It is mainly in the last ten years that investigations in this area have been intensifying. A number of fairly recent review articles confirm the increased interest in various aspects of this "interdiscipline" [1-4]. In the present paper we should like to make a new assessment of the state of knowledge. We shall firstly discuss heteroimmune response differences between males and females in humans, rodents and birds and then the roles of gender and sex hormones in autoimmune disease in various species. The general conclusions are the following. Gender and sex hormones have a clear effect on various hetero- and auto-immune responses but the mechanisms of action are still unknown; starting from sex hormones, steroids can be devised which have favourable effects on immune processes but lack undesirable hormonal effects; such hormonomimetics should be, in principle, applicable for the treatment of autoimmune disease.

Animals↗
PubMed1989

Sex hormones and autoimmune disease.

Evidence for the influence of sex hormones--androgens, oestrogens and progestogens--on autoimmune disease is reviewed. Androgens and, perhaps, progestogens may protect from autoimmune disease; oestrogens seem to protect from rheumatoid arthritis but to be deleterious in systemic lupus erythematosus.

Androgens↗
PubMed1986

Effects of steroids with different endocrine profiles on the development, morphology and function of the bursa of Fabricius in chickens.

This paper describes the effect of various steroids on the anlage of the bursa of Fabricius in chickens. The steroids were administered by dipping embryonated eggs on the third day of incubation in ethanolic solutions of these steroids. The results with about 30 different steroids show that the capacity to inhibit the development of the bursa does not correlate with the endocrine properties of these steroids as measured in routine screening tests for androgenic, anabolic, progestational and oestrogenic activities or with the relative binding affinities for various endocrine receptors. More elaborate studies with several representative steroids show that testosterone (10 mg/ml), nandrolone (10 mg/ml), 11 alpha-hydroxynandrolone (10 mg/ml), ethylestrenol (1 mg/ml), lynestrenol (1 mg/ml), and Org OD14 [tibolone] (0.1 mg/ml) induce also histomorphological changes in the remaining bursa tissue still present in 10 day- and 53-day old chickens and in the bursa-dependent sites of their spleens (53-day old chickens only). Testosterone and lynestrenol induced smaller changes than nandrolone or ethylestrenol. Tibolone and 11 alpha-hydroxynandrolone were more effective than nandrolone. All drugs, except testosterone and lynestrenol, imparied antibody formation to Newcastle Disease Virus and decreased the serum levels of total IgG, but not of total IgM. Also these effects were not correlated with endocrine properties. In other studies (for references, see text) we found that several of these steroids, notably tibolone, favourably influence the course of spontaneous autoimmune diseases of NZB/W mice and Obese Strain chickens. Since this autoimmunosuppression is likely to be caused by inhibitory effects on bursa or bursa equivalent, we may use this approach for developing medically useful autoimmunosuppressive steroids with minimal endocrine effects.

Animals↗
PubMed1986

Effects of tibolone, lynestrenol, ethylestrenol, and desogestrel on autoimmune disorders in NZB/W mice.

The effects of two progestagens--lynestrenol, desogestrel--an anabolic steroid--ethylestrenol--and a compound with weak progestational, anabolic, androgenic, and estrogenic activities--tibolone--on the development of systemic lupus erythematosus and Sjögren's syndrome-like disorders were studied in the NZB/W mouse. All four compounds inhibited the expression of autoimmune disease. Tibolone was 10-40 times more potent--depending on the parameter used--in preventing symptoms of autoimmunity than the second most effective compound lynestrenol. Ethylestrenol was the third effective compound and desogestrel the least effective compound in this series. Combined with literature data, these results show that steroids with different endocrine profiles can prevent the development of autoimmunity in the NZB/W mice. Since the NZB/W mouse is a good animal model for human systemic lupus erythematosus and Sjögren's syndrome and since tibolone, lynestrenol, and ethylestrenol have endocrinological profiles which are not prohibitive for treatment of male and female patients, investigation whether these compounds have a value in the treatment of human autoimmune diseases seems warranted.

Anabolic Agents↗