Hofland, J.

Local Control of Steroid Hormone Biosynthesis (Doctoral Thesis)

2012-05-30T00:00:00Z

Steroids are essential for vertebrate physiology during pre- and postnatal life. Whereas the skeleton structure of cyclopenta[α]phenanthrene rings is common to all steroid molecules, differences occur in methyl- of ethylgroups attached to the four rings or the oxidation state of the carbon atoms in the rings (Figure 1).1 Endogenous production of steroids is realized in steroidogenic tissues. From these tissues, steroid molecules can be secreted into the circulation to act in an endocrine fashion. By binding to receptors in target tissues they manipulate gene transcription, influencing a wide variety of cellular functions. Steroids can also exert local effects in the steroidogenic tissues after secretion into the extracellular space (paracrine or autocrine) or directly within the cell in which they are produced (intracrine).

Inhibins and activins: Their roles in the adrenal gland and the development of adrenocortical tumors (Article)

2011-07-14T00:00:00Z

The adrenal gland is composed of two separate endocrine tissues that control a multitude of bodily functions in their adaptation to external and internal stressors through hormone secretion. The functions of the adrenal gland are regulated by circulating, neural and local factors that ensure proper cell growth and hormone production. Activins and inhibins are among the locally expressed growth factors affecting adrenal cell function. They have been found to influence several aspects of adrenal cell development, adrenocortical steroidogenesis, adrenocortical tumor formation and adrenomedullary cell differentiation. Especially the finding that inhibin α-subunit knockout mice develop adrenocortical carcinomas after gonadectomy has prompted research on the physiological and pathophysiological roles of activin and inhibin in the adrenal cortex. It is now clear that both peptides control adrenocortical physiology and are involved in adrenocortical tumorigenesis at multiple levels, both in murine models as well as in human patients.

Effect of remote ischemic conditioning on atrial fibrillation and outcome after coronary artery bypass grafting (RICO-trial) (Article)

2011-05-23T00:00:00Z

Background: Pre- and postconditioning describe mechanisms whereby short ischemic periods protect an organ against a longer period of ischemia. Interestingly, short ischemic periods of a limb, in itself harmless, may increase the ischemia tolerance of remote organs, e.g. the heart (remote conditioning, RC). Although several studies have shown reduced biomarker release by RC, a reduction of complications and improvement of patient outcome still has to be demonstrated. Atrial fibrillation (AF) is one of the most common complications after coronary artery bypass graft surgery (CABG), affecting 27-46% of patients. It is associated with increased mortality, adverse cardiovascular events, and prolonged in-hospital stay. We hypothesize that remote ischemic pre- and/or post-conditioning reduce the incidence of AF following CABG, and improve patient outcome.Methods/design: This study is a randomized, controlled, patient and investigator blinded multicenter trial. Elective CABG patients are randomized to one of the following four groups: 1) control, 2) remote ischemic preconditioning, 3) remote ischemic postconditioning, or 4) remote ischemic pre- and postconditioning. Remote conditioning is applied at the arm by 3 cycles of 5 minutes of ischemia and reperfusion. Primary endpoint is the incidence AF in the first 72 hours after surgery, detected using a Holter-monitor. Secondary endpoints include length-of-stay on the intensive care unit and in-hospital, and the occurrence of major adverse cardiovascular events at 30 days, 3 months and 1 year.Based on an expected incidence in the control group of 27%, 195 patients per group are needed to detect with 80% power a reduction by 45% following either pre- or postconditioning, while allowing for a 10% dropout and at an alpha of 0.05. With the combined intervention expected to be stronger, we need 75 patients in this group to detect a reduction in incidence of AF of 60%.Discussion: The RICO-trial (the effect of Remote Ischemic Conditioning on atrial fibrillation and Outcome) is a randomized controlled multicenter trial, designed to investigate whether remote ischemic pre- and/or post-conditioning of the arm reduce the incidence of AF following CABG surgery.Trial registration: ClinicalTrials.gov under NCT01107184.

Intraprostatic steroidogenic enzymes - Response (Letter To Editor)

2010-10-15T00:00:00Z

Steroidogenesis vs. steroid uptake in the heart: Do corticosteroids mediate effects via cardiac mineralocorticoid receptors? (Article)

2010-05-01T00:00:00Z

Objective: To test whether glucocorticoids act as the endogenous agonist of cardiac mineralocorticoid receptors, we evaluated the cardiac effects of aldosterone and corticosterone and cardiac steroidogenesis vs. steroid uptake from plasma. Methods and Results: Both corticosterone and aldosterone increased left ventricular pressure in the rat heart. Aldosterone decreased coronary flow, whereas corticosterone increased it. All corticosterone effects were blocked by the glucocorticoid receptor antagonist, RU486, and unaltered by the mineralocorticoid receptor antagonist, canrenoate, or the 11β- hydroxysteroid dehydrogenase (HSD11B)2 inhibitor, carbenoxolone. Unlike mineralocorticoid receptor blockade, RU486 did not ameliorate postischemia infarct size and arrhythmias. Corticosterone, when added to the perfusion buffer, rapidly accumulated at cardiac tissue sites, reaching steady-state levels that were identical to those in coronary effluent, independently of the presence of aldosterone, RU486 or canrenoate. After stopping the perfusion, cardiac corticosterone fully washed away with a half-life of less than 1 min. Measurements of steroid-synthesizing enzyme gene expression levels in human ventricular and atrial tissue pieces from heart-beating organ donors, patients with end-stage heart failure and hypertrophic cardiomyopathy patients revealed that under no condition, the human heart was capable of synthesizing aldosterone or cortisol de novo. Yet, expression of HSD11B1, HSD11B2, mineralocorticoid receptors and glucocorticoid receptors was found, and HSD11B2 and mineralocorticoid receptors were upregulated in pathological conditions. Moreover, aldosterone reduced cardiac inotropy in a Na+/K+/2Cl-cotransporter-dependent manner. Conclusion: Both cortisol/corticosterone and aldosterone accumulate in the cardiac interstitium. The presence of HSD11B2 and mineralocorticoid receptors/glucocorticoid receptors at cardiac tissue sites allows both steroids to exert their effects via separate mechanisms.

Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer (Article)

2010-02-01T00:00:00Z

Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC.

Alveolar recruitment strategy and PEEP improve oxygenation, dynamic compliance of respiratory system and end-expiratory lung volume in pediatric patients undergoing cardiac surgery for congenital heart disease (Article)

2009-12-01T00:00:00Z

Objective: Optimizing alveolar recruitment by alveolar recruitment strategy (ARS) and maintaining lung volume with adequate positive end-expiratory pressure (PEEP) allow preventing ventilator-induced lung injury (VILI). Knowing that PEEP has its most beneficial effects when dynamic compliance of respiratory system (Crs) is maximized, we hypothesize that the use of 8 cm H2O PEEP with ARS results in an increase in Crs and end-expiratory lung volume (EELV) compared to 8 cm H2O PEEP without ARS and to zero PEEP in pediatric patients undergoing cardiac surgery for congenital heart disease. Methods: Twenty consecutive children were studied. Three different ventilation strategies were applied to each patient in the following order: 0 cm H2O PEEP, 8 cm H2O PEEP without an ARS, and 8 cm H2O PEEP with a standardized ARS. At the end of each ventilation strategy, Crs, EELV, and arterial blood gases were measured. Results: EELV, Crs, and PaO2/FiO2ratio changed significantly (P < 0.001) with the application of 8 cm H2O + ARS. Mean PaCO2- PETCO2difference between 0 PEEP and 8 cm H2O PEEP + ARS was also significant (P < 0.05). Conclusion: An alveolar recruitment strategy with relative high PEEP significantly improves Crs, oxygenation, PaCO2- PETCO2difference, and EELV in pediatric patients undergoing cardiac surgery for congenital heart disease.

Intravenous fluid restriction after major abdominal surgery: A randomized blinded clinical trial (Article)

2009-07-07T00:00:00Z

Background: Intravenous (IV) fluid administration is an essential part of postoperative care. Some studies suggest that a restricted post-operative fluid regime reduces complications and postoperative hospital stay after surgery. We investigated the effects of postoperative fluid restriction in surgical patients undergoing major abdominal surgery. Methods: In a blinded randomized trial, 62 patients (ASA I-III) undergoing elective major abdominal surgical procedures in a university hospital were allocated either to a restricted (1.5 L/24 h) or a standard postoperative IV fluid regime (2.5 L/24 h). Primary endpoint was length of postoperative hospital stay (PHS). Secondary endpoints included postoperative complications and time to restore gastric functions. Results: After a 1-year inclusion period, an unplanned interim analysis was made because of many protocol violations due to patient deterioration. In the group with the restricted regime we found a significantly increased PHS (12.3 vs. 8.3 days; p = 0.049) and significantly more major complications: 12 in 30 (40%) vs. 5 in 32 (16%) patients (Absolute Risk Increase: 0.24 [95%CI: 0.03 to 0.46], i.e. a number needed to harm of 4 [95%CI: 2-33]). Therefore, the trial was stopped prematurely. Intention to treat analysis showed no differences in time to restore gastric functions between the groups. Conclusion: Restricted postoperative IV fluid management, as performed in this trial, in patients undergoing major abdominal surgery appears harmful as it is accompanied by an increased risk of major postoperative complications and a prolonged postoperative hospital stay.

Intraoperative transesophageal echocardiography is beneficial for hemodynamic stabilization during left ventricular assist device implantation in children (Article)

2009-04-01T00:00:00Z

Background: Mechanical circulatory support, with a left ventricular assist device (LVAD) is used in an increasing number of children for treatment of advanced heart failure as bridge-to-transplant. To date no data are available and no studies have defined the role of intraoperative transesophageal echocardiography (TEE) for hemodynamic stabilization during Centrimag Levitronix centrifugal pump implantation in children. Methods: Children with therapy resistant heart failure, undergoing LVAD implantation using Berlin Heart Excor pediatric cannula connected to a Levitronix Centrifumag pump, are intraoperatively monitored using an Oldelft micromultiplane TEE. Intraoperative TEE is specially used to monitor right ventricular (RV) and left ventricular (LV) function, correct position of the cannulas and response to pharmacological treatment. Results: In five consecutive patients RV function was assessed by TEE after starting LVAD Levitronix centrifugal pump. Initial RV failure presents with RV dilation and LV collapse. After titration of vasopressor and inotropic agents, RV contractility improved and thereby the filling of the LV. In one child, despite those measures the RV showed no improvement by TEE and a Levitronix right ventricular assist device to support the RV function was implanted as well. All patients could hemodynamically be stabilized before transport to the intensive care unit. Conclusion: The complex interaction of the RV and LV function and correct positioning of the cannula, during LVAD implantation in children with end-stage cardiac failure is improved by simultaneous visualization of cardiac performance of both ventricles and cannula positioning by means of intraoperative multiplane TEE.

Intraoperative real time three-dimensional transesophageal echocardiographic measurement of hemodynamic, anatomic and functional changes after aortic valve replacement (Article)

2009-01-01T00:00:00Z

The traditional intraoperative two-dimensional transesophageal echocardiography (2DTEE) has limitations in measuring left ventricular ejection fraction (LVEF) because measurements rely on geometric assumptions. The availability of online software and real time three-dimensional transesophageal echocardiography (RT3D-TEE) makes intraoperative LVEF measurements fast and easy. This is the first report of intraoperative measurement of LVEF and aortic valve area (AVA) by RT3-DTEE in a patient who received transcatheter-based transapical aortic valve implantation.

Usefulness of intraoperative real-time 3D transesophageal echocardiography in cardiac surgery (Article)

2008-11-01T00:00:00Z

Background: Recent advances in three-dimensional (3D) echocardiography allow to obtain real-time 3D transesophageal (RT3DTEE) images intraoperatively. Methods: Preoperative transthoral echocardiography (TTE) revealed: hypertrophic ventricular septum (TTE:19.3 mm), systolic anterior motion (SAM) not causing obstruction and malcoaptation of the anterior mitral valve leaflet (AMVL), and posterior mitral valve leaflet (PMVL) with severe mitral regurgitation. Results: Intraoperative TEE with a x7-2t MATRIX-array transducer (Philips, Andover, MA, USA) with a transducer frequency of x7-2 t mHz, connected to a iE33 (Philips), shows us that the main mechanism and site of regurgitation was an AMVL cleft. We also measured a 24.3-mm thickness of the ventricular septum and analyzing the 3D full volume acquisition revealed that there was no SAM. Conclusion: Intraoperative RT3DTEE permitted comprehensive 3D viewing of the mitral valve revealing the mechanism of mitral valve regurgitation, SAM, and the exact width of the hypertrophic ventricular septum.

Impaired sublingual microvascular perfusion during surgery with cardiopulmonary bypass: A pilot study (Article)

2008-07-01T00:00:00Z

Objective: Complications after cardiac surgery may involve multiple organ failure, which carries a high mortality. Development of multiple organ failure may be related to impaired microcirculatory perfusion as a result of systemic inflammation. Microcirculatory blood flow alterations have been associated with impaired outcome. We investigated whether these alterations occurred before, during, and after coronary artery bypass grafting. Methods: We observed 25 consecutive patients who underwent elective coronary artery bypass grafting with cardiopulmonary bypass. The sublingual microcirculation was investigated using side-stream dark-field imaging. Side-stream dark-field imaging was performed before (baseline), during, and after surgery. Microvascular blood flow was estimated with a semiquantitative microvascular flow index in small, medium, and large microvessels. Changes in microvascular flow were tested with Wilcoxon signed rank test. Results: Median microvascular flow index of medium blood vessels decreased after starting cardiopulmonary bypass relative to that after anesthetic induction (2.6, interquartile range 1.6-3.0, vs 3.0, interquartile range 2.8-3.0, P = .02). There was a trend toward decreased microvascular flow index of small and large vessels relative to baseline (P = .08 and P = .05, respectively). Decreases in microvascular flow index occurred irrespective of changes in systemic blood pressure. After each patient's return to the intensive care unit, microvascular flow index increased and normalized in all microvessels. Conclusion: For the first time, sublingual microvascular blood flow alterations have been observed during cardiopulmonary bypass-assisted coronary artery bypass grafting.

Intraoperative real time three-dimensional transesophageal echocardiographic evaluation of right atrial tumor (Article)

2008-07-01T00:00:00Z

Right atrial myxomas are uncommon heart tumors that can simulate nonspecific symptoms, such as fever, paroxysmal palpitations, chronic anemia, weight loss, and may escape timely diagnosis until the development of severe complications due to embolism. We present a patient with a history of palpitations. In search for the source of palpitations, a 2D transthoracic echocardiography was performed, showing a right atrial mass. Real time three-dimensional transesophageal echocardiography (RT3DTEE) was performed intraoperative and demonstrated very accurate information about the size and the morphology of the tumor. This is the first case report of a right atrial myxoma visualized intraoperatively by RT3DTEE.

Low molecular starch versus gelatin plasma expander during CPB: Does it make a difference? (Article)

2007-12-01T00:00:00Z

Background: Non-protein plasma expanders carry a risk of potentially severe allergic reactions. As prime for cardiopulmonary bypass, we routinely use a gelatin plasma expander. Plasma expanding during anesthesia is achieved with high molecular starch (200/0.5 kDalton) in combination with Ringer Lactate solution (RL) and in the Intensive Care Unit (ICU) with a low molecular starch (130/0.4 kDalton). We evaluated the feasibility of low molecular starch in combination with RL (group LMSRL) versus gelatin plasma expanding (group GPE) for priming CPB circuits in patients undergoing cardiac surgery in a randomized prospective trial. Methods: One hundred and eighty adults who underwent primary valve or coronary artery bypass graft (CABG) surgery were equally stratified into 3 series of 60 patients with the routinely used oxygenators; Capiox RX-25, CML Duo and Quadrox-D. Then they were randomised by drawing lots and allocated into the LMSRL or GPE groups. We compared hematocrit, hemoglobin, platelet count, activated clotting time (ACT), lactate and colloid osmotic pressure (COP), blood loss, transfusion need, urine production and ICU stay. In addition, we monitored the average trans-oxygenator fluid resistance (AFR) for each type of oxygenator. Results: The COP is significantly lower in the LMSRL group (20 mmHg ± 0.2 versus 18 mmHg ± 0.2, p < 0.0001); as was the total use of plasma expanders (3846 ml ± 98 versus 3059 ml ± 77, p <0.001). All other parameters were not significantly different. When comparing the observed AFR for the three types of oxygenators, a lower AFR in the LMSRL group (p < 0.02) was noted for the Capiox RX-25®. Conclusions: This study shows a lower need for plasma expanders in patients who receive only starch plasma expanders. Further, we noted a lower COP in the LMSRL group, but since the mean COP was > 17 ± 0.2 mmHg, this cannot be considered of clinical importance. In conclusion, our study result supports the use of low molecular starch as a good alternative choice for priming CPB.

Bloodless (liver) surgery? The anesthetist's view (Article)

2007-07-01T00:00:00Z

Background/Aims: An increasing amount of literature concerning blood conservation, restrictive transfusion strategies, pharmacological manipulation of the hemostatic and fibrinolytic systems, minimal invasive surgery, local hemostatic agents and guidelines for blood transfusion, is being published each year. Is 'bloodless (liver) surgery' or rather minimization of perioperative blood loss and transfusion requirement necessary? Methods: To answer this question, we studied key articles and checked cross-references with the support of PubMed and the Cochrane Database of systematic reviews. Results: At present there is still a need to reduce the use of blood. Pre-donation, set of transfusion triggers, (non-)pharmacological approaches to decrease surgical blood loss, hemodilution techniques, peri- and postoperative cell salvage and postoperative re-transfusion can contribute to the success of a bloodless (liver) surgery program. Conclusion: We conclude that a multidisciplinary effort has to be made through the entire chain, from the outpatient clinic through discharge from the hospital, with the utmost exertion of all team members in which surgeons play a key role in the adaptation of a bloodless (liver) surgery program to the specific needs of patients. Copyright

Expression of activin and inhibin subunits, receptors and binding proteins in human pheochromocytomas: A study based on mRNA analysis and immunohistochemistry (Article)

2007-03-01T00:00:00Z

Objective: Pheochromocytomas are uncommon tumours arising from chromaffin cells of the adrenal medulla and related paraganglia. So far, one of the few reported markers to discriminate malignant from benign tumours is the βB-subunit of inhibin and activin, members of the transforming growth factor (TGF)-β superfamily of growth and differentiation factors. Design: We investigated the expression of the mRNAs coding for activin and inhibin subunits, their receptors and binding proteins by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and studied the presence of the inhibin βB-subunit in human pheochromocytomas by immunohistochemistry. Patients: Samples from resected pheochromocytomas of patients operated between 1973 and 2003 were used for experiments. Results: The immunohistochemical investigations revealed that staining of the inhibin βB-subunit was positive in 12 of 36 (33%) benign and 5 of 34 (15%) malignant pheochromocytomas (P > 0.05). Therefore, it was not possible to discriminate between benign and malignant tumours solely on the basis of inhibin βB-subunit immunohistochemistry. Quantitative real-time RT-PCR in nine benign and four malignant tumours showed expression of inhibin α-, βA- and βB-subunits, the activin receptors Alk-4, ActRIIA, and ActRIIB, and the inhibin- and activin-binding proteins betaglycan and follistatin in all samples. No correlations were detected between individually coupled expression of mRNAs of these activin- and inhibin-related genes in the 13 pheochromocytomas. Only inhibin βA-subunit expression was different in malignant compared to benign pheochromocytomas (P = 0.020). Conclusions: No clear role for activin and inhibin was found in discriminating between benign and malignant pheochromocytomas.

Anaesthetic aspects of simultaneous aortocaval occlusion (Doctoral Thesis)

2003-09-19T00:00:00Z

Major elective surgery is known to contribute to intensive care occupancy, with a significant mortality rate. Routine preoperative optimisation of patients undergoing major elective surgery is found to give a significant and cost effective improvement in perioperative care. Criteria that were used to select patients for routine preoperative optimisation for a large randomised controlled trial are shown at Table 1. When performing major surgery, the extent of necessary perioperative monitoring is usually dependent on the view of the anaesthetist, while the site of postoperative care is dependent on the anticipated development of complications and the availability of intensive care or high dependency beds.

Cardiovascular effects of simultaneous occlusion of the inferior vena cava and aorta in patients treated with hypoxic abdominal perfusion for chemotherapy (Article)

2002-01-01T00:00:00Z

BACKGROUND: Animal studies suggest less cardiovascular disturbance if the aorta and vena cava are occluded simultaneously. We set out to establish the effects of simultaneous clamping in humans, because oncologists suggested that perfusion for chemotherapy could be done under local anaesthesia without invasive haemodynamic monitoring. METHODS: We studied the cardiovascular effects of the onset and removal of simultaneous occlusion of the thoracic aorta and inferior vena cava, in seven ASA II patients. Two stop-flow catheters positioned in the aorta and in the inferior vena cava were inflated to allow hypoxic abdominal perfusion to treat pancreatic cancer. We measured the arterial pressure, heart rate (HR), right atrial pressure (RAP), pulmonary artery pressure (PAP), pulmonary artery wedge pressure (PAWP) and cardiac output (CO), and calculated systemic vascular resistance index (SVRi), pulmonary vascular resistance index (PVRi), left ventricular stroke work index (LVSWi) and right ventricular stroke work index (RVSWi). Three patients were studied with transoesophageal echocardiography. RESULTS: Six patients needed intravenous nitroprusside during the occlusion because mean arterial pressure (MAP) increased to more than 20% of baseline (SVRi increased by 87%). One minute after occlusion release, all patients had a 50% decrease in MAP, and mPAP increased by 50%. The procedure had severe cardiovascular effects, shown by a 100% increase in cardiac index at occlusion release with increases in left and right ventricular stroke work indices of 75% and 147%. Left ventricular wall motion abnormalities were seen on transoesophageal echocardiography. CONCLUSIONS: Serious haemodynamic changes occur during simultaneous occlusion of the thoracic aorta and inferior vena cava, which may need invasive haemodynamic monitoring.

Xenon anaesthesia for laparoscopic cholecystectomy in a patient with Eisenmenger's syndrome (Article)

2001-01-01T00:00:00Z

There are few reports on anaesthesia for patients with Eisenmenger's syndrome requiring non-cardiac surgery and none of the use of xenon. We describe the use of xenon with a closed-circuit system in a patient with Eisenmenger's syndrome having a laparoscopic cholecystectomy.