Motivators of becoming and staying a neurosurgeon in the Netherlands: a survey and focus group.

OBJECTIVE: The aim of this study was to gain insight in motivators and demotivators of the Dutch neurosurgical residents and neurosurgeons. METHODS: A mixed method study was conducted. A survey was sent by the Dutch Neurosurgical Society to all Dutch neurosurgeons and residents in the framework of the yearly national quality conference. The focus groups were held during the Dutch national training days for neurosurgical residents. Baseline statistics were made of all survey data. Focus group recordings were transcribed verbatim and open coded in a constant comparative manner. RESULTS: The survey yielded a response rate of 47.3% of neurosurgeons and 72.5% of residents. 42.5% of residents participated in the focus groups. Overall, motivators according to residents and neurosurgeons were divided between autonomous and controlled motivation. For residents, the motivators to become a neurosurgeon were mostly patient-centered. Neurosurgeons had the same general motivators as residents. Around one-third of neurosurgeons considered ending their career as a neurosurgeon. Among residents, 9.5% considered quitting residency. Neurosurgeons and residents indicated that no time for their family life, increased administrative burden and non-patient-related tasks were reasons to consider leaving the profession. Also, less perceived respect from patients and society was a reason to consider ending their career as a neurosurgeon. CONCLUSION: Neurosurgeons and residents in neurosurgery are mostly motivated by intrinsic motivators. Factors such as administrative burden, less perceived respect from patients and society, and increase in non-patient-related tasks are large demotivators for both neurosurgeons and residents.

The diagnostic value of the pulsatility curve to predict shunt responsiveness in patients with idiopathic normal pressure hydrocephalus.

OBJECTIVE: The aim of this study was to investigate the diagnostic accuracy of the pulsatility curve to predict shunt response in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Lumbar cerebrospinal fluid dynamics were derived from an automatic lumbar infusion test (LIT) protocol. All patients were treated with ventriculoperitoneal shunting and re-examined 6 months after shunting. Patient demographics and outcomes were gathered in a prospective, electronic database that spanned from January 2012 to January 2020. A validated iNPH scale was used to assess patients preoperatively and 6 months postoperatively. The relationship of the relative pulse pressure coefficient (RPPC), delta amplitude, successful lowering of amplitude, and the pressure-value at a hypothetical amplitude of zero (P0), resistance to outflow (Rout), and outcome, were assessed using receiver operating characteristic (ROC) curves. RESULTS: We included 38 patients. The RPPC, delta amplitude, successful lowering of amplitude, and P0 parameters did not predict shunt response. Mean P0 was 0.5 (IQR 0.4-0.9) in improved patients and 0.4 (IQR 0-1.2) in non-improved patients. The delta amplitude was 0.16 kPa (IQR 0.10-0.23) in improved patients and 0.18 kPa (IQR 0.11-0.24) in non-improved patients. Furthermore, we found a technical failure rate of pulsatility curve measurements of 32%. CONCLUSION: Pulsatility curve results were not suitable in predicting shunt response in our cohort. The diagnostic value of LIT in case of normal pressure hydrocephalus should be subject to more rigorous research.

Pharyngo-cervicospinal fistula with destructive osteomyelitis after laryngopharyngectomy and radiotherapy, managed successfully with a vascularized fibula free flap.

Total laryngectomy is an operation mainly employed in recurrent laryngeal and hypopharyngeal carcinoma after previous radiotherapy. The most feared complication after this procedure is a pharyngocutaneous fistula. An extremely rare complication is the development of osteomyelitis of the cervical spine, which is associated with high rates of neurological impairment and epidural empyema, often requiring surgical treatment. This report describes the case of a patient with neck and shoulder pain and progressive motor weakness of the left deltoid and biceps muscle, caused by a pharyngo-cervicospinal fistula with spinal empyema. This condition resulted in destructive osteomyelitis of the cervical spine. A successful reconstruction of the cervical spine and neopharynx was performed using a free vascularized fibula bone and skin graft in a complex area because of previous treatments. It appears that no similar case has been described previously.

Assessing fatty acid oxidation flux in rodent cardiomyocyte models.

The healthy adult heart primarily relies on fatty acid oxidation (FAO) for energy production but instantaneously adapts its substrate preference in response to physiological or pathological challenges. Accurate FAO measurements are crucial to investigate early metabolic (mal)adaptations. While measurements in intact cardiomyocytes offer greater physiological relevance, current FAO protocols mainly employ cell-free systems and/or require expensive equipment. Here, we present an easy-to-use, inexpensive, and sensitive method to measure, compare and modulate FAO in various cardiomyocyte models. Basal FAO was 2-fold higher in fresh versus cultured adult rat cardiomyocytes (aRCM), while OXPHOS protein levels were maintained. Basal FAO was higher in cultured (3-fold) and fresh (8-fold) aRCM, versus widely used neonatal rat cardiomyocytes (nRCM) and mouse HL1 cardiomyocytes. Moreover, we utilized chemical and pharmacological treatments in order to modulate the FAO flux at different cellular signalling levels. Our data indicate that caution should be taken when studying metabolism in nRCM and HL1 cell models, as these display significantly lower FAO than aRCM. Accurate FAO measurement in cultured aRCM opens new avenues for studying the complex cardiomyocyte metabolic responses to mechanical, nutritional, pharmacological, and genetic manipulations.

The basic helix-loop-helix protein upstream stimulating factor regulates the cardiac ventricular myosin light-chain 2 gene via independent cis regulatory elements.

Previous studies have documented that 250 bp of the rat cardiac ventricular myosin light-chain 2 (MLC-2v) promoter is sufficient to confer cardiac muscle-specific expression on a luciferase reporter gene in both transgenic mice and primary cultured neonatal rat myocardial cells. Utilizing ligation-mediated PCR to perform in vivo dimethyl sulfate footprinting, the present study has identified protein-DNA interaction within the position from -176 to -165. This region, identified as MLE1, contains a core sequence, CACGTG, which conforms to the consensus E-box site and is identical to the upstream stimulating factor (USF)-binding site of the adenovirus major late promoter. Transient assays of luciferase reporter genes containing point mutations of the site demonstrate the importance of this cis regulatory element in the transcriptional activation of this cardiac muscle gene in ventricular muscle cells. The protein complex that occupies this site is capable of binding to HF-1a and PRE B sites which are known to be required for cardiac muscle-specific expression of rat MLC-2v and alpha-myosin heavy-chain genes, respectively. This study provides direct evidence that USF, a member of the basic helix-loop-helix leucine zipper family, binds to MLE1, HF-1a, and PRE B sites and suggests that it is a component of protein complexes that may coordinately control the expression of MLC-2v and alpha-myosin heavy-chain genes. The current study also provides evidence that USF can positively and negatively regulate the MLC-2v gene via independent cis regulatory elements.

A novel, tissue-restricted zinc finger protein (HF-1b) binds to the cardiac regulatory element (HF-1b/MEF-2) in the rat myosin light-chain 2 gene.

The AT-rich element MEF-2 plays an important role in the maintenance of the muscle-specific expression of a number of cardiac and skeletal muscle genes. In the MLC-2 gene, an AT-rich element (HF-1b) which contains a consensus MEF-2 site is required for cardiac tissue-specific expression. The present study reports the isolation and characterization of a cDNA which encodes a novel C2H2 zinc finger (HF-1b) that binds in a sequence-specific manner to the HF-1b/MEF-2 site in the MLC-2 promoter. A number of independent criteria suggest that this HF-1b zinc finger protein is a component of the endogenous HF-1b/MEF-2 binding activity in cardiac muscle cells and that it can serve as a transcriptional activator of the MLC-2 promoter in transient assays. These studies suggest that, in addition to the previously reported RSRF proteins, structurally divergent transcriptional factors can bind to MEF-2-like sites in muscle promoters. These results underscore the complexity of the regulation of the muscle gene program via these AT-rich elements in cardiac and skeletal muscle.

Release of fatty acid-binding protein from isolated rat heart subjected to ischemia and reperfusion or to the calcium paradox.

The release of cardiac fatty acid-binding protein (cFABP) and of fatty acids from isolated rat hearts was measured during both reperfusion following 60 min of ischemia and the calcium paradox (readmission of Ca2+ after a period of Ca2+-free perfusion). Total cFABP release was much more pronounced after Ca2+ readmission (over 50% of tissue content) than during post-ischemic reperfusion (on average, 3% of tissue content), but in both cases, it closely paralleled the release of lactate dehydrogenase. Only minor amounts of long-chain fatty acids, if any, were released from the heart. These observations are challenging the idea that cFABP plays a fatty acid-buffering role under the pathophysiological conditions studied.

Lactate-induced stimulation of myocardial triacylglycerol turnover.

The addition of lactate (5.6 mM) to a perfusion medium containing glucose (11 mM) stimulated the turnover of the cardiac triacylglycerol pool throughout the perfusion period as indicated by increased glycerol release in association with maintained levels of triacylglycerols. Attenuation of feedback inhibition of triacylglycerol lipase by fatty acids as a possible cause of the elevated triacylglycerol turnover rate should be ruled out, since tissue fatty acid levels were 3-times higher in glucose plus lactate perfused hearts than in hearts perfused with glucose as the sole substrate. The present findings are in favor of the notion that lactate enhances triacylglycerol turnover through increased glycerol 3-phosphate levels.

Hypoxia induces aortic hypertrophic growth, left ventricular dysfunction, and sympathetic hyperinnervation of peripheral arteries in the chick embryo.

BACKGROUND: Low birth weight is associated with an increased incidence of cardiovascular diseases, including hypertension, later in life. This suggests that antenatal insults program for fetal adaptations of the circulatory system. In the present study, we evaluated the effects of mild hypoxia on cardiac function, blood pressure control, and arterial structure and function in near-term chick embryos. METHODS AND RESULTS: Chick embryos were incubated under normoxic (21% O2) or hypoxic (15% O2) conditions and evaluated at incubation day 19 by use of histological techniques, isolated heart preparations, and in vivo measurements of sympathetic arterial tone and systemic hemodynamics. Chronic hypoxia caused a 33% increase in mortality and an 11% reduction in body weight in surviving embryos. The lumen of the ascending aorta in hypoxic embryos was 23% smaller. Left ventricular systolic pressure was 22% lower, and heart weight/body weight ratio was 14% higher. In resistance arteries of hypoxic embryos, in vivo baseline tone was 23% higher, norepinephrine sensitivity was similar, and norepinephrine release from sympathetic nerves increased 2-fold, indicating sympathetic hyperinnervation. Mean arterial pressure and heart rate were similar under resting conditions, but chronically hypoxic embryos failed to maintain blood pressure during acute stress. CONCLUSIONS: This study indicates that mild hypoxia during embryonic development induces alterations in cardiac and vascular function and structure and affects hemodynamic regulation. These findings reveal that antenatal insults have profound effects on the control and design of the circulatory system that are already established at birth and may program for hypertension and heart failure at a later age.

Cardiac fatty acid uptake and transport in health and disease.

Fatty acids are important energy donors for the healthy heart. These substrates are supplied to the myocardium bound to albumin to overcome their low solubility in aqueous solutions such as blood plasma. Transport from the microvascular compartment to the mitochondria inside the cardiomyocytes is most likely a combination of passive and protein-mediated diffusion. Alterations in tissue content of fatty acid-transport proteins may contribute to myocardial diseases such as the diabetic heart, and cardiac hypertrophy and failure.

Hunting down nucleic acid binding factors in the cardiovascular system.

Transcription regulation of genes active in the cardiovascular system is a complex process, involving DNA and RNA binding proteins. Nucleic acid binding proteins bind to the regulatory DNA and interact with other proteins, including RNA polymerase to initiate and control the level of transcription. The RNA binding proteins have a function in spliceosome formation and in stabilising mRNA. In this review the currently available molecular approaches to analyse regulatory DNA in relation to DNA binding proteins are discussed. Similar techniques that have been developed for RNA binding protein studies are included. In addition to an explanation of the various methods, examples are provided from DNA-protein interactions on genes active in the cardiovascular system, together with strategies for identification and characterisation of new nucleic acid binding proteins active in cardiac or vascular cell types.

Evaluation of the anterior mandibular donor site one year after secondary reconstruction of an alveolar cleft: 3-dimensional analysis using cone-beam computed tomography.

The aim of this study was to analyse changes in the volume of the chin after harvest of a bone graft for secondary reconstruction of an alveolar cleft. Cone-beam computed tomographic (CT) scans of 27 patients taken preoperatively, and immediately and one year postoperatively, were analysed, and 3-dimensional hard-tissue reconstructions made. The hard-tissue segmentation of the scan taken one year postoperatively was subtracted from the segmentation of the preoperative scan to calculate the alteration in the volume of bone at the donor site (chin). A centrally-orientated persistent concavity at the buccal side of the chin was found (mean (range) 160 (0-500) mm(3)). At the lingual side of the chin, a central concavity remained (mean (range) volume 20 (0-80) mm(3)). Remarkably, at the periphery of this concavity there was overgrowth of new bone (mean (range) volume 350 (0-1600) mm(3)). Re-attachment of the muscles of the tongue resulted in a significantly larger central lingual defect one year postoperatively (p=0.01). We also measured minor alterations in volume of the chin at one year. Whether these alterations influence facial appearance and long term bony quality is to be the subject of further research.

Transcription factors and the cardiac gene programme.

During the past decade, major advances have been made in uncovering the mechanisms that switch genes on and off. Gene methylation and histones play an important role in gene (in)activation. Following gene activation, the initiation of transcription by RNA polymerase requires the assembly of multiple protein complexes on the promoter region of a gene. How a cell type-specific gene expression pattern can be induced is a key question in cardiovascular biology today. Members of the helix-loop-helix-family of the transcription factors play a dominant role in skeletal muscle formation. In cardiac muscle the situation is less obvious. Recent studies identified muscle transcription factors like MEF-2, TEF-1 and MNF, which are common to both the skeletal and cardiac muscle lineages. A few transcription factors, among which Nkx 2.5 and GATA-4, are expressed predominantly in the heart. The absence of master regulators in the heart points to the importance of interaction between ubiquitous factors and tissue restricted factors to initiate the cardiac gene programme and to lock these cells in their differentiated state. The recent development of murine transgenic and gene-targeting technology provides tools to study the role of mammalian transcription factors in vivo. Interesting cardiac phenotypes are found in gene targeted mice, indicating a crucial role for retinoic acid and homeobox genes in murine cardiogenesis.

Accumulation of arachidonic acid in ischemic/reperfused cardiac tissue: possible causes and consequences.

Under physiological conditions, the content of unesterified arachidonic acid in cardiac tissue is very low. The bulk of arachidonic acid is present in the membrane phospholipid pool. Incorporation of arachidonic acid into phospholipids (reacylation) and liberation of this fatty acid from the phospholipid pool (deacylation) are controlled by a set of finely tuned enzymes, including lysophospholipid acyltransferase and phospholipase A2. At present, at least three subtypes of phospholipase A2 have been identified in cardiac structures, i.e., a low molecular mass group II phospholipase A2, a cytoplasmic high molecular mass phospholipase A2 and a plasmalogen-specific phospholipase A2. Cessation of flow to the heart (ischemia) gives rise to net degradation of membrane phospholipids accompanied by accumulation of fatty acids, including (unesterified) arachidonic acid. Restoration of flow to the previously ischemic cells results in a continued accumulation of fatty acids. The mechanism(s) underlying net phospholipid degradation in ischemic/reperfused myocardial tissue is (are) incompletely understood. Impaired reacylation, enhanced hydrolysis of phospholipids, or a combination of both may be responsible for the phenomena observed. Elevated tissue levels of arachidonic acid may exert both direct and indirect effects on the affected myocardium and healthy cardiac cells adjacent to the injured cardiomyocytes. Indirect effects might be evoked by arachidonic acid metabolites, i.e., eicosanoids. Arachidonic acid may directly influence ion channel activity, substrate metabolism and signal transduction, thereby affecting the functional characteristics of the ischemic/reperfused myocardium.

Long-term effects of fatty acids on cell viability and gene expression of neonatal cardiac myocytes.

Fatty acids are the most important source of energy for the adult heart. However, cardiac substrate preference changes during development and alters in pathophysiological states. Fatty acids have also been shown to be involved in signal transduction pathways, thereby affecting gene expression in various cell systems. In the present paper the significance of changes in substrate preference and the potential role of fatty acids in signal transduction in the cardiomyocyte are briefly reviewed. Furthermore, the development of a cellular model system, useful in exploring the long-term effects of fatty acids on the normal and hypertrophic cardiomyocyte, is described. Some aspects of this model system are illustrated by showing the effects of different fatty acid species on cell viability and the effects of fatty acids on the expression of heart type fatty acid-binding protein (H-FABP), a 15 kDa protein thought to be involved in intracellular trafficking of fatty acids. To this end primary cultures of rat neonatal ventricular myocytes were kept in defined medium containing various (combinations of) substrates for up to 48 h. First, the effects of prolonged exposure to different fatty acid species, complexed to BSA, on cell viability were investigated. Exposure of the cells to saturated fatty acids (C16:0 or C18:0), but not mono-unsaturated (C16:1 or C18:1) fatty acids, resulted in cell death, as evidenced by the release of intracellular proteins like lactate dehydrogenase. The detrimental effects of saturated fatty acids were nullified by the co-addition of mono-unsaturated fatty acids. Accordingly, the combination of C16:0/C18:1 was used to examine the effects of fatty acids on the expression of H-FABP. Therefore, the cells were incubated with either (i) glucose only, (ii) fatty acids only, or (iii) glucose plus fatty acids. Incubation with fatty acids (with or without glucose) resulted in a nearly four-fold increase of the H-FABP mRNA level. Similarly, at the protein level the cellular H-FABP/LDH ratio increased almost two-fold. In hypertrophic cardiomyocytes (stimulated with the alpha1-adrenergic agonist phenylephrine) the stimulatory effect of fatty acids on H-FABP expression was mitigated. These findings strongly suggest that fatty acids are able to modulate gene expression in the context of the cardiac muscle cell.

The effect of diltiazem on myocardial recovery after regional ischemia in dogs.

The effect of diltiazem on post-ischemic metabolic and functional recovery was investigated in regionally ischemic dog hearts. The duration of ischemia was 60 min, followed by 60 min of reperfusion. Diltiazem (bolus injection of 0.1 mg X kg-1 body weight prior to ischemia, followed by a continuous infusion of 0.1 mg X kg-1 X h-1) had no effect on residual coronary flow in the centre of the ischemic area, but blunted the reactive hyperemia response after restoration of flow. The drug partially prevented the depletion of ATP and glycogen in the severely underperfused subendocardial layers, i.e. when residual flow was below 0.1 ml X min-1 X g-1. Reduction of the content of these substances in the subepicardial layers was moderate and not influenced by diltiazem. Segment shortening in the subepicardial layers disappeared whereas segment lengthening was observed in the subendocardial layers during the ischemic period. Diltiazem did not prevent the loss of contractile function. Despite an initial restoration of contractile function within 10 min after reperfusion, no significant beneficial effect of diltiazem treatment on mechanical function of the reperfused area was present thereafter.

Mechanoperception and mechanotransduction in cardiac adaptation: mechanical and molecular aspects.

Cardiomyocytes grow in hypertrophy due to a net increase in the synthesis of proteins, especially contractile proteins, in the cell. There is abundant information about the molecular and biochemical changes involved in this process, but it is not completely understood how cells sense mechanical stimuli and how these stimuli are transferred into a biochemical signal inducing the growth response. This mechanotransduction most likely takes place at the cellular membrane. The resulting signal is transferred to the nucleus, where it can initiate alterations in gene expression.

A microcomputer system for haemodynamic measurements in isolated, working rat hearts.

This study describes the application of an Apple IIe microcomputer in combination with a pre-processor in the on-line calculation of haemodynamic variables of the isolated working rat heart and of relative rapid changes in these variables, induced by variations in left atrial filling pressure (preload) and end-diastolic aortic pressure (afterload). Variables such as heart rate, systolic and diastolic left ventricular pressure, the maximal positive and negative first derivative of the left ventricular pressure, systolic and diastolic aortic pressure and aortic flow were continuously calculated and printed at minimal intervals of 6 s. A newly designed procedure to detect the activation of the electrogram, which was necessary to start the detection of a new cardiac cycle, is described.

Fatty acids and cardiac disease: fuel carrying a message.

From the viewpoint of the prevention of cardiovascular disease (CVD) burden, there has been a continuous interest in the detrimental effects of the Western-type high-fat diet for more than half a century. More recently, this general view has been subject to change as epidemiological studies showed that replacing fat by carbohydrate may even be worse and that various polyunsaturated fatty acids (FA) have beneficial rather than detrimental effects on CVD outcome. At the same time, advances in lipid biology have provided insight into the mechanisms by which the different lipid components of the Western diet affect the cardiovascular system. In fact, this still is a rapidly growing field of research and in recent years novel FA derivatives and FA receptors have been discovered. This includes fish-oil derived FA-derivatives with anti-inflammatory properties, the so-called resolvins, and various G-protein-coupled receptors that recognize FA as ligands. In the present review, we will extensively discuss the role of FA and their metabolites on cardiac disease, with special emphasis on the role of the different saturated and polyunsaturated FA and their respective metabolites in cellular signal transduction and the possible implications for the development of cardiac hypertrophy and cardiac failure.