Coronary CT angiography for suspected acute coronary syndrome: sex-associated differences.

AIM: The optimal diagnostic test in the work-up of suspected acute coronary syndrome (ACS) may differ between men and women. The aim of this study was to compare sex-associated differences between using a diagnostic strategy including early coronary computed tomography angiography (CCTA) and standard of care (SOC). METHODS: In total, 500 patients who presented with symptoms suggestive of ACS at the emergency department were randomised between a diagnostic strategy supplemented with early CCTA and SOC. RESULTS: Women were generally older than men (mean ± standard deviation 56 ± 10 vs 53 ± 10 years, p < 0.01) and were less often admitted to hospital (33% vs 44%, p = 0.02). Obstructive coronary artery disease on CCTA (> 50% luminal narrowing) was less frequently seen in women (14% vs 26%, p = 0.02), and ACS was diagnosed less often in women (5% vs 10%, p = 0.03). Women underwent less outpatient testing when early CCTA was used in the emergency department evaluation of suspected ACS (p = 0.008). CONCLUSION: Women had a lower incidence of obstructive CAD on CCTA and were less often admitted to hospital than men. They were subjected to less outpatient testing when early CCTA was used in the emergency department evaluation of suspected ACS.

Serial high-sensitivity cardiac troponin T measurements to rule out acute myocardial infarction and a single high baseline measurement for swift rule-in: A systematic review and meta-analysis.

AIMS: The purpose of this study was to determine (a) the ability of serial high-sensitivity cardiac troponin T measurements to rule out acute myocardial infarction and (b) the ability of a single high baseline high-sensitivity cardiac troponin T measurement to rule in acute myocardial infarction in patients presenting to the emergency department with acute chest pain. METHODS AND RESULTS: Embase, Medline, Cochrane, Web of Science and Google scholar were searched for prospective cohort studies that evaluated parameters of diagnostic accuracy of serial high-sensitivity cardiac troponin T to rule out acute myocardial infarction and a single baseline high-sensitivity cardiac troponin T value>50 ng/l to rule in acute myocardial infarction. The search yielded 21 studies for the systematic review, of which 14 were included in the meta-analysis, with a total of 11,929 patients and an overall prevalence of acute myocardial infarction of 13.0%. For rule-out, six studies presented the sensitivity of serial measurements <14 ng/l. This cut-off classified 60.1% of patients as rule-out and the summary sensitivity was 96.7% (95% confidence interval: 92.3-99.3). Three studies presented the sensitivity of a one-hour algorithm with a baseline high-sensitivity cardiac troponin T value<12 ng/l and delta 1 hour <3 ng/l. This algorithm classified 60.2% of patients as rule-out and the summary sensitivity was 98.9% (96.4-100). For rule-in, six studies reported the specificity of baseline high-sensitivity cardiac troponin T value>50 ng/l. The summary specificity was 94.6% (91.5-97.1). CONCLUSION: Serial high-sensitivity cardiac troponin T measurement strategies to rule out acute myocardial infarction perform well, and a single baseline high-sensitivity cardiac troponin T value>50 ng/l to rule in acute myocardial infarction has a high specificity.

[New drugs; exenatide and sitagliptin]. / Nieuwe geneesmiddelen; exenatide en sitagliptine.

Incretin hormones, secreted upon food intake, play an important role in the regulation of blood glucose levels. In type 2 diabetes mellitus, the incretin response is decreased. Substitution of incretin is a novel pharmacological target which restores postprandial glucose homeostasis. Exenatide is a mimetic of the incretin glucagon-like peptide-I (GLP-I). Sitagliptin is an inhibitor of the enzyme dipeptidyl peptidase 4 (DPP-4), which breaks down GLP-I. Both drugs increase the GLP-I concentration, thereby improving insulin secretion from pancreatic p cells, restoring glycaemic control, preventing beta cell destruction, delaying gastric emptying, and reducing food intake.

[New drugs; natalizumab]. / Nieuwe geneesmiddelen; natalizumab.

The drug natalizumab represents a new pharmacological approach in the treatment ofvery active relapsing-remitting multiple sclerosis (MS). It is a humanised murine monoclonal antibody and binds to an integrin on the surface oflymphocytes, thereby preventing them from transmigrating across the endothelium and causing inflammation in the nervous tissue. The drug has been shown to decrease the occurrence of relapses and progression of MS. A few severe adverse effects (such as the viral progressive multifocal leuko-encephalopathy) have been reported, and its clinical and long-term effects are not fully known at present. Therefore, further research is required to determine the role of natalizumab in clinical practice.

[New drugs; pegaptanib and ranibizumab]. / Nieuwe geneesmiddelen; pegaptanib en ranibizumab.

The neovascular ('wet') form of age-related macular degeneration (AMD) is characterized by vascular growth and leakage in the retina. Two new drugs, pegaptanib and ranibizumab, have been shown to improve vision or slow the progression of AMD. Both drugs inhibit the action of vascular endothelial growth factor--pegaptanib as an oligonucleotide and ranibizumab as a monoclonal antibody--thereby decreasing angiogenesis in the eye. Adverse effects are associated with the intravitreal administration of both drugs and include increased intraocular pressure, local bleeding, and infection.

[New drugs; rimonabant]. / Nieuwe geneesmiddelen; rimonabant.

The endocannabinoid system controls the regulation of food intake and appetite in the brain and lipogenesis in adipose tissue. Rimonabant belongs to the new drug class of cannabinoid-1 receptor antagonists. It can decrease appetite and food intake and thus stimulate weight loss. Rimonabant is indicated for severe obesity and as an adjunct to lifestyle modifications for obese patients with type 2 diabetes or hyperlipidaemia. Safety concerns limit the clinical applicability of the drug. The drug has not been approved in the US due to its neurological and psychiatric adverse effects. Rimonabant is approved in Europe but is contraindicated in patients with major depression and those taking antidepressants.

[New drugs; varenicline]. / Nieuwe geneesmiddelen; varenicline.

Nicotine acts in the brain by releasing dopamine in the mesolimbic pathway which results in a reward effect and in dependence when used chronically. The effect of nicotine is mediated via nicotinergic acetylcholine receptors of the alpha4beta2 subtype ofwhich varenicline is a partial agonist. Varenicline can be used for quitting smoking because of two mechanisms: it acts as a partial agonist and thus reduces the symptoms of craving when quitting smoking, and it has antagonistic actions by binding the receptor instead of nicotine and therefore decreases the reward effect of nicotine. The most important side effects of varenicline are nausea, vomiting and headache. After one year, 22% of the treated group continued to abstain from smoking.

[New drugs; daptomycin]. / Nieuwe geneesmiddelen; daptomycine.

Being a cyclic lipopeptide, daptomycin belongs to a new class of antibiotics. It acts by forming a pore in the bacterial membrane thus causing leakage of potassium and subsequent depolarization and arrest of cell function. Daptomycin has a bactericidal action on Gram-positive bacteria and is registered for the treatment of adults with complicated skin and soft tissue infections caused by Gram-positive microorganisms. There is limited experience with treatment of Staphylococcus aureus bacteraemia. Its main adverse effects include gastrointestinal symptoms, skin reactions at the site of infusion, and raised serum creatine kinase.

[New drugs; sunitinib and sorafenib]. / Nieuwe geneesmiddelen; sunitinib en sorafenib.

Sunitinib and sorafenib are both indicated for the treatment of advanced kidney carcinoma of the 'clear cell' type after failure of, or resistance to, other treatments. Both drugs inhibit the tyrosine-kinase activity of a number of growth factor receptors; sorafenib has an additional inhibitory effect on serine/threonine-kinase activity. This mechanism decreases signal transduction and results in an inhibition of tumour cell growth and angiogenesis. The adverse effects of the two drugs are different: sunitinib causes mainly fatigue and gastrointestinal discomfort, whereas sorafenib's most frequent adverse effects are diarrhoea, rash, the palmar-plantar erythrodysaesthesia syndrome, and hypertension.

[New medications; erlotinib]. / Nieuwe geneesmiddelen; erlotinib.

Erlotinib inhibits the phosphorylation of the epidermal growth-factor receptor (EGFR/HERI), a tyrosinekinase protein. This results in an inhibition of signal transduction and therefore decreased cell division and increased cell death. The agent is indicated for the treatment of patients with advanced local or metastasised non-small-cell pulmonary carcinoma after other cytostatic therapy has failed.

[New drugs; palifermin]. / Nieuwe geneesmiddelen; palifermine.

Palifermin is a human keratinocyte growth factor that is produced in Escherichia coli by recombinant-DNA-technology. This substance protects against oral mucositis in adults undergoing myeloablative therapy. The safety of this product--being a growth factor --in the long term has not yet been shown. Adverse effects may occur in the skin and mucous membranes.

[New drugs; omalizumab]. / Nieuwe geneesmiddelen; omalizumab.

Omalizumab is a humanised monoclonal antibody that binds to circulating IgE, inhibiting its binding to the surface of mast cells and basophilic granulocytes. This prevents the release of pro-inflammatory mediators that produce an allergic response. This targeted mechanism of action provides a novel therapeutic approach for the treatment of patients with severe persistent, therapy-resistant allergic asthma. Omalizumab is administered subcutaneously in addition to other anti-asthma therapy. Until recently, the most important side effects are skin reactions at the site of administration and headache. Prospective data on additional long-term side effects are still being collected.

[Integration of training in pharmacology and pharmacotherapy in the medical curriculum in Leiden, the Netherlands]. / Integratie van onderwijs in farmacologie en farmacotherapie in het geneeskundecurriculum in Leiden.

In the new medical curriculum at Leiden University Medical Centre, the Netherlands, two aspects of the training in pharmacology and pharmacotherapy--the acquisition of knowledge and its application--have been integrated. On the basis of the approved subject matter and goals, four computer programmes were developed: the Teaching Resource Centre (TRC) Pharmacology database, the interactive TRC teaching programme, the Individual Therapy: Evaluation and Plan (ITEP), and the relational curriculum database. Together, these programmes provide the necessary knowledge in pharmacodynamics and pharmacokinetics, pharmacotherapy and the mechanisms of drug action, as well as possibilities for monitoring the educational process. The figures are created with the aid of a symbolic language, assuring a uniform presentation of all the information throughout the curriculum. Attention is also paid to the integration of these aspects with other subjects in the medical curriculum. Implementation of the teaching system in pharmacology was started at the beginning of 2001. Currently, the TRC database contains almost all the subject matter that is planned to be included. The next step in the process will be the assessment of both the knowledge and its application. TRC Pharmacology is a new method of integrating basic knowledge of pharmacology and pharmacotherapy in a medical school curriculum.

Evolutionary development of three gonadotropin-releasing hormone (GnRH) systems in vertebrates.

Gonadotropin-releasing hormone (GnRH) is the neuropeptide that links the brain to the reproductive system. Most vertebrate species express two forms of GnRH, which differ in amino acid sequence, localization, distribution, and embryological origin. The GnRH system in the ventral forebrain produces a species-specific GnRH form and projects toward the gonadotropic cell in the pituitary. The GnRH neurons of this system originate from the olfactory placode and migrate into the brain during early development. The other GnRH system is localized in a nucleus in the midbrain, where large cells express chicken-GnRH-II, of which the function is still unclear. In modern teleosts, a third GnRH system is present in the terminal nerve, which contains salmon GnRH. The three GnRH systems appear at different times during fish evolution. Besides the two accepted lineages in GnRH evolution (of conserved chicken GnRH-II in the midbrain and of mammalian GnRH or species-specific GnRH in the hypophysiotropic system), we propose a third lineage: of salmon GnRH in the terminal nerve.

Development of three distinct GnRH neuron populations expressing two different GnRH forms in the brain of the African catfish (Clarias gariepinus).

The early development of both the catfish gonadotropin-releasing hormone (cfGnRH)- and the chicken GnRH-II (cGnRH-II) system was investigated in African catfish by immunocytochemistry by using antibodies against the GnRH-associated peptide (GAP) of the respective preprohormones. Weakly cfGnRH-immunoreactive (ir) neurons and fibers were present at 2 weeks after hatching (ph) but only in the ventral telencephalon and pituitary. Two weeks later, cfGnRH fibers and neurons were also observed in more rostral and in more caudal brain areas, mainly in the preoptic area and hypothalamus. Based on differences in temporal, spatial, and morphologic appearance, two distinct cfGnRH populations were identified in the ventral forebrain: a population innervating the pituitary (ventral forebrain system) and a so-called terminal nerve (TN) population. DiI tracing studies revealed that the TN population has no neuronal connections with the pituitary. The cGnRH-II system is present from 2 weeks ph onward in the midbrain tegmentum and only their size and staining intensity increased during development. Based on the comparison of GnRH systems amongst vertebrates, we hypothesize that during fish evolution, three different GnRH systems evolved, each expressing their own molecular form: the cGnRH-II system in the midbrain, a hypophysiotropic GnRH system in the hypothalamus with a species-specific GnRH form, and a salmon GnRH-expressing TN population. This hypothesis is supported by phylogenetic analysis of known GnRH precursor amino acid sequences. We hypothesize, because the African catfish is a less advanced teleost species, that it contains the cfGnRH form both in the ventral forebrain system and in the TN population.

Gonadal steroids and the maturation of the species-specific gonadotropin-releasing hormone system in brain and pituitary of the male African catfish (Clarias gariepinus).

The effect of testosterone (T), 11-ketotestosterone (KT) and estradiol (E(2)) on the development of the catfish gonadotropin-releasing hormone system (cfGnRH) of male African catfish (Clarias gariepinus), at the onset of puberty [between 10 and 12 weeks post hatching (ph)] was investigated. The cfGnRH neurons, located in the ventral forebrain, were visualized by immunofluorescence and their numbers were determined and the amounts of cfGnRH-associated peptide (cfGAP) in the pituitary were measured by RIA. Steroid treatments did not significantly alter the numbers of immunoreactive GnRH neurons. However, T and E(2) caused an increase in the amount of GnRH, demonstrated by the intensity of the immunostaining of GnRH neurons and fibers in the brain and the amount of cfGAP in the pituitary. Treatment with KT, the main circulating androgen in adult male catfish, neither changed the number of cfGnRH neurons, nor elevated the cfGnRH content in the pituitary. In previous experiments with younger, prepubertal fish (2-6 weeks ph), T caused an elevation of the number of cfGnRH neurons to the same level as present in pubertal fish of 12-14 weeks. We conclude that the onset of puberty in the male African catfish coincides with the completion of the steroid-dependent structural maturation of the cfGnRH system in the brain. T and/or E(2), however, are still able to exert a positive influence on the amounts of cfGnRH during the later stages of pubertal development, thus still playing a role in the control of the cfGnRH system.

When to stress patients after coronary artery bypass surgery? Risk stratification in patients early and late post-CABG using stress myocardial perfusion SPECT: implications of appropriate clinical strategies.

OBJECTIVES: The study compared the prognostic significance of myocardial perfusion single-photon emission computed tomography (SPECT) (MPS) in patients early and late after coronary artery bypass graft surgery (CABG). BACKGROUND: The long-term effectiveness of CABG is limited by graft stenosis. The greatest incidence of graft occlusion occurs between five and eight years after surgery. However, little is known regarding the appropriate time to stress patients post-CABG with respect to risk stratification. METHODS: We identified 1,765 patients, who underwent MPS 7.1 +/- 5.0 years post-CABG. All patients underwent rest T1-201/stress Tc-99m sestamibi MPS and were followed up > or =1 year after testing. Patients with early CABG or PTCA (<60 days after MPS) were censored. The prognostic population consisted of 1,544 patients. A semiquantitative visual analysis employing a 20-segment model was used to define summed stress score (SSS), summed rest score (SRS), summed difference score (SDS), and the number of nonreversible segments (NRS). RESULTS: During follow-up, 53 cardiac deaths (CD) occurred. There was a significant increase in annual CD rates as a function of SSS. A multivariate analysis identified age, ischemia (SDS), and infarct size (NRS) as independent predictors of CD. Nuclear variables added incremental value to prescan information. The annual CD rate was relatively low (1.3%) in patients < or =5 years post-CABG. In this subgroup only age and infarct size (NRS) were predictive of CD. CONCLUSION: MPS is strongly predictive of subsequent CD in post-CABG patients and adds incremental value over clinical and treadmill test information. Our data suggest that symptomatic patients < or =5 years and all patients >5 years post-CABG may benefit from testing.

Gonadotropin-releasing hormone fibers innervate the pituitary of the male African catfish (Clarias gariepinus) during puberty.

The development of the catfish gonadotropin-releasing hormone (cfGnRH) fiber network in the pituitary of male African catfish (Clarias gariepinus) was investigated in relation to puberty. Double immunolabeling studied by confocal laser scanning microscopy revealed a concomitant development of gonadotropes and of pituitary cfGnRH innervation during the first wave of spermatogenesis. Catfish GnRH-immunoreactive fibers in the proximal pars distalis (PPD) of the pituitary were initially observed at the age of 10 weeks (onset of spermatogonial proliferation) and gradually reached the adult pattern at the age of 20 weeks (spermatozoa present in the testis). The content of cfGnRH-associated peptide (cfGAP, part of the prohormone) in the pituitary similarly increased during puberty. At the electron microscopical level, fibers containing cfGAP-ir granules came into close proximity of the gonadotropes at 18 weeks of age. In vitro studies indicated a progressively increasing basal and cfGnRH-stimulated luteinizing hormone (LH) secretion during pubertal development. The LH secretion patterns were similar in response to exogenous cfGnRH (0.1 microM) or to endogenous cfGnRH, the release of which was induced by forskolin (1 microM). Castration experiments demonstrated that the innervation of the pituitary with cfGnRH fibers continued after surgery, accompanied by an increase in the cfGAP levels. However, gonadotrope development was retarded, suggesting a differential regulation of the two maturational processes. Since testosterone stimulates both processes, other testicular factors may also be involved. Puberty-associated changes in LH release patterns appear to reflect changes in the GnRH sensitivity and in the pool of releasable LH, while availability of cfGnRH does not appear to be a limiting factor.

Testosterone accelerates the development of the catfish GnRH system in the brain of immature African catfish (Clarias gariepinus).

The effects of two endogenous steroids on the maturation of the catfish GnRH and the chicken GnRH-II system in the African catfish were investigated. Immature fish (2 weeks of age, which is before sexual differentiation; thus male and female genotypes present) were fed with food pellets containing either testosterone (T), 11beta-hydroxyandrostenedione (OHA) or no steroid (control). After 2 and 4 weeks of treatment, the effects on the two GnRH systems were investigated immunocytochemically, using specific antibodies against the respective GnRH-associated peptides. By means of fluorescence microscopy the number of GnRH perikarya and the cell surfaces were determined. Confocal laser scanning microscopy was applied to verify spatial distribution and staining intensity. After 2 weeks of treatment no difference in any of the parameters between the groups was observed. However, 4 weeks T treatment resulted in significantly more cfGnRH-ir perikarya in the brain compared to the OHA and control groups. In addition, in the T group the number of immunoreactive fibers was markedly higher and the staining of the perikarya and axons was more intense. The distribution of cfGnRH-ir neurons over the ventral forebrain differed between the two age groups: in 4-week-old fish, the largest concentration of neurons was localized in the ventral telencephalon, while 2 weeks later the number of neurons in the supraoptic area had markedly increased, suggesting that the cfGnRH system is still undergoing developmental changes during this period. In 6-week-old fish the average volume of the cfGnRH perikarya (expressed as surface size in the microscopical sections) in both the OHA and the T group was significantly bigger than that in the control group. The cGnRH-II-ir neurons in the midbrain tegmentum showed strong immunoreactivity in all groups, both treated and nontreated. In contrast to the cfGnRH neurons, the staining intensity and the number of cGnRH-II neurons did not change after steroid treatment. The results of this study show that T is able to accelerate the development of the cfGnRH system, whereas OHA has only minimal effects; the cGnRH-II system develops independent from these steroids.

Registration of MR and SPECT without using external fiducial markers.

The aim of our work is to present, test and validate an automated registration method used for matching brain SPECT scans with corresponding MR scans. The method was applied on a data set consisting of ten brain IDEX SPECT scans and ten T1- and T2-weighted MR scans of the same subjects. Of two subjects a CT scan was also made. (Semi-) automated algorithms were used to extract the brain from the MR, CT and SPECT images. Next, a surface registration technique called chamfer matching was used to match the segmented brains. A perturbation study was performed to determine the sensitivity of the matching results to the choice of the starting values. Furthermore, the SPECT segmentation threshold was varied to study its effect on the resulting parameters and a comparison between the use of MR T1- and T2-weighted images was made. Finally, the two sets of CT scans were used to estimate the accuracy by matching MR to CT and comparing the MR-SPECT match to the SPECT-CT match. The perturbation study showed that for initial perturbations up to 6 cm the algorithm fails in less than 4% of the cases. A variation of the SPECT segmentation threshold over a realistic range (25%) caused an average variation in the optimal match of 0.28 cm vector length. When T2 is used instead of T1 the stability of the algorithm is comparable but the results are less realistic due the large deformations. Finally, a comparison of the direct SPECT-MR match and the indirect match with CT as intermediate yields a discrepancy of 0.4 cm vector length. We conclude that the accuracy of our automatic matching algorithm for SPECT and MR, in which no external markers were used, is comparable to the accuracies reported in the literature for non-automatic methods or methods based on external markers. The proposed method is efficient and insensitive to small variations in SPECT segmentation.