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Contains fulltext : 47626reimer.pdf (Publisher’s version ) (Closed access) To evaluate the indications, underlying cardiac disorders, efficacy and complications involved with implantable cardioverter-defibrillators (ICDs) in paediatric patients in The Netherlands, the records of all patients aged 18 years or younger who underwent ICD placement were reviewed retrospectively. Between January 1995 and September 2002, 23 patients (11 males, 12 females; median age 12 years, range 6 months to 16 years) underwent ICD implantation. The ICD was implanted for aborted sudden cardiac death ( n = 14), syncope ( n = 5) or for primary prevention of sudden cardiac death ( n = 4). Underlying cardiac disorders were electrical diseases ( n = 16), hypertrophic or dilated cardiomyopathy ( n = 4) and congenital cardiac malformations ( n = 3). Five patients had an epicardially placed ICD, while 18 underwent a transvenous approach. The generator was placed in an abdominal position in eight patients, whereas it was placed in the subpectoral region in 15. There was no early mortality. Median hospital stay was 5 days (range 2-30 days). Median follow-up time was 29 months (range 1 month to 7 years). Seven patients experienced an inappropriate shock after a median period of 7 months; five patients an appropriate shock after a median period of 3 months. The reasons for inappropriate shock were supraventricular tachycardia ( n = 1), sinus tachycardia ( n = 4) or T-wave sensing (n = 2). One patient with malignant long QT syndrome died of intractable arrhythmias and irreversible cardiomyopathy. Generator replacement was necessary in four patients after 28, 44, 51 and 54 months respectively. CONCLUSION: Implantable cardioverter-defibrillator implantation in paediatric patients is a safe procedure with a good medium-term outcome. The most serious problem is the occurrence of a significant number of inappropriate shocks.

Item does not contain fulltext The fetal brain develops rapidly during the last trimester of pregnancy. Therefore, the brain of infants who are born preterm is vulnerable to changes in oxygen and nutrient supply in the neonatal period. The objective was to determine the effect of gestational age (GA) on the cerebral O2 supply threshold level for preservation of brain function during hypotension in near-term-born lambs. Lambs were delivered at 141 or 127 d of gestation. Hypotension was induced by stepwise withdrawal of blood. Mean arterial blood pressure (MABP) baseline levels were 63.2 (6.4) in 141-d and 54.4 (15.5) mm Hg in 127-d lambs. The MABP threshold below which MABP and blood flow in the left carotid artery were linearly related was 36.1 (13.1) mm Hg in 141-d lambs. In 127-d lambs, MABP and blood flow in the left carotid artery were linearly related over the whole range of recorded MABP values. Electrocortical brain activity (ECBA) was used as a measure of brain function. Thresholds of MABP for maintenance of ECBA were reached at, respectively, 31.6% (4.9%) of baseline in 141-d and 61.9% (13.0%) of baseline MABP in 127-d lambs. However, thresholds of cerebral O2 supply for maintenance of ECBA were similar in both GA groups. We conclude that thresholds of cerebral O2 supply for maintenance of brain cell function are independent of GA but are reached at higher MABP levels in 127-d than in 141-d lambs and therefore places the sick preterm infant easily at risk for ischemic cerebral injury.

Contains fulltext : 47994.pdf (Publisher’s version ) (Closed access) Uptake of radiolabeled peptides in the kidneys may obscure abdominal tumors in radiopeptide scintigraphy. This problem is much more pronounced in peptide receptor radionuclide therapy (i.e., radiopeptide therapy), possibly leading to renal damage or even failure. Cationic peptide uptake in the kidneys can be reduced by the application of cationic amino acids, such as lysine or arginine. The aim of this study was to develop a suitable method to reduce anionic peptide uptake in the kidneys. (111)In-Diethylenetriaminepentaacetic acid dGlu(1)-minigastrin ((111)In-DTPA-dGlu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH(2)) was chosen as a model compound with a sequence of 6 negatively charged glutamic acids in a chain and an additional aspartic acid. METHODS: TT (human medullary carcinoma cells)-bearing nu/nu mice of the Institute of Cancer Research genotype received intraperitoneal injections of different chain lengths and weights of glutamic acids, aspartic acids, and derivatives of glutamic acids. Uptake in tumors and organs was determined and compared with the values for untreated control mice. RESULTS: Accretion of (111)In-DTPA-dGlu(1)-minigastrin in the kidneys could be reduced by up to 90%. The uptake values for all other organs and the tumors were not affected. These results were obtained with a chain of 5 or more glutamic acids, whereas uptake in kidneys was affected not at all or only slightly with poly-d-glutamic or polyaspartic acids and with Glu(x) (x = 1-4). CONCLUSION: These studies indicated a specific blocking of uptake by Glu(5) sequences in the kidneys. Application of polyglutamic acids is a new, successful method of reducing uptake of negatively charged peptides in the kidneys during radiopeptide therapy.

Contains fulltext : 47567.pdf (Publisher’s version ) (Closed access) The aim of this study was to evaluate 3 new (99m)Tc-labeled minigastrin analogs modified with open chain tetraamines at the N-terminus for their suitability in the CCK-2/gastrin-R-targeted imaging of tumors (CCK-2/gastrin-R = cholecystokinin subtype 2/gastrin receptor). METHODS: The [(D)Glu(1)]minigastrin sequence was assembled on the solid support and the respective tetraamine precursors coupled at the N-terminus. Purified peptide conjugates were labeled with (99m)Tc under alkaline conditions. Saturation binding experiments were performed for (radio)metallated peptides [(99m)Tc/(99g)Tc]Demogastrin 1-3 in rat acinar pancreatic AR4-2J cell membranes. Internalization was studied in AR4-2J cells at 37 degrees C. Radiopeptide stability was tested in murine plasma, urine, and kidney homogenates. Tissue distribution of the peptides was compared in healthy mice and athymic mice bearing AR4-2J tumors. RESULTS: Peptide conjugates were obtained in 10%-30% overall yields by solid-phase techniques. Radiolabeling afforded >98% pure [(99m)Tc]Demogastrin 1-3 species in specific activities of approximately 37 GBq/mumol. Radiopeptides retained a high affinity for the CCK-2/gastrin-R in vitro (50% inhibitory concentration values of approximately 1 nmol/L) and internalized rapidly in CCK-2/gastrin-R-positive cells. After injection in mice they displayed rapid, high, and specific localization in the CCK-2/gastrin-R-expressing tissues (stomach and AR4-2J tumor) and were excreted from the body via the kidneys in the form of hydrophilic metabolites. CONCLUSION: The promising characteristics of [(99m)Tc]Demogastrin 1-3 both in vitro and in animal models illustrate their suitability for CCK-2/gastrin-R-targeted tumor imaging. These qualities could be confirmed for [(99m)Tc]Demogastrin 2, which provided excellent delineation of tumor deposits in a first patient with metastatic medullary thyroid cancer.

Contains fulltext : 69134.pdf (Publisher’s version ) (Closed access)

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Contains fulltext : 119288.pdf (Publisher’s version ) (Closed access) 01 juli 2013

Contains fulltext : 118877.pdf (Publisher’s version ) (Open Access) Atherosclerotic plaque rupture can initiate stroke or myocardial infarction. Lipid-rich plaques with thin fibrous caps have a higher risk to rupture than fibrotic plaques. Elastic moduli differ for lipid-rich and fibrous tissue and can be reconstructed using tissue displacements estimated from intravascular ultrasound radiofrequency (RF) data acquisitions. This study investigated if modulus reconstruction is possible for noninvasive RF acquisitions of vessels in transverse imaging planes using an iterative 2D cross-correlation based displacement estimation algorithm. Furthermore, since it is known that displacements can be improved by compounding of displacements estimated at various beam steering angles, we compared the performance of the modulus reconstruction with and without compounding. For the comparison, simulated and experimental RF data were generated of various vessel-mimicking phantoms. Reconstruction errors were less than 10%, which seems adequate for distinguishing lipid-rich from fibrous tissue. Compounding outperformed single-angle reconstruction: the interquartile range of the reconstructed moduli for the various homogeneous phantom layers was approximately two times smaller. Additionally, the estimated lateral displacements were a factor of 2-3 better matched to the displacements corresponding to the reconstructed modulus distribution. Thus, noninvasive elastic modulus reconstruction is possible for transverse vessel cross sections using this cross-correlation method and is more accurate with compounding.

ObjectiveShort stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment.Design and methodsDuring the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl,n=23; Ox 0.03,n=27; and Ox 0.06,n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition.ResultsHeight gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2±4.9 cm, Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency.ConclusionOx 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe.

Contains fulltext : 101050.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 15 januari 2013 Promotores : Gotthardt, M., Boerman, O.C.

Contains fulltext : 127313.pdf (Publisher’s version ) (Open Access) Background Postcancer fatigue is a frequently occurring problem, impairing quality of life. Until now, little is known about (neuro) physiological factors determining postcancer fatigue. For non-cancer patients with chronic fatigue syndrome, certain characteristics of brain morphology and metabolism have been identified in previous studies. We investigated whether these volumetric and metabolic traits are a reflection of fatigue in general and thus also of importance for postcancer fatigue. Methods Fatigued patients were randomly assigned to either the intervention condition (cognitive behavior therapy) or the waiting list condition. Twenty-five patients in the intervention condition and fourteen patients in the waiting list condition were assessed twice, at baseline and six months later. Baseline measurements of 20 fatigued patients were compared with 20 matched non-fatigued controls. All participants had completed treatment of a malignant, solid tumor minimal one year earlier. Global brain volumes, subcortical brain volumes, metabolite tissue concentrations, and metabolite ratios were primary outcome measures. Results Volumetric and metabolic parameters were not significantly different between fatigued and non-fatigued patients. Change scores of volumetric and metabolic parameters from baseline to follow-up were not significantly different between patients in the therapy and the waiting list group. Patients in the therapy group reported a significant larger decrease in fatigue scores than patients in the waiting list group. Conclusions No relation was found between postcancer fatigue and the studied volumetric and metabolic markers. This may suggest that, although postcancer fatigue and chronic fatigue syndrome show strong resemblances as a clinical syndrome, the underlying physiology is different.

Item does not contain fulltext OBJECTIVES: The absence of a pulmonary valve (PV) after tetralogy of Fallot (TOF) repair has been shown to impact postoperative right ventricular (RV) function. The purposes of this study were to (i) compare early outcomes after PV-sparing vs transannular patching (TAP) with monocusp valve reconstruction or TAP alone and (b) assess the mid-term results after polytetrafluoroethylene (PTFE) membrane monocusp reconstruction. METHODS: From 2003 to 2009, 163 patients underwent TOF repair. Sixty-nine patients (42.3%) underwent a PV-sparing procedure (Group A), 74 (45.4%) underwent PTFE membrane monocusp valve reconstruction (Group B) and 20 (12.3%) underwent TAP only (Group C). Early outcomes were evaluated by the right-to-left ventricular pressure ratio, RV outflow tract gradient, tricuspid and PV function, intensive care unit (ICU) parameters and need for reintervention. Group B patients were also evaluated at intermediate term for clinical and echocardiographic parameters, including tricuspid and monocusp valve function and mobility. RESULTS: The median age, weight and PV Z-value of Group B patients were significantly lower; 20.5 months, 9.3 kg and -4, respectively. Postoperatively, the right-to-left ventricular pressure ratio was

Contains fulltext : 117883.pdf (Publisher’s version ) (Closed access) BACKGROUND: /st> The transpulmonary thermodilution (TPTD) technique is widely used in clinical practice for measuring cardiac output (CO). This study was designed to investigate the influence of various levels of pulmonary oedema on the reliability of CO measurements by the TPTD method. METHODS: /st> In 11 newborn lambs pulmonary oedema was induced using a surfactant washout technique. Serial CO measurements using TPTD (COTPTD) were performed at various amounts of lung water. Simultaneously, CO was measured by an ultrasound flow probe around the main pulmonary artery (COMPA) and used as the standard reference. CO was divided by the body surface area to calculate cardiac index (CI). Data were analysed using correlational statistics and Bland-Altman analysis. RESULTS: /st> One lamb died prematurely. A total of 56 measurements in 10 lambs were analysed with a median CIMPA of 2.95 (IQR 1.04) litre min(-1) m(-2). Mean percentage increase in extravascular lung water (EVLW) between the start and the end of the study was 126.4% (sd 40.4). Comparison of the two CO methods showed a mean bias CI of -0.16 litre min(-1) m(-2) (limits of agreement +/-0.73 litre min(-1) m(-2)) and a percentage error of 23.8%. Intraclass correlation coefficients were 0.91 (95% CI 0.81-0.95) for absolute agreement and 0.92 (95% CI 0.87-0.95) for consistency. Acceptable agreement was confirmed by a tolerability-agreement ratio of 0.39. The within-subject correlation between the amount of EVLWI and the bias between the two methods was not significant (-0.02; P=0.91). CONCLUSIONS: /st> CO measurements by the transpulmonary thermodilution technique over a wide range of CI values are not affected by the presence of high EVLWI. The slight underestimation of the CO is independent of the amount of pulmonary oedema.

Item does not contain fulltext AIMS: The aim of this study was to investigate myocardial 2D strain echocardiography and cardiac biomarkers in the assessment of cardiac function in children with acute lymphoblastic leukaemia (ALL) during and shortly after treatment with anthracyclines. METHODS AND RESULTS: Cardiac function of 60 children with ALL was prospectively studied with measurements of cardiac troponin T (cTnT) and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) and conventional and myocardial 2D strain echocardiography before start (T = 0), after 3 months (T = 1), and after 1 year (T = 2), and were compared with 60 healthy age-matched controls. None of the patients showed clinical signs of cardiac failure or abnormal fractional shortening. Cardiac function decreased significantly during treatment and was significantly decreased compared with normal controls. Cardiac troponin T levels were abnormal in 11% of the patients at T = 1 and were significantly related to increased time to global peak systolic longitudinal strain at T = 2 (P = 0.003). N-terminal-pro-brain natriuretic peptide levels were abnormal in 13% of patients at T = 1 and in 20% at T = 2, absolute values increased throughout treatment in 59%. Predictors for abnormal NT-pro-BNP at T = 2 were abnormal NT-pro-BNP at T = 0 and T = 1, for abnormal myocardial 2D strain parameters at T = 2 cumulative anthracycline dose and z-score of the diastolic left ventricular internal diameter at baseline. CONCLUSION: Children with newly diagnosed ALL showed decline of systolic and diastolic function during treatment with anthracyclines using cardiac biomarkers and myocardial 2D strain echocardiography. N-terminal-pro-brain natriuretic peptide levels were not related to echocardiographic strain parameters and cTnT was not a predictor for abnormal strain at T = 2.Therefore, the combination of cardiac biomarkers and myocardial 2D strain echocardiography is important in the assessment of cardiac function of children with ALL treated with anthracyclines.

Item does not contain fulltext Adenylosuccinate lyase (ADSL) deficiency is a rare inborn error of metabolism resulting in accumulation of metabolites including succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado) in the brain and other tissues. Patients with ADSL have progressive psychomotor retardation, neonatal seizures, global developmental delay, hypotonia, and autistic features, although variable clinical manifestations may make the initial diagnosis challenging. Two cases of the severe form of the disease are reported here: an 18-month-old boy with global developmental delay, intractable neonatal seizures, progressive cerebral atrophy, and marked hypomyelination, and a 3-month-old girl presenting with microcephaly, neonatal seizures, and marked psychomotor retardation. In both patients in vivo proton magnetic resonance spectroscopy (MRS) showed the presence of S-Ado signal at 8.3 ppm, consistent with a prior report. Interestingly, SAICAr signal was also detectable at 7.5 ppm in affected white matter, which has not been reported in vivo before. A novel splice-site mutation, c.IVS12 + 1/G > C, in the ADSL gene was identified in the second patient. Our findings confirm the utility of in vivo proton MRS in suggesting a specific diagnosis of ADSL deficiency, and also demonstrate an additional in vivo resonance (7.5 ppm) of SAICAr in the cases of severe disease. J. Magn. Reson. Imaging 2013;37:974-980. (c) 2012 Wiley Periodicals, Inc.

Contains fulltext : 118937.pdf (Publisher’s version ) (Open Access) Patients with type 1 diabetes mellitus (T1DM) experience, on average, 2 to 3 hypoglycemic episodes per week. This study investigated the effect of hypoglycemia on cerebral glucose metabolism in patients with uncomplicated T1DM. For this purpose, hyperinsulinemic euglycemic and hypoglycemic glucose clamps were performed on separate days, using [1-13C]glucose infusion to increase plasma 13C enrichment. In vivo brain 13C magnetic resonance spectroscopy was used to measure the time course of 13C label incorporation into different metabolites and to calculate the tricarboxylic acid cycle flux (VTCA) by a one-compartment metabolic model. We found that cerebral glucose metabolism, as reflected by the VTCA, was not significantly different comparing euglycemic and hypoglycemic conditions in patients with T1DM. However, the VTCA was inversely related to the HbA1C and was, under hypoglycemic conditions, approximately 45\% higher than that in a previously investigated group of healthy subjects. These data suggest that the brains of patients with T1DM are better able to endure moderate hypoglycemia than those of subjects without diabetes.

Contains fulltext : 128551.pdf (Publisher’s version ) (Open Access) OBJECTIVES: This study aimed to update and validate a prediction rule for respiratory syncytial virus (RSV) hospitalization in preterm infants 33-35 weeks gestational age (WGA). STUDY DESIGN: The RISK study consisted of 2 multicenter prospective birth cohorts in 41 hospitals. Risk factors were assessed at birth among healthy preterm infants 33-35 WGA. All hospitalizations for respiratory tract infection were screened for proven RSV infection by immunofluorescence or polymerase chain reaction. Multivariate logistic regression analysis was used to update an existing prediction model in the derivation cohort (n = 1,227). In the validation cohort (n = 1,194), predicted versus actual RSV hospitalization rates were compared to determine validity of the model. RESULTS: RSV hospitalization risk in both cohorts was comparable (5.7% versus 4.9%). In the derivation cohort, a prediction rule to determine probability of RSV hospitalization was developed using 4 predictors: family atopy (OR 1.9; 95%CI, 1.1-3.2), birth period (OR 2.6; 1.6-4.2), breastfeeding (OR 1.7; 1.0-2.7) and siblings or daycare attendance (OR 4.7; 1.7-13.1). The model showed good discrimination (c-statistic 0.703; 0.64-0.76, 0.702 after bootstrapping). External validation showed good discrimination and calibration (c-statistic 0.678; 0.61-0.74). CONCLUSIONS: Our prospectively validated prediction rule identifies infants at increased RSV hospitalization risk, who may benefit from targeted preventive interventions. This prediction rule can facilitate country-specific, cost-effective use of RSV prophylaxis in late preterm infants.

Invasive Candida infections associated with medical devices are very difficult to cure without device removal. We present a case of neonatal cerebrospinal fluid shunt-associated Candida meningitis, in which removal of the device was precluded, that was successfully treated with caspofungin. Pharmacokinetic assessment of caspofungin concentrations in cerebrospinal fluid showed that exposure was adequate in the presence of a high systemic exposure. In complex cases of neonatal Candida infections involving medical devices, the addition of caspofungin might be beneficial.

Contains fulltext : 108726.pdf (Publisher’s version ) (Open Access) BACKGROUND: Extremely preterm infants are at high risk of neonatal mortality and adverse outcome. Survival rates are slowly improving, but increased survival may come at the expense of more handicaps. METHODOLOGY/PRINCIPAL FINDINGS: Prospective population-based cohort study of all infants born at 23 to 27 weeks of gestation in the Netherlands in 2007. 276 of 345 (80%) infants were born alive. Early neonatal death occurred in 96 (34.8%) live born infants, including 61 cases of delivery room death. 29 (10.5%) infants died during the late neonatal period. Survival rates for live born infants at 23, 24, 25 and 26 weeks of gestation were 0%, 6.7%, 57.9% and 71% respectively. 43.1% of 144 surviving infants developed severe neonatal morbidity (retinopathy of prematurity grade >/=3, bronchopulmonary dysplasia and/or severe brain injury). At two years of age 70.6% of the children had no disability, 17.6% was mild disabled and 11.8% had a moderate-to-severe disability. Severe brain injury (p = 0.028), retinopathy of prematurity grade >/=3 (p = 0.024), low gestational age (p = 0.019) and non-Dutch nationality of the mother (p = 0.004) increased the risk of disability. CONCLUSIONS/SIGNIFICANCE: 52% of extremely preterm infants born in the Netherlands in 2007 survived. Surviving infants had less severe neonatal morbidity compared to previous studies. At two years of age less than 30% of the infants were disabled. Disability was associated with gestational age and neonatal morbidity.

Contains fulltext : 107818.pdf (Publisher’s version ) (Open Access) The management of patients with isolated congenital complete atrioventricular block (CCAVB) has changed during the last decades. The current policy is to pace the majority of patients based on a variety of criteria, among which is limited exercise capacity. Data regarding exercise capacity in this population stems from previous publications reporting small case series of unpaced patients. Therefore, we have investigated the exercise capacity of a group of contemporary children with CCAVB. Sixteen children (mean age 11.5 +/- 4; seven boys, nine girls) with CCAVB were tested. In 13 patients, a median number of three pacemakers were implanted, whereas in three patients no pacemaker was given. All patients had an echocardiogram and completed a cardiopulmonary cycle exercise test. Exercise parameters were determined and compared with reference values obtained from healthy Dutch peers. The peak oxygen uptake/body mass was reduced to 34.4 +/- 9.5 ml kg(-1) min(-1) (79 +/- 24% of predicted) and the ventilatory threshold was reduced to 52 +/- 17% of peak oxygen uptake (78 +/- 21% of predicted), whereas the peak work load/body mass was 2.8 +/- 0.6 W/kg (91 +/- 24% of predicted), which was similar to controls. Importantly, 25% of the paced patients showed upper rate restriction by the pacemaker. In conclusion, children with CCAVB show a reduced peak oxygen uptake and ventilatory threshold, whereas they show normal peak work rates. This indicates that they generate more energy during exercise from anaerobic energy sources. Paced children with CCAVB do not perform better than unpaced children. 01 april 2012

Hydroxynitrile lyases (HNLs) catalyze the cleavage of cyanohydrins. In the reverse reaction, they catalyze the formation of carbon-carbon bonds by enantioselective condensation of hydrocyanic acid with carbonyls. In this study, we describe two proteins from endophytic bacteria that display activity in the cleavage and the synthesis reaction of ( R )-mandelonitrile with up to 74% conversion of benzaldehyde (enantiopreference ee 89%). Both showed high similarity to proteins of the cupin superfamily which so far were not known to exhibit HNL activity.

Item does not contain fulltext BACKGROUND AND OBJECTIVES: The few existing studies of sexual dysfunction in women on hemodialysis are limited by small sample size. This large, cross-sectional study evaluated the prevalence and correlates of female sexual dysfunction in advanced kidney disease. DESIGN, SETTING, PARTICIPANTS, METHODS: A total of 1472 women with ESRD undergoing hemodialysis were recruited to a multinational, cross-sectional study conducted within a collaborative dialysis network in Europe and South America. Sexual dysfunction was identified by the Female Sexual Function Index. Correlates of self-reported sexual dysfunction were identified by regression analyses. RESULTS: Of the 1472 women, 659 completed questionnaires (45%). More than half (362 of 659 [55%]) lived with a partner, and 232 of 659 (35%) reported being sexually active. Of these 659 respondents, 555 (84%) reported sexual dysfunction. Women with a partner (282 of 362 [78%]) were less likely to report sexual dysfunction than those without a partner (273 of 297 [92%]) (P

Item does not contain fulltext BACKGROUND: Factors associated with erectile dysfunction in men on haemodialysis are incompletely identified due to suboptimal existing studies. We determined the prevalence and correlates of erectile dysfunction and identified combinations of clinical characteristics associated with a higher risk of erectile dysfunction using recursive partitioning and amalgamation (REPCAM) analysis. METHODS: We conducted a multinational cross-sectional study in men on haemodialysis within a collaborative network. Erectile dysfunction and depressive symptoms were evaluated using the erectile function domain of the International Index of Erectile Function questionnaire and the Center for Epidemiological Studies-Depression Scale, respectively. RESULTS: Nine hundred and forty-six (59%) of 1611 eligible men provided complete data for erectile dysfunction. Eighty-three per cent reported erectile dysfunction and 47% reported severe erectile dysfunction. Four per cent of those with erectile dysfunction were receiving pharmacological treatment. Depressive symptoms were the strongest correlate of erectile dysfunction [adjusted odds ratio 2.41 (95% confidence interval (CI) 1.57-3.71)]. Erectile dysfunction was also associated with age (1.06, 1.05-1.08), being unemployed (1.80, 1.17-2.79) or receiving a pension (2.05, 1.14-3.69) and interdialytic weight gain (1.9-2.87 kg, 1.92 [CI 1.19-3.09]; >2.87 kg, 1.57 [CI 1.00-2.45]). Married men had a lower risk of erectile dysfunction (0.49, 0.31-0.76). The prevalence of erectile dysfunction was highest (94%) in unmarried and unemployed or retired men who have depressive symptoms. CONCLUSIONS: Most men on haemodialysis experience erectile dysfunction and are untreated. Given the prevalence of this condition and the relative lack of efficacy data for pharmacological agents, we suggest that large trials of pharmacological and non-pharmacological interventions for erectile dysfunction and depression are needed.

Item does not contain fulltext Dopamine has been implicated in reward-related impulsivity, but the exact relationship between dopamine, reward and impulsivity in humans remains unknown. We address this question in Parkinson's disease (PD), which is characterized by severe dopamine depletion. PD is associated primarily with motor and cognitive inflexibility, but can also be accompanied by reward-related impulsivity. This paradoxical symptom of PD has often been attributed to dopaminergic overstimulation by antiparkinson medication, which is necessary to relieve the motor and cognitive inflexibility. However, factors other than medication may also contribute to aberrant impact of reward. Here we assess whether cognitive inflexibility and aberrant reward impact in PD are two sides of the same coin, namely dopamine cell loss. To measure dopamine cell loss, we employed (123)I-FP-CIT Single Photon Emission Computed Tomography (SPECT) in 32 PD patients (10 never-medicated patients and 22 patients after withdrawal of all medication for >12h) and related the values to behavior on a rewarded task-switching paradigm. Dopamine cell loss was associated not only with cognitive inflexibility (under low reward), but also with aberrant impact of reward. These effects could not be attributed to medication use. Relative to controls (n=26), aberrant reward processing in PD was particularly expressed as reduced capacity to maintain (i.e., repeat) the current task-set under high reward. Our findings demonstrate that factors intrinsically related to PD may underlie the paradoxical symptoms of inflexibility and reward-related impulsivity in PD. The present results concur with observations that low baseline dopamine states predispose to drug and other addictions.

Contains fulltext : 108269.pdf (Publisher’s version ) (Open Access) ABSTRACT: BACKGROUND: In single photon emission computed tomography [SPECT], high specific activity of 111In-labelled tracers will allow administration of low amounts of tracer to prevent receptor saturation and/or side effects. To increase the specific activity, we studied the effect of the buffer used during the labelling procedure: NaAc, NH4Ac, HEPES and MES buffer. The effect of the ageing of the 111InCl3 stock and cadmium contamination, the decay product of 111In, was also examined in these buffers. METHODS: Escalating amounts of 111InCl3 were added to 1 mug of the diethylene triamine pentaacetic acid [DTPA]- and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA]-conjugated compounds (exendin-3, octreotide and anti-carbonic anhydrase IX [CAIX] antibody). Five volumes of 2-(N-morpholino)ethanesulfonic acid [MES], 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [HEPES], NH4Ac or NaAc (0.1 M, pH 5.5) were added. After 20 min at 20 degrees C (DTPA-conjugated compounds), at 95 degrees C (DOTA-exendin-3 and DOTA-octreotide) or at 45 degrees C (DOTA-anti-CAIX antibody), the labelling efficiency was determined by instant thin layer chromatography. The effect of the ageing of the 111InCl3 stock on the labelling efficiency of DTPA-exendin-3 as well as the effect of increasing concentrations of Cd2+ (the decay product of 111In) were also examined. RESULTS: Specific activities obtained for DTPA-octreotide and DOTA-anti-CAIX antibody were five times higher in MES and HEPES buffer. Radiolabelling of DTPA-exendin-3, DOTA-exendin-3 and DTPA-anti-CAIX antibody in MES and HEPES buffer resulted in twofold higher specific activities than that in NaAc and NH4Ac. Labelling of DTPA-exendin-3 decreased with 66% and 73% for NaAc and NH4Ac, respectively, at day 11 after the production date of 111InCl3, while for MES and HEPES, the maximal decrease in the specific activity was 10% and 4% at day 11, respectively. The presence of 1 pM Cd2+ in the labelling mixture of DTPA-exendin-3 in NaAc and NH4Ac markedly reduced the labelling efficiency, whereas Cd2+ concentrations up to 0.1 nM did not affect the labelling efficiency in MES and HEPES buffer. CONCLUSIONS: We showed improved labelling of DTPA- and DOTA-conjugated compounds with 111In in HEPES and MES buffer. The enhanced labelling efficiency appears to be due to the reduced competitive chelation of cadmium. The enhanced labelling efficiency will allow more sensitive imaging of the biomarkers with SPECT.

To the Editor: With great interest we read the article by Chen et al. regarding factors that affect heart-to-mediastinal ratio (H/M ratio) in I-123 meta-iodobenzylguanidine (MIBG) cardiac sympathetic imaging [1]. The authors describe the variation of H/M ratio among institutions and the factors that contribute to this. Furthermore, they provide different protocols that could minimize this variation. One of the significant contributors to the variation of H/M ratio in cardiac imaging, are the settings of the regions of interest (ROIs) that are used. Currently, as correctly described by Chen et al. [1, 2], there are three main approaches for drawing the heart ROI. One is to place the ROI over the whole heart, thereby neglecting the “dilution” effect in patients with a dilated heart (ie, lower blood pool activity in the cavity than the myocardium) but resulting in high reproducibility [1, 3]. The second approach is to place the ROI along the left ventricular (LV) wall, inter alia described by Gerson et al. [4], which possibly leads to greater inter- and intraobserver bias [1]. In the third approach a smaller ROI is placed along the anterior part of the LV wall [2]. In our current ongoing study in pediatric patients by van der Palen et al.., we compared both approaches described by Chen et al. (ie, the “whole heart ROI” and the “small anterior wall ROI”). The reason for comparing those instead of the “LV wall ROI” by Gerson et al. is twofold: possible comparison of our results with Chen’s references and potential inaccurate placement of an ROI along the complete LV wall in small pediatric hearts (ie, the child’s heart is often too small for exact placement over the LV wall). Several studies in pediatric cardiology also use this approach [5, 6]. When studying the subsequently calculated H/M ratios we noticed that the interobserver variability when using these methods of ROI placement was only minor, when H/M ratios were obtained independently by two observers at 4 and 24 h post injection in our population of 30 pediatric patients. Intraclass correlation coefficients (ICCs) were as follows: for the small anterior wall ROI H/M ratio 0.882 (95 % CI: 0.578–0.956) and for the whole heart ROI H/M ratio 0.955 (95 % CI: 0.904–0.979) at 4 h. At 24 h, the ICC was 0.911 (95 % CI: 0.716–0.965) for the small anterior wall ROI H/M ratio and 0.951 (95 % CI: 0.896–0.977) for the whole heart ROI H/M ratio. Therefore, it can be concluded that the use of both ROI definition methods in children results in substantial to almost perfect interobserver agreement concerning H/M ratio. Furthermore, this suggests that whole H/M ratio has better agreement than small H/M ratio for both 4 and 24 h post injection scans. Besides, both methods also showed a high within-patient ICC ratio of 0.865. This implies that intrapatient variability is fairly small and both methods give almost identical results. Although the ICCs of both methods of ROI placement are rather similar, the most promising method is the whole H/M ratio 4 h post injection. To reduce differences in H/M ratios due to interobserver variability the method of ROI placement should be standardized, and it is reasonable to define this method as the gold standard for H/M ratio measurement. However, as stated in the article by Chen et al. [1], this method could underestimate the H/M ratio in patients with a dilated heart (being the target population in the article by Chen et al.) and a relatively high negative contribution of the myocardial cavity. This, however, has no impact on our population, which does not contain patients with cardiomyopathy. Small anterior wall H/M ratios do not have this disadvantage and showed adequate intraobserver agreement. Therefore, we can conclude that the best method to determinate the H/M ratio in cardiac sympathetic imaging depends on the patient characteristics of the study group. In pediatric patients we recommend the use of the whole heart H/M ratio, since it shows the best intraobserver agreement. With Chen we would like to emphasize the importance to standardize ROI placement methods to compare study results and minimize the intrapatient, interpatient, and interinstitutional variation.

Contains fulltext : 110488.pdf (Publisher’s version ) (Closed access) BACKGROUND: Cardiac output (CO) monitoring remains complex in newborns as most of the current technologies fail to accurately measure systemic blood flow in the presence of shunts. We validated CO measurements using transpulmonary ultrasound dilution (TPUD) in a neonatal lamb model with a left-to-right shunt. METHODS: Regular arterial and central venous catheters were inserted into seven lambs (3.5-8.3 kg). A surgically constructed left-to-right aorto-pulmonary Gore-Tex((R)) shunt was intermittently opened and closed, while CO was manipulated by creating haemorrhagic hypotension. CO measurements with TPUD (COtpud) were compared with those obtained by an ultrasonic transit-time flow probe positioned around the main pulmonary artery (COufp). RESULTS: We performed 72 sessions of three paired CO measurements. The mean COufp was 1.00 litre min(-1) (range 0.47-1.75 litre min(-1)) and mean COtpud 1.05 litre min(-1) (range 0.54-1.87 litre min(-1)). With an open shunt, the mean Qp/Qs ratio was 1.8 (range 1.3-2.6). A comparison between COufp and COtpud showed a mean bias (sd) of 0.03 (0.09) and 0.07 (0.10) litre min(-1), respectively, for measurements with a closed and an open shunt. The percentage error was 18% and 20% for measurements with a closed and an open shunt. Polar plot analysis showed good trending ability for both closed and open shunt groups. CONCLUSIONS: TPUD is a reliable technology to measure CO in the presence of a left-to-right shunt. 01 maart 2012

The objective of this study was to investigate the relationship between plasma and brain glucose levels during euglycemia and hypoglycemia in healthy subjects and patients with type 1 diabetes mellitus (T1DM). Hyperinsulinemic euglycemic (5 mmol/L) and hypoglycemic (3 mmol/L) [1-13C]glucose clamps were performed in eight healthy subjects and nine patients with uncomplicated T1DM (HbA1c 7.7 ± 1.4%). Brain glucose levels were measured by 13C magnetic resonance spectroscopy. Linear regression analysis was used to fit the relationship between plasma and brain glucose levels and calculate reversible Michaelis-Menten (MM) kinetic parameters. Brain glucose values during euglycemia (1.1 ± 0.4 μmol/g vs. 1.1 ± 0.3 μmol/g; P = 0.95) and hypoglycemia (0.5 ± 0.2 μmol/g vs. 0.6 ± 0.3 μmol/g; P = 0.52) were comparable between healthy subjects and T1DM patients. MM kinetic parameters of combined data were calculated to be maximum transport rate/cerebral metabolic rate of glucose (Tmax/CMRglc) = 2.25 ± 0.32 and substrate concentration at half maximal transport (Kt) = 1.53 ± 0.88 mmol/L, which is in line with previously published data obtained under hyperglycemic conditions. In conclusion, the linear MM relationship between plasma and brain glucose can be extended to low plasma glucose levels. We found no evidence that the plasma to brain glucose relationship or the kinetics describing glucose transport over the blood–brain barrier differ between healthy subjects and patients with uncomplicated, reasonably well-controlled T1DM.

Item does not contain fulltext BACKGROUND: Growth retardation in utero leading to small-for-gestational-age (SGA) newborns is associated with increased neonatal morbidity and mortality and with lifelong consequences such as poor cognitive function and cardiovascular diseases. Maternal total homocysteine (tHcy) concentrations have been linked to a wide range of adverse pregnancy outcomes and could possibly influence birth weight. OBJECTIVE: We performed a systematic review of and meta-analysis on the association of maternal tHcy and birth weight. DESIGN: A literature search of English, German, and French publications with the use of the PubMed database (January 1966-July 2010) found 78 abstracts. Search terms were as follows: homocysteine AND (birth weight OR small for gestational age OR intrauterine growth retardation). Studies were eligible if information on maternal tHcy and birth weight and the possible association between maternal tHcy and birth weight was available. Effect size estimates were converted to ORs as estimates of the RR of a woman to deliver SGA offspring when maternal tHcy exceeded the 90th percentile. RESULTS: The search yielded 19 studies for analysis, consisting of 21,326 individuals. Pooled analysis resulted in a crude OR of 1.25 (95% CI: 1.09, 1.44). When this estimate was expressed as a linear effect, it corresponded to a decrease in birth weight of 31 g (95% CI: -13, -51 g) for a 1-SD increase in maternal tHcy. CONCLUSIONS: Higher maternal tHcy concentrations are associated with a small increased risk for SGA offspring. The small estimated birth weight difference might be of little clinical relevance for the individual newborn; however, it could be of greater importance at a population level. 01 januari 2012

Item does not contain fulltext Two-dimensional speckle tracking echocardiography (2DSTE) offers valuable information in the echocardiographic assessment of ventricular myocardial function. It enables the quantification and timing of systolic ventricular myocardial deformation. In addition, 2DSTE can be used to identify mechanical dyssynchrony, which is an important parameter in predicting the response to cardiac resynchronization therapy for heart failure. Detailed knowledge of normal timing of systolic deformation and its degree of synchronicity in children is lacking. We aimed to establish the normal timing of left ventricular myocardial systolic deformation using 2DSTE in a large cohort of healthy children and young adults. Transthoracic echocardiograms were acquired in 195 healthy subjects (139 children and 56 young adult

Item does not contain fulltext AIM: Periventricular haemorrhagic infarction (PVHI) is a complication of preterm birth associated with cardiorespiratory instability. To date, the role of thrombophilia as a possible additional risk factor in infants with atypical timing and presentation of PVHI has not been investigated. METHOD: This was a retrospective cohort study of preterm infants who developed PVHI with an atypical timing and presentation either of antenatal onset or late in the postnatal course in the absence of a preceding sudden deterioration of their clinical condition. In infants with atypical PVHI mutation analysis of the factor V Leiden (G1691A), prothrombin (G20210A) gene, and C677T and A1298C polymorphisms in the MTHFR gene was performed, and plasma lipoprotein(a) and homocysteine levels were measured. RESULTS: Sixty-two preterm infants who presented with a PVHI were studied. Seventeen had an atypical presentation (seven males, 10 females; median birthweight 1170g [range 580-1990g]; median gestational age 30.6wks [range 28.7-33.7wks]). The typical PVHI group comprised 28 males and 17 females (median birthweight 1200g [range 670-2210g]; median gestational age 29.6wks [range 25.3-33.6wks]). Among the 17 infants with atypical presentation, the factor V Leiden mutation was found in seven infants (41%) as well as in the mothers of six of these seven infants; in one infant this was concomitant with a prothrombin gene mutation. A polymorphism in the MTHFR gene was also present in these infants. In two infants with an atypical presentation who were tested for this, a mutation in the COL4A1 gene was found (reported previously). All but two of the infants with an atypical presentation developed spastic unilateral cerebral palsy. INTERPRETATION: An atypical presentation of PVHI in preterm infants tends to occur more often in the presence of thrombophilia. Testing of thrombophilia, especially factor V Leiden and prothrombin gene mutation, is recommended in these infants. 01 februari 2012

Contains fulltext : 109263.pdf (author's version ) (Open Access) Internalizing agonists are usually selected for peptide receptor targeting. There is increasing evidence that non-internalizing receptor antagonists can be used for this purpose. We investigated whether the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin(9-39) can be used for in vivo targeting of GLP-1R expressing tumours and compared the in vitro and in vivo characteristics with the GLP-1R agonists exendin-3 and exendin-4. The binding and internalization kinetics of labelled [Lys(40) (DTPA)]exendin-3, [Lys(40) (DTPA)]exendin-4 and [Lys(40) (DTPA)]exendin(9-39) were determined in vitro using INS-1 cells. The in vivo targeting properties of [Lys(40) ((111) In-DTPA)]exendin-3, [Lys(40) ((111) In-DTPA)]exendin-4 and [Lys(40) ((111) In-DTPA)]exendin(9-39) were examined in BALB/c nude mice with subcutaneous INS-1 tumours. (nat) In-labelled [Lys(40) (DTPA)]exendin-3, [Lys(40) (DTPA)]exendin-4 and [Lys(40) (DTPA)]exendin(9-39) exhibited similar IC(50) values (13.5, 14.4 and 13.4 n m, respectively) and bound to 26 x 10(3) , 41 x 10(3) and 37 x 10(3) receptors per cell, respectively. [Lys(40) ((111) In-DTPA)]exendin-3 and [Lys(40) ((111) In-DTPA)]exendin-4 showed rapid in vitro binding and internalization kinetics, whereas [Lys(40) ((111) In-DTPA)]exendin(9-39) showed lower binding and minimal internalization in vitro. In mice, high specific uptake of [Lys(40) ((111) In-DTPA)]exendin-3 [25.0 +/- 6.0% injected dose (ID) g(-1) ] in the tumour was observed at 0.5 h post-injection (p.i.) with similar uptake up to 4 h p.i. [Lys(40) ((111) In-DTPA)]exendin-4 showed higher tumour uptake at 1 and 4 h p.i. (40.8 +/- 7.0 and 41.9 +/- 7.2% ID g(-1), respectively). Remarkably, [Lys(40) ((111) In-DTPA)]exendin(9-39) showed only low specific uptake in the tumour at 0.5 h p.i. (3.2 +/- 0.7% ID g(-1)), rapidly decreasing over time. In conclusion, the GLP-1R agonists [Lys(40) (DTPA)]exendin-3 and [Lys(40) (DTPA)]exendin-4 labelled with (111) In could be useful for in vivo GLP-1R targeting, whereas [Lys(40) (DTPA)]exendin(9-39) is not suited for in vivo targeting of the GLP-1R.

Contains fulltext : 108119.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Higher levels of high density lipoprotein (HDL) subfractions HDL3-chol and particularly HDL2-chol protect against cardiovascular disease (CVD), but inflammation reduces the HDL level and may impair its anti-atherogenic effect. Changed HDL composition through the impact of inflammation on HDL subfractions may contribute to the excess risk of CVD in rheumatoid arthritis (RA). In this study, we investigated whether HDL2-chol and HDL3-chol concentrations differ between RA patients and healthy controls, and whether these levels are related to the level of RA disease activity. METHODS: Non-fasting blood samples were collected from 45 RA patients and 45 healthy controls. None of the participants had a history of CVD, diabetes, or used lipid-lowering drugs. HDL2-chol and HDL3-chol concentrations were obtained by ultracentrifugation. Regression modeling was used to compare HDL subfraction levels between RA patients and healthy controls, and to analyze the effect of disease activity on HDL2-chol and HDL3-chol. RESULTS: HDL2-chol and HDL3-chol were significantly lower in RA patients compared to healthy controls (P = 0.01, P = 0.005, respectively). The HDL2:HDL3 ratio was significantly lower in patients compared to controls (P = 0.04). Reduced HDL2-chol and HDL3-chol levels were primarily present in female RA patients and not in male RA patients. A modest effect of the disease activity score in 28 joins ( DAS28) on HDL2-chol concentrations was found, after correction for disease duration, glucocorticosteroid use and body mass index (BMI), with a 0.06 mmol/L decrease with every point increase in DAS28 (P = 0.05). DAS28 did not significantly affect HDL3-chol concentrations (P = 0.186). CONCLUSIONS: Both HDL subfractions but particularly HDL2-chol concentrations were decreased in RA, primarily in women. This seems to be associated with disease activity and is of clinical relevance. The reduction of the HDL subfraction concentrations, particularly the supposedly beneficial HDL2-chol, may negatively impact the cardiovascular risk profile of women with RA.

Djang, David S W Janssen, Marcel J R Bohnen, Nicolaas Booij, Jan Henderson, Theodore A Herholz, Karl Minoshima, Satoshi Rowe, Christopher C Sabri, Osama Seibyl, John Van Berckel, Bart N M Wanner, Michele United States Journal of nuclear medicine : official publication, Society of Nuclear Medicine J Nucl Med. 2012 Jan;53(1):154-63. Epub 2011 Dec 8.

Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM) are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5–13 years) with a predominant presentation of dilated cardiomyopathy (DCM). Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG). Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations., Author Summary Idiopathic dilated cardiomyopathy (DCM) is estimated to be of genetic origin in 20%–48% of the patients. Almost all currently known genetic defects show dominant inheritance, although especially in younger children recessive causes have been proposed to contribute considerably to DCM. Knowledge of the genetic causes and pathophysiological mechanisms is essential for prognosis and treatment. Here, we studied several individual young patients (5–13 years old) with idiopathic and sometimes asymptomatic dilated cardiomyopathy. The key to identification of the gene was the finding of abnormal protein N-glycosylation. Via homozygosity mapping and functional knowledge of the N-glycosylation pathway, the causative gene could be identified as dolichol kinase (DOLK). Since DCM is very rare in N-glycosylation disorders (Congenital Disorders of Glycosylation, CDG) and most patients with CDG present with a multisystem involvement, we studied the underlying pathophysiological cause of this life-threatening disease. Biochemical experiments in affected heart tissue showed deficient O-mannosylation of alpha-dystroglycan, which could be correlated with the dilated cardiomyopathy. Our results thus highlight nonsyndromic DCM as a novel presentation of DOLK-CDG, via deficient O-mannosylation of alpha-dystroglycan.

Background— Incidence and prevalence rates for pediatric pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are unknown. This study describes the nationwide epidemiological features of pediatric PH in the Netherlands during a 15-year period and the clinical course of pediatric PAH. Methods and Results— Two registries were used to retrospectively identify children (0–17 years) with PH. Overall, 3263 pediatric patients were identified with PH due to left heart disease (n=160; 5%), lung disease/hypoxemia (n=253; 8%), thromboembolic disease (n=5; Conclusions— Pediatric PH is characterized by various age-specific diagnoses, the majority of which comprise transient forms of PAH. Incidence of pediatric iPAH is lower whereas incidence of pediatric PAH-CHD is higher than reported in adults. Pediatric PAH-CHD represents a heterogeneous group with highly variable clinical courses.

Item does not contain fulltext Accurate and precise bilirubin and albumin measurements are essential for proper management of jaundiced neonates. Data hereon are lacking for Dutch laboratories. We aimed to determine variability of measurements of bilirubin and albumin concentrations typical for (preterm) neonates. Aqueous, human serum albumin-based samples with different concentrations of bilirubin (100, 200, 300, 400, and 500 mumol/L) and albumin (0, 10, 15, 20, 25, and 30 g/L) were sent to laboratories of all Dutch neonatal intensive care units (n = 10). Bilirubin and albumin recoveries of the specimens were measured using locally available routine analytical methods. The mean, standard deviation, and coefficients of variations (CV) were calculated per sample. Bilirubin concentrations were underestimated in the absence of albumin (maximal CV 26.0%). When the albumin concentration was 10 or 20 g/L, the bilirubin concentrations of the samples were overestimated (maximal CV 14.1% and 9.2%, respectively). Variability increased with higher weighed-in bilirubin concentrations. Measured albumin levels were ~10% lower than albumin levels of manufactured samples. Bilirubin concentration did not influence albumin measurements. The maximal CV was 6.8%. In conclusion, interlaboratory variability of bilirubin and albumin measurements is high. Recalibration and introduction of a specific quality assessment scheme for neonatal samples is recommended to ensure exchangeability of bilirubin and albumin measurements among laboratories and to control the observed large variability.

Contains fulltext : 97337.pdf (Publisher’s version ) (Closed access) New antitumor agents have resulted in significant survival benefits for cancer patients. However, several agents may have serious cardiovascular side effects. Left ventricular ejection fraction measurement by (99m)Tc multigated radionuclide angiography is regarded as the gold standard to measure cardiotoxicity in adult patients. It identifies left ventricular dysfunction with high reproducibility and low interobserver variability. A decrease in left ventricular ejection fraction, however, is a relatively late manifestation of myocardial damage. Nuclear cardiologic techniques that visualize pathophysiologic processes at the tissue level could detect myocardial injury at an earlier stage. These techniques may give the opportunity for timely intervention to prevent further damage and could provide insights into the mechanisms and pathophysiology of cardiotoxicity caused by anticancer agents. This review provides an overview of past, current, and promising newly developed radiopharmaceuticals and describes the role and recent advances of scintigraphic techniques to measure cardiotoxicity. Both first-order functional imaging techniques (visualizing mechanical [pump] function), such as (99m)Tc multigated radionuclide angiography and (99m)Tc gated blood-pool SPECT, and third-order functional imaging techniques (visualizing pathophysiologic and neurophysiologic processes at the tissue level) are discussed. Third-order functional imaging techniques comprise (123)I-metaiodobenzylguanidine scintigraphy, which images the efferent sympathetic nervous innervations; sympathetic neuronal PET, with its wide range of tracers; (111)In-antimyosin, which is a specific marker for myocardial cell injury and necrosis; (99m)Tc-annexin V scintigraphy, which visualizes apoptosis and cell death; fatty-acid-use scintigraphy, which visualizes the storage of free fatty acids in the lipid pool of the cytosol (which can be impaired by cardiotoxic agents); and (111)In-trastuzumab imaging, to study trastuzumab targeting to the myocardium. To define the prognostic importance and clinical value of each of these functional imaging techniques, prospective clinical trials are warranted.

Contains fulltext : 97859.pdf (Publisher’s version ) (Closed access) arnts i.j.j., heijnen j.a., wilbers h.t.m., van der wilt g.j., groenewoud j.m.m. & liem k.d. (2011) Effectiveness of heparin solution versus normal saline in maintaining patency of intravenous locks in neonates: a double blind randomized controlled study. Journal of Advanced Nursing67(12), 2677-2685. ABSTRACT: Aim. The aim of this study was to evaluate the effect of heparin versus saline as flush solution for maintaining patency in peripheral intravenous locks in neonates and to investigate whether other variables influence the longevity of intravenous locks. Background. Heparin is usually used as a regular flush solution to prevent occlusion of peripheral intravenous locks in neonates. There is no clear recommendation using heparin or saline flushing peripheral intravenous locks in neonates. The disadvantage of heparin cannot be ignored, especially in this patient group. Methods. In a double blind prospective randomized study, neonates (gestational age >27 weeks) with intravenous locks were randomly assigned to receive heparin or saline as a flush solution in a 21-month period (2002-2004). The main outcome was the duration of patency. Results. Eighty-eight neonates were included. No statistically significant difference was found in patency of peripheral intravenous locks flushed with 0.7 mL heparin (10 units/mL) (N = 42, median 56 hours) or 0.7 mL saline (N = 46, median 61 hours). When the analysis was confined to removed locks because of non-elective events, no statistically significant difference was found in duration of patency (P = 0.27). Conclusion. As no difference in patency could be established, using saline as a flush solution is preferable to heparin in peripheral intravenous locks in neonates, given the greater likelihood of complications associated with heparin. Although these data are more than 5 years old, the relevance of the outcome is still important for the clinical practice because of the potential adverse effects of heparin in these vulnerable infants.

Item does not contain fulltext BACKGROUND: The transpulmonary thermodilution (TPTD) technique for measuring cardiac output (CO) has never been validated in the presence of a left-to-right shunt. METHODS: In this experimental, paediatric animal model, nine lambs with a surgically constructed aorta-pulmonary left-to-right shunt were studied under various haemodynamic conditions. CO was measured with closed and open shunt using the TPTD technique (CO(TPTD)) with central venous injections of ice-cold saline. An ultrasound transit time perivascular flow probe around the main pulmonary artery served as the standard reference measurement (CO(MPA)). RESULTS: Seven lambs were eligible for further analysis. Mean (sd) weight was 6.6 (1.6) kg. The mean CO(MPA) was 1.21 litre min(-1) (range 0.61-2.06 l min(-1)) with closed shunt and 0.93 litre min(-1) (range 0.48-1.45 litre min(-1)) with open shunt. The open shunt resulted in a mean Q(p)/Q(s) ratio of 1.8 (range 1.6-2.4). The bias between the two CO methods was 0.17 litre min(-1) [limits of agreement (LOA) of 0.27 litre min(-1)] with closed shunt and 0.14 litre min(-1) (LOA of 0.32 litre min(-1)) with open shunt. The percentage errors were 22% with closed shunt and 34% with open shunt. The correlation (r) between the two methods was 0.93 (P

Contains fulltext : 97426.pdf (Publisher’s version ) (Closed access) In obesity, insulin-stimulated glucose uptake in skeletal muscle is decreased. We investigated whether the stimulatory effect of acute exercise on glucose uptake and subsequent glycogen synthesis was normal. The study was performed on 18 healthy volunteers, 9 obese (BMI = 32.6 +/- 1.2 kg/m(2), mean +/- SEM) and 9 lean (BMI = 22.0 +/- 0.9 kg/m(2)), matched for age and gender. All participants underwent a euglycemic hyperinsulinemic clamp, showing reduced glucose uptake in the obese group (P = 0.01), during which they performed a short intense local exercise (single-legged toe lifting). Dynamic glucose incorporation into glycogen in the gastrocnemius muscle before and after exercise was assessed by (13)C magnetic resonance spectroscopy combined with infusion of [1-(13)C]glucose. Blood flow was measured to investigate its potential contribution to glucose uptake. Before exercise, glycogen synthesis rate tended to be lower in obese subjects compared with lean (78 +/- 14 vs. 132 +/- 24 mumol/kg muscle/min; P = 0.07). Exercise induced highly significant rises in glycogen synthesis rates in both groups, but the increase in obese subjects was reduced compared with lean (112 +/- 15 vs. 186 +/- 27 mumol/kg muscle/min; P = 0.03), although the relative increase was similar (184 +/- 35 vs. 202 +/- 51%; P = 0.78). After exercise, blood flow increased equally in both groups, without a temporal relationship with the rate of glycogen synthesis. In conclusion, this study shows a stimulatory effect of a short bout of acute exercise on insulin-induced glycogen synthesis rate that is reduced in absolute values but similar in percentages in obese subjects. These results suggest a shared pathway between insulin- and exercise-induced glucose uptake and subsequent glycogen synthesis.

Aims/hypothesis Hepatic steatosis is strongly associated with hepatic and whole-body insulin resistance. It has proved difficult to determine whether hepatic steatosis itself is a direct cause of insulin resistance. In patients with familial hypobetalipoproteinaemia (FHBL), hepatic steatosis is a direct consequence of impaired hepatic VLDL excretion, independently of metabolic derangements. Thus, patients with FHBL provide a unique opportunity to investigate the relation between increased liver fat and insulin sensitivity. Methods We included seven male participants with FHBL and seven healthy matched controls. Intrahepatic triacylglycerol content and intramyocellular lipid content were measured using localised proton magnetic resonance spectroscopy (¹H-MRS). A two-step hyperinsulinaemic–euglycaemic clamp, using stable isotopes, was assessed to determine hepatic and peripheral insulin sensitivity. Results ¹H-MRS showed moderate to severe hepatic steatosis in patients with FHBL. Basal endogenous glucose production (EGP) and glucose levels did not differ between the two groups, whereas insulin levels tended to be higher in patients compared with controls. Insulin-mediated suppression of EGP during lower dose insulin infusion and insulin-mediated peripheral glucose uptake during higher dose insulin infusion were comparable between FHBL participants and controls. Baseline fatty acids and lipolysis (glycerol turnover) at baseline and during the clamp did not differ between groups. Conclusions/interpretation In spite of moderate to severe hepatic steatosis, people with FHBL do not display a reduction in hepatic or peripheral insulin sensitivity compared with healthy matched controls. These results indicate that hepatic steatosis per se is not a causal factor leading to insulin resistance. Trial registration: ISRCTN35161775 Funding: This study was funded by the Departments of Vascular Medicine and Endocrinology and Metabolism of the Academic Medical Center Amsterdam. Electronic supplementary material The online version of this article (doi:10.1007/s00125-011-2157-x) contains supplementary material, which is available to authorised users.

Contains fulltext : 95767.pdf (Publisher’s version ) (Open Access) Clinical diagnosis of heart disease might be substantially supported by automated segmentation of the endocardial surface in three-dimensional (3-D) echographic images. Because of the poor echogenicity contrast between blood and myocardial tissue in some regions and the inherent speckle noise, automated analysis of these images is challenging. A priori knowledge on the shape of the heart cannot always be relied on, e.g., in children with congenital heart disease, segmentation should be based on the echo features solely. The objective of this study was to investigate the merit of using temporal cross-correlation of radio-frequency (RF) data for automated segmentation of 3-D echocardiographic images. Maximum temporal cross-correlation (MCC) values were determined locally from the RF-data using an iterative 3-D technique. MCC values as well as a combination of MCC values and adaptive filtered, demodulated RF-data were used as an additional, external force in a deformable model approach to segment the endocardial surface and were tested against manually segmented surfaces. Results on 3-D full volume images (Philips, iE33) of 10 healthy children demonstrate that MCC values derived from the RF signal yield a useful parameter to distinguish between blood and myocardium in regions with low echogenicity contrast and incorporation of MCC improves the segmentation results significantly. Further investigation of the MCC over the whole cardiac cycle is required to exploit the full benefit of it for automated segmentation.

Contains fulltext : 97745.pdf (Publisher’s version ) (Closed access) PURPOSE: Cholecystokinin 2 (CCK-2) receptor overexpression has been demonstrated in various tumours such as medullary thyroid carcinomas and small-cell lung cancers. Due to this high expression, CCK-2 receptors might be suitable targets for radionuclide imaging and/or radionuclide therapy. Several CCK-2 receptor-binding radiopeptides have been developed and some have been tested in patients. Here we aimed to compare the in vivo tumour targeting properties of 12 (111)In-labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated gastrin/CCK2 receptor-binding peptides. METHODS: Two CCK8-based peptides and ten gastrin-based peptide analogues were tested. All peptides were conjugated with DOTA and labelled with (111)In. Biodistribution studies were performed in mice with subcutaneous CCK2/gastrin receptor-expressing tumours and with receptor-negative tumours contralaterally. Biodistribution was studied by counting dissected tissues at 1 and 4 h after injection. RESULTS: Both the CCK analogues displayed relatively low tumour uptake (approximately 2.5%ID/g) as compared to minigastrin analogues. Two linear minigastrin peptides (MG0 and sargastrin) displayed moderate tumour uptake at both 1 and 4 h after injection, but also very high kidney uptake (both higher than 48%ID/g). The linear MG11, lacking the penta-Glu sequence, showed lower tumour uptake and also low kidney uptake. Varying the N-terminal Glu residues in the minigastrin analogues led to improved tumour targeting properties, with PP-F11 displaying the optimal biodistribution. Besides the monomeric linear peptides, a cyclized peptide and a divalent peptide were tested. CONCLUSION: Based on these studies, optimal peptides for peptide receptor radionuclide targeting of CCK2/gastrin receptor-expressing tumours were the linear minigastrin analogue with six D-Glu residues (PP-F11), the divalent analogue MGD5 and the cyclic peptide cyclo-MG1. These peptides combined high tumour uptake with low kidney retention, and may therefore be good candidates for future clinical studies.

Hemodynamic monitoring plays a fundamental role in the management of acutely ill patients. With increased concerns about the use of invasive techniques, notably the pulmonary artery catheter, to measure cardiac output, recent years have seen an influx of new, less-invasive means of measuring hemodynamic variables, leaving the clinician somewhat bewildered as to which technique, if any, is best and which he/she should use. In this consensus paper, we try to provide some clarification, offering an objective review of the available monitoring systems, including their specific advantages and limitations, and highlighting some key principles underlying hemodynamic monitoring in critically ill patients., Journal Article, Research Support, Non-U.S. Gov't, Review, SCOPUS: re.j, info:eu-repo/semantics/published

Contains fulltext : 88195.pdf (Publisher’s version ) (Closed access) Nuclear medicine imaging procedures play an important role in the assessment of inflammatory diseases. With the advent of 3-dimensional anatomic imaging, there has been a tendency to replace traditional planar scintigraphy by CT or MRI. Furthermore, scintigraphic techniques may have to be combined with other imaging modalities to achieve high sensitivity and specificity, and some may require time-consuming labeling procedures. On the other hand, new developments such as combined SPECT/CT increase the diagnostic power of scintigraphy. Also, the advent of PET had a considerable impact on the use of nuclear medicine imaging techniques. In this review, we aim to provide nuclear medicine specialists and clinicians with the relevant information on rational and efficient use of nuclear medicine imaging techniques in the assessment of patients with osteomyelitis, infected vascular prostheses, metastatic infectious disease, rheumatoid arthritis, vasculitis, inflammatory bowel disease, sarcoidosis, and fever of unknown origin. 01 december 2010

Contains fulltext : 96519.pdf (Publisher’s version ) (Closed access) Birth weight and longitudinal growth in the first 4 years of life of term singletons conceived with the use of IVF and intracytoplasmic sperm injection (ICSI) were compared with those of naturally conceived singletons. Although IVF and ICSI singletons had a statistically significantly lower birth weight than naturally conceived singletons, the average individual weight curves showed that this difference was lost before the age of 4 years in all subgroups: IVF, ICSI, boys, and girls.

Contains fulltext : 88548.pdf (Publisher’s version ) (Closed access) Ultrasound strain imaging is used to measure local tissue deformations. Usually, only strains along the ultrasound beam are estimated, because those estimates are most precise, due to the availability of phase information. For estimating strain in other directions we propose to steer the ultrasound beam at an angle, which allows estimating different projections of the 2D strain tensor, while phase information remains available. This study investigates beam steering at maximally three different angles to determine the full 2D strain tensor. The method was tested on simulated and experimental data of an inclusion phantom and a vessel phantom. The combination of data from a non-steered acquisition and acquisitions at a large positive and an equally large but negative steering angle enabled the most precise estimation of the strain components. The method outperforms conventional methods that do not use beam steering.

Contains fulltext : 88920.pdf (Publisher’s version ) (Closed access) To assess the prevalence, history, and treatment of arrhythmias, in particular preexcitation and Wolff-Parkinson-White (WPW) syndrome, in patients with Ebstein anomaly (EA) during childhood and adolescence, we performed a multicenter retrospective study of all consecutive live-born patients with EA, diagnosed, and followed by pediatric cardiologists between 1980 and 2005 in The Netherlands. During a follow-up after EA diagnosis of 13 years 3 months (range: 6 days to 28 years 2 months), 16 (17%) of the 93 pediatric EA patients exhibited rhythm disturbances. Nine patients showed arrhythmic events starting as of the neonatal period. Supraventricular tachycardia was noted in 11 patients. One patient died in the neonatal period due to intractable supraventricular tachycardia resulting in heart failure and one patient died at 5 weeks of age most probably due to an arrhythmic event. The 14 surviving patients all show preexcitation, albeit 4 of them intermittently, and all have a right-sided accessory pathway location. Nine patients underwent catheter ablation of an accessory pathway. Only four patients are currently on antiarrhythmic drugs. The 17% prevalence of rhythm disturbances in pediatric EA patients, most commonly supraventricular arrhythmias, is significantly lower than in adult EA patients. Life-threatening rhythm disturbances are not frequent early in life. Symptomatic patients are well treated with radiofrequency catheter ablation. 01 februari 2010

Contains fulltext : 89924_pub.pdf (Publisher’s version ) (Closed access) Contains fulltext : 89924_aut.pdf (author's version ) (Open Access) The effect of insulin-induced hypoglycemia on cerebral glucose metabolism is largely unknown. (13)C MRS is a unique tool to study cerebral glucose metabolism, but the concurrent requirement for [1-(13)C]glucose administration limits its use under hypoglycemic conditions. To facilitate (13)C MRS data analysis we designed separate [1-(13)C]glucose infusion protocols for hyperinsulinemic euglycemic and hypoglycemic clamps in such a way that plasma isotopic enrichment of glucose was stable and comparable under both glycemic conditions. (13)C MR spectra were acquired with optimized (13)C MRS measurement techniques to obtain high quality (13)C MR spectra with these protocols.