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Background— Loss-of-function mutations in CHD7 cause Coloboma, Heart Disease, Atresia of Choanae, Retardation of Growth and/or Development, Genital Hypoplasia, and Ear Abnormalities With or Without Deafness (CHARGE) syndrome, a variable combination of multiple congenital malformations including heart defects. Heart defects are reported in 70% to 92% of patients with a CHD7 mutation, but most studies are small and do not provide a detailed classification of the defects. We present the first, detailed, descriptive study on the cardiac phenotype of 299 patients with a CHD7 mutation and discuss the role of CHD7 in cardiac development. Methods and Results— We collected information on congenital heart defects in 299 patients with a pathogenic CHD7 mutation, of whom 220 (74%) had a congenital heart defect. Detailed information on the heart defects was available for 202 of these patients. We classified the heart defects based on embryonic cardiac development and compared the distribution to 1007 equally classified nonsyndromic heart defects of patients registered by EUROCAT, a European Registry of Congenital Anomalies. Heart defects are highly variable in patients with CHD7 mutations, but atrioventricular septal defects and conotruncal heart defects are over-represented. Sex did not have an effect on the presence of heart defects, but truncating CHD7 mutations resulted in a heart defect significantly more often than missense or splice-site mutations (χ 2 , P Conclusions— CHD7 plays an important role in cardiac development, given that we found a wide range of heart defects in 74% of a large cohort of patients with a CHD7 mutation. Conotruncal defects and atrioventricular septal defects are over-represented in patients with CHD7 mutations compared with patients with nonsyndromic heart defects.

Item does not contain fulltext Proper functioning of pancreatic islets requires that numerous beta-cells are properly coordinated. With evolution, many mechanisms have converged, which now allow individual beta-cells to sense the state of activity of their neighbors as well as the changes taking place in the extracellular medium, and to regulate accordingly their own function. Here, we review one such mechanism for intercellular coordination, which depends on connexins. These integral membrane proteins accumulate at sites of close apposition between adjacent islet cell membranes, referred to as gap junctions. Recent evidence demonstrates that connexin-dependent signaling is relevant for the in vivo control of insulin biosynthesis and release, as well as for the survival of beta-cells under stressing conditions. The data suggest that alterations of this signaling may be implicated in the beta-cell alterations which characterize most forms of diabetes, raising the tantalizing possibility that targeting of the direct intercellular communications beta-cells establish within each pancreatic islet may provide a novel, therapeutically useful strategy.

Item does not contain fulltext BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are typically overweight and have an increased liver fat content (LFAT). High LFAT may be explained by an increased efflux of free fatty acids from the adipose tissue, which is partly instigated by inflammatory changes. This would imply an association between inflammatory features of the adipose tissue and liver fat content. OBJECTIVE: To analyse associations between inflammatory features of the adipose tissue and liver fat content. DESIGN: A cross-sectional study. PATIENTS: Twenty-seven obese patients with insulin-treated T2DM were studied. MEASUREMENTS: LFAT content was measured by proton magnetic resonance spectroscopy. A subcutaneous (sc) fat biopsy was obtained to determine morphology and protein levels within adipose tissue. In addition to fat cell size, the percentage of macrophages and the presence of crown-like structures (CLSs) within sc fat were assessed by CD68-immunohistochemical staining. RESULTS: Mean LFAT percentage was 11.1 +/- 1.7% (range: 0.75-32.9%); 63% of the patients were diagnosed with an elevated LFAT (upper range of normal

SummaryAim: Cardiac 123I metaiodobenzylguanidine (MIBG) imaging can be influenced by several factors. We evaluated the relationship between catecholamine measurements and cardiac 123I MIBG uptake in neuroblastoma patients. Patients, methods: 30 neuroblastoma patients were retrospectively assessed on cardiac 123I MIBG uptake and urinary catecholamine dopamine and metabolites, homovanillic acid (HVA) and vanillylmandelic acid (VMA). Cardiac 123I MIBG uptake was quantified by heart-to-mediastinum (H/M) ratios, which were calculated into standard deviation scores (SDS) using age-specific reference values. Results: In 17 (57%) and 12 patients (40%) H/M ratio measurements were below –1.0 and –2.0 SDS at diagnosis. A significant inverse correlation between the average of urine metabolites HVA and VMA, and H/M ratio SDS was observed (r -.39, p = 0.04). Furthermore, there was a significant correlation between the urinary catecholamine metabolite HVA and H/M ratio SDS (r -.40, p = 0.04). Conclusion: Routine calculation of H/M ratios in 123I MIBG scintigrams of neuroblastoma patients is not helpful because it will not identify cardiac ventricular dysfunction in this patient category. A low H/M ratio on 123I MIBG scintigraphy is explained by increased cathecholamine levels secreted by neuroblastoma tumours.

Item does not contain fulltext Mid-aortic syndrome is characterized by narrowing of the abdominal aorta, usually with the involvement of renal arteries and other visceral branches. The combination of the presence of an abdominal bruit, diminished or absent pulsations of the lower extremities, and a blood pressure discrepancy between upper and lower extremities is the classic triad associated with mid-aortic syndrome. However, it has a wide variety of clinical symptoms, and awareness of the variable presentation can lead to early diagnosis of the vascular anomaly. We report three cases presenting at three different stages of this disease, such as hydrops fetalis, refractory hypertension, and intracerebral bleeding. In conclusion, these cases highlight the importance of blood pressure measurements in all patients and accurate physical examination for early recognition of a mid-aortic syndrome. 01 maart 2013

Item does not contain fulltext Chemotherapy and particularly anthracycline exposure are associated with acute and chronic cardiotoxicity. Few data exist on the effect of cardiac function after in utero exposure to maternal chemotherapy. Our recently published multicenter prospective study showed no significant changes in systolic function using conventional echocardiographic parameters. The purpose of this study was to further investigate whether early functional changes can be detected using tissue Doppler imaging (TDI) and two-dimensional (2D) speckle tracking echocardiography (STE). Sixty-two children (median/range age 1.7 (1-9.8) years) exposed to chemotherapy during fetal life were enrolled and compared to 62 age- and gender-matched controls. TDI velocities were measured at the basal interventricular septum (IVS) and right and left ventricular (LV) free walls. LV global longitudinal and circumferential systolic strains were derived using 2D STE. We found small but significant differences between the groups (patients versus controls) in LV fractional shortening [35 (29-46)% versus 39 (28-53)%, p < 0.001], LV ejection fraction [66 (57-79)% versus 70 (57-83)%, p < 0.001], LV posterior wall thickness z score [-0.15 (-2.32-1.81) versus -0.10 (-1.9-2.0), p < 0.001], and IVS thickness z score [-1.06 (-2.6-1.3) versus -0.5 (-2.1-1.7), p < 0.001]. No significant differences in TDI velocities or LV global strains were observed. Within the patient group, the cardiac functional parameters did not correlate to the number of cycles of anthracycline or the cumulative anthracycline dose. Children exposed to fetal chemotherapy have a lower normal fractional shortening and mildly lower left ventricular wall thickness. Tissue Doppler and strain measurements are within normal range and not statistically different from normal controls. The long-term implications of these findings will be further studied in this prospective cohort study.

Item does not contain fulltext BACKGROUND: Data on myocardial deformation during the internationally widely used second-trimester screening are scarce and confusing. Reference values of time to peak strain are missing. The aims of this study were to assess reference values derived from two-dimensional speckle-tracking echocardiography for global and regional longitudinal right ventricular (RV) and left ventricular (LV) strain, strain rate, and time to peak global strain and to determine the influence of heart rate and gender on these strain parameters. METHODS: Seventy-five healthy fetuses were enrolled during second-trimester ultrasound (20-24 weeks). Clips with high frame rates (mean, 132 frames/sec) and two-dimensional (B-mode) grayscale images of apical or basal four-chamber views of both ventricles were used for offline analyses. RESULTS: There were no statistically significant differences in global strain and strain rate between both ventricles (P = .679 and P = .734, respectively) or among the RV, septal, and LV free walls. Regional measurements, modeled also as an interaction of wall and segment (basal mid and apical), showed only a small, statistically significant difference between the basal RV and LV free walls. Strain and strain rate values were independent of heart rate. The mean time to peak LV global strain adjusted for heart rate was statistically significantly shorter than the RV value (P < .0001]). Strain, strain rate, and time to peak global strain were not found to be associated with gender. CONCLUSIONS: The establishment of second-trimester two-dimensional speckle-tracking echocardiographic reference values for global and regional strain, strain rate, and time to peak global strain in a healthy fetal cohort is a mandatory prerequisite for its use in evaluating (pathologic) changes in both ventricular functions during pregnancy.

Item does not contain fulltext Cardiac pathologies are the major aspect in the treatment strategies for Marfan syndrome (MFS). In this progressive disease, less is known about manifestations and progression of cardiovascular symptoms in children. To define a certain decision regarding therapeutic options, knowledge concerning the onset of cardiovascular findings is essential. From 1998 to 2011, suspected pediatric Marfan patients were subjected to a standardized diagnostic program. Cardiovascular findings were analyzed in terms of age at first clinical manifestation, prevalence and gender differences, morbidity, mortality, and treatment. Marfan syndrome was diagnosed in 82 patients (46 boys; mean age at diagnosis, 9.0 +/- 5.7 years). At first presentation, aortic root dilation was found in 56 % of patients, mitral valve prolapse in 31 %, whereas pulmonary artery dilation was detected in 22 % and tricuspid valve prolapse in only 17 % of patients. Aortic (2.5 %) and mitral valve regurgitations (22 %) are significantly correlated with aortic root dilation (p < 0.01) and mitral valve prolapse (p < 0.05) but without relevant progression during childhood. Prophylactic medication was initiated for 42 % of the patients (mean age, 8.0 +/- 4.5 years) because of progressive aortic root dilation. Aortic dissection did not appear. Aortic root surgery was needed for 4 % of the patients. Gender-specific differences in cardiovascular findings, progression of disease, or treatment did not appear. Comparable with adults, aortic root dilation is the most frequent cardiovascular finding in children and associated with relevant morbidity, whereas aortic and mitral valve regurgitation are of minor clinical relevance. Manifestation at an early age and slow progression of cardiovascular findings underscore the necessity of repeated echocardiographic examinations for early diagnosis and start of prophylactic treatment. 01 april 2013

Item does not contain fulltext There is increasing evidence that supports the hypothesis that elevated cyclic shear strain in the adventitia of the common carotid artery promotes plaque progression. In this article, we estimated cyclic shear strain in the carotid arterial wall in 16 asymptomatic human participants using radio-frequency (RF) ultrasound. In each participant, we acquired two separate RF ultrasound recordings. We correlated the cyclic shear strain with the distension waveform (representing the blood pressure waveform) of the carotid artery and the brachial blood pressure. There were no significant differences between the shear strains estimated from the two separate RF ultrasound recordings. The point-in-time of the maximum shear strain showed a significant correlation with that of the dicrotic notch in the distension waveform (Spearman's coefficient = 0.7, p < 0.001). The pulse shear strain (difference between maximum and minimum shear strain) was significantly correlated with the pulse pressure as measured in the brachial artery (Spearman's coefficient = 0.4, p < 0.01). In this study, we show that the cyclic shear strain in the adventitia of the common carotid artery can be estimated using RF ultrasound. We found indications that the estimated cyclic shear strain was induced by the pulsating blood pressure and it was found to be higher in participants with an elevated pulse pressure.

Item does not contain fulltext BACKGROUND: The aim of this study was to investige serial changes of myocardial deformation using two-dimensional speckle-tracking echocardiographic (2DSTE) imaging in children undergoing balloon valvuloplasty for congenital valvular aortic stenosis (VAS). METHODS: Thirty-seven children with isolated congenital VAS were enrolled in this study prospectively. Patients underwent echocardiographic evaluation at three instances: before balloon valvuloplasty, 6 months after intervention, and 3 years after intervention. Longitudinal, circumferential, and radial peak systolic strain values were determined, as well as systolic strain rate and the time to peak global systolic strain. Linear mixed statistical models were used to assess changes in 2DSTE parameters after balloon intervention. Using one-way analysis of variance, 2DSTE results at 3-year follow-up were compared with 2DSTE measurements in 74 healthy age-matched children and 76 children with uncorrected VAS whose severity of stenosis corresponded to residual stenosis of study subjects at 3-year follow-up. RESULTS: Global peak strain and strain rate measurements in all three directions were decreased before intervention compared with healthy children. Global peak strain and strain rate measurements increased significantly (P < .001) several months after balloon valvuloplasty and continued to increase at 3-year follow-up. However, at 3-year follow-up, global peak strain and strain rate in the longitudinal and circumferential directions were significantly lower (P < .001) compared with both control groups. Measurements of time to peak global systolic strain were significantly shorter at early follow-up compared with measurements before intervention (P < .05). CONCLUSIONS: Shortly after balloon valvuloplasty for severe congenital VAS, there is an improvement in systolic myocardial deformation. However, 2DSTE parameters do not return to normal at 3-year follow-up. These abnormalities in systolic deformation cannot be fully attributed to residual stenosis or aortic regurgitation. 01 mei 2012

For more than a decade, researchers have been trying to develop non-invasive imaging techniques for the in vivo measurement of viable pancreatic beta cells. However, in spite of intense research efforts, only one tracer for positron emission tomography (PET) imaging is currently under clinical evaluation. To many diabetologists it may remain unclear why the imaging world struggles to develop an effective method for non-invasive beta cell imaging (BCI), which could be useful for both research and clinical purposes. Here, we provide a concise overview of the obstacles and challenges encountered on the way to such BCI, in both native and transplanted islets. We discuss the major difficulties posed by the anatomical and cell biological features of pancreatic islets, as well as the chemical and physical limits of the main imaging modalities, with special focus on PET, SPECT and MRI. We conclude by indicating new avenues for future research in the field, based on several remarkable recent results., Journal Article, Research Support, Non-U.S. Gov't, Review, SCOPUS: re.j, info:eu-repo/semantics/published

Contains fulltext : 97020.pdf (Publisher’s version ) (Closed access) OBJECTIVE: : To estimate whether normotensive women who were born small for gestational age have low plasma volume in adult life, which is associated with later chronic hypertension. METHODS: : In 280 normotensive women with a history of hypertension in pregnancy, we recorded recalled gestational age and weight at birth and measured plasma volume (I-human serum albumin indicator dilution method). To correct for possible confounders, we recorded recent obstetric history and measured in each individual all constituents of the metabolic syndrome (World Health Organization criteria), sex hormones (progesterone and estradiol), renal function, and cardiac performance at rest (echocardiography). We estimated daily activity level with a validated questionnaire (Short Questionnaire to Assess Health-enhancing physical activity). We studied the relation between women's own birth weight centile and her adult plasma volume (mL) and adjusted for the effects of confounding variables using multiple linear regression analysis. RESULTS: : Birth weight correlated positively with adult plasma volume (P

Contains fulltext : 95780.pdf (Publisher’s version ) (Closed access) Recent evidence implies that impaired metabolism of glutathione has a role in the pathogenesis of nephropathic cystinosis. This recessive inherited disorder is characterized by lysosomal cystine accumulation and results in renal Fanconi syndrome progressing to end stage renal disease in the majority of patients. The most common treatment involves intracellular cystine depletion by cysteamine, delaying the development of end stage renal disease by a yet elusive mechanism. However, cystine depletion does not arrest the disease nor cures Fanconi syndrome in patients, indicating involvement of other yet unknown pathologic pathways. Using a newly developed proximal tubular epithelial cell model from cystinotic patients, we investigate the effect of cystine accumulation and cysteamine on both glutathione and ATP metabolism. In addition to the expected increase in cystine and defective sodium-dependent phosphate reabsorption, we observed less negative glutathione redox status and decreased intracellular ATP levels. No differences between control and cystinosis cell lines were observed with respect to protein turnover, albumin uptake, cytosolic and mitochondrial ATP production, total glutathione levels, protein oxidation and lipid peroxidation. Cysteamine treatment increased total glutathione in both control and cystinotic cells and normalized cystine levels and glutathione redox status in cystinotic cells. However, cysteamine did not improve decreased sodium-dependent phosphate uptake. Our data implicate that cysteamine increases total glutathione and restores glutathione redox status in cystinosis, which is a positive side-effect of this agent next to cystine depletion. This beneficial effect points to a potential role of cysteamine as anti-oxidant for other renal disorders associated with enhanced oxidative stress.

OBJECTIVE To investigate the effect of acute insulin-induced hypoglycemia on cerebral glucose metabolism in healthy humans, measured by 13C magnetic resonance spectroscopy (MRS). RESEARCH DESIGN AND METHODS Hyperinsulinemic glucose clamps were performed at plasma glucose levels of 5 mmol/L (euglycemia) or 3 mmol/L (hypoglycemia) in random order in eight healthy subjects (four women) on two occasions, separated by at least 3 weeks. Enriched [1-13C]glucose 20% w/w was used for the clamps to maintain stable plasma glucose labeling. The levels of the 13C-labeled glucose metabolites glutamate C4 and C3 were measured over time in the occipital cortex during the clamp by continuous 13C MRS in a 3T magnetic resonance scanner. Time courses of glutamate C4 and C3 labeling were fitted using a one-compartment model to calculate metabolic rates in the brain. RESULTS Plasma glucose 13C isotopic enrichment was stable at 35.1 ± 1.8% during euglycemia and at 30.2 ± 5.5% during hypoglycemia. Hypoglycemia stimulated release of counterregulatory hormones (all P < 0.05) and tended to increase plasma lactate levels (P = 0.07). After correction for the ambient 13C enrichment values, label incorporation into glucose metabolites was virtually identical under both glycemic conditions. Calculated tricarboxylic acid cycle rates (VTCA) were 0.48 ± 0.03 μmol/g/min during euglycemia and 0.43 ± 0.08 μmol/g/min during hypoglycemia (P = 0.42). CONCLUSIONS These results indicate that acute moderate hypoglycemia does not affect fluxes through the main pathways of glucose metabolism in the brain of healthy nondiabetic subjects.

Contains fulltext : 88176.pdf (Publisher’s version ) (Open Access) In this study, first we propose a biplane strain imaging method using a commercial ultrasound system, yielding estimation of the strain in three orthogonal directions. Secondly, an animal model of a child's heart was introduced that is suitable to simulate congenital heart disease and was used to test the method in vivo. The proposed approach can serve as a framework to monitor the development of cardiac hypertrophy and fibrosis. A 2D strain estimation technique using radio frequency (RF) ultrasound data was applied. Biplane image acquisition was performed at a relatively low frame rate (

ContextPatients with congenital adrenal hyperplasia (CAH) are chronically treated with supraphysiological doses of glucocorticoids, which are known to induce insulin resistance. Thiazolidinediones might reverse this effect and improve insulin sensitivity.ObjectivesTo assess insulin sensitivity in CAH patients and the effect of pioglitazone treatment on insulin sensitivity in CAH patients. Secondary objectives were the effects of treatment with pioglitazone on blood pressure, body fat distribution, lipid, and steroid profiles.DesignRandomized placebo controlled crossover trial.ParticipantsTwelve CAH patients and 12 body mass and age-matched control subjects.InterventionSixteen-week treatment with pioglitazone (45 mg/day) or placebo.Main outcome measureInsulin sensitivity measured by euglycemic clamp and oral glucose tolerance test. Further measures were 24-h blood pressure profiles, body fat distribution measured by magnetic resonance imaging, dual energy x-ray absorptiometry (DEXA) and bioimpedance procedures, liver fat by magnetic resonance spectroscopy, lipid, and steroid profiles.ResultsCAH patients were insulin resistant compared with healthy controls. Treatment with pioglitazone significantly improved insulin sensitivity in CAH patients (glucose infusion rate (GIR) from 28.5±11.6 to 38.9±11.0 μmol/kg per min, P=0.000, GIR in controls 46.2±23.4 μmol/kg per min, PPPConclusionsCAH patients are insulin resistant compared with matched control subjects. Treatment with pioglitazone improves insulin sensitivity and decreases blood pressure in CAH patients.

Item does not contain fulltext OBJECTIVE: To evaluate the effect of furosemide on renal function and water balance in preterm infants treated with indomethacin (3 x 0.2 mg/kg at 12-h intervals) for symptomatic patent ductus arteriosus. Patients and METHODS: We performed a retrospective multi-centre double cohort study in preterm infants

Agouti-related protein (AGRP) is a homolog of the agouti protein and acts as an antagonist of peptides derived from propiomelanocortin through melanocortin receptors. This peptide is produced mainly in the hypothalamus, particularly during negative energy balance and influences increased food intake. In the hypothalamus, this peptide is co-expressed in arcuate nuclei with neuropeptide Y, another important peptide that regulates energy metabolisms. In our study, we analyzed changes in the Agrp mRNA level in the hypothalamus as well as mRNA and protein levels in placenta during different stages of rat pregnancy. We also investigated the AGRP level in the blood serum. In this study, we found the AGRP level in serum increased, while its gene expression in the hypothalamus increased only up to the 13th day of pregnancy, and decreased on the 18th day. This study demonstrates that AGRP is expressed during late pregnancy in placenta. Moreover, we found that AGRP expression is higher on the 18th than on the 13th day of pregnancy. Our results indicate that AGRP may play an important role during pregnancy in the mother's and, possibly, also in the fetus's energy balance.

Contains fulltext : 81813.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Lipid-induced immune modulation might contribute to the increased infection rate that is observed in patients using parenteral nutrition. We previously showed that emulsions containing medium-chain triglycerides (LCT/MCTs or pure MCTs), but not pure long-chain triglycerides (LCTs), impair neutrophil functions, modulate cell-signaling and induce neutrophil activation in vitro. It has recently been shown that medium-chain fatty acids are ligands for GPR84, a pertussis toxin (PT)-sensitive G-protein-coupled receptor (GPCR). This finding urged us to investigate whether MCT-induced neutrophil activation is mediated by PT-sensitive GPCRs. METHODS: Neutrophils isolated from blood of healthy volunteers were pre-incubated with PT (0.5-1 microg/mL, 1.5 h) and analyzed for the effect of this pre-incubation on LCT/MCT (2.5 mmol/L)-dependent modulation of serum-treated zymosan (STZ)-induced intracellular Ca(2+) mobilization and on LCT/MCT (5 mmol/L)-induced expression of cell surface adhesion (CD11b) and degranulation (CD66b) markers and oxygen radical (ROS) production. RESULTS: PT did not inhibit the effects of LCT/MCT on the STZ-induced increase in cytosolic free Ca(2+) concentration. LCT/MCT increased ROS production to 146% of unstimulated cells. However, pre-incubation with PT did not inhibit the LCT/MCT-induced ROS production. Furthermore, the LCT/MCT-induced increase in CD11b and CD66b expression (196% and 235% of unstimulated cells, respectively) was not inhibited by pre-incubation with PT. CONCLUSION: LCT/MCT-induced neutrophil activation does not involve the action of a PT-sensitive G-protein-coupled receptor.

OBJECTIVES Neuromedin U (NmU) is a neuropeptide with anorexigenic activity. Two receptor subtypes (NmUR1 and NmUR2) confer the effects of NmU on target cells. We have recently demonstrated that NmU reduces insulin secretion from isolated pancreatic islets. Aim of our current study is to investigate the role of somatostatin at mediating the effects of NmU on insulin secretion. METHODS Expression of NmU in the pancreas was detected by immunohistochemistry. Insulin and somatostatin secretion from in situ perfused rat pancreas and isolated pancreatic islets was measured by radioimmunoassay. The paracrine effects of somatostatin within pancreatic islets were blocked by cyclosomatostatin, a somatostatin receptor antagonist. RESULTS Receptor subtype NmUR1, but not NmUR2, was expressed in the endocrine pancreas, predominantly in the periphery. Neuromedin U reduced insulin secretion from in situ perfused rat pancreas and stimulated somatostatin secretion from isolated pancreatic islets. Neuromedin U stimulated somatostatin secretion at both physiological and supraphysiological glucose concentrations. Cyclosomatostatin increased insulin secretion and reduced NmU-induced inhibition of insulin secretion. CONCLUSIONS Neuromedin U reduces insulin and increases somatostatin secretion. Blockade of somatostatin action abolishes the inhibition of insulin secretion by NmU. The results of the study suggest that somatostatin mediates the inhibitory action of NmU on insulin secretion.

Item does not contain fulltext PURPOSE: To assess pulmonary artery (PA) size, flow variables, and wall shear stress (WSS) in patients after Fontan operation at a young age. MATERIALS AND METHODS: Flow in the branch PA was obtained with phase contrast velocity-encoded cardiovascular magnetic resonance imaging in 14 patients before and after low-dose dobutamine stress (7.5 microg/kg/min) and in 17 healthy controls at rest. RESULTS: At rest, stroke index, total flow, average, and peak flow rate were all statistically significantly lower in patients than in controls (P

Contains fulltext : 69461.pdf (Publisher’s version ) (Closed access) After Fontan operation, patients are limited in increasing cardiac output and in exercise capacity. This has been related to impaired preload or other factors leading to decreased global ventricular performance with stress. To study these factors, the stress responses of functionally univentricular hearts were assessed at rest and during low-dose dobutamine stress using cardiovascular magnetic resonance imaging. Thirty-two patients after Fontan completion at young age were included (27 with total cavopulmonary connection, 5 with atriopulmonary connection; mean age 13.3 years, range 7.5 to 22.2; 23 male patients; median follow-up after Fontan operation 8.1 years, range 5.2 to 17.8). A multiphase short-axis stack of 10 to 12 contiguous slices of the systemic ventricle was obtained at rest and during low-dose dobutamine stress cardiovascular magnetic resonance imaging (maximum 7.5 microg/kg/min). With stress-testing, heart rate, ejection fraction, and cardiac index increased adequately (p

Contains fulltext : 69748.pdf (Publisher’s version ) (Closed access) Congenital diaphragmatic hernia (CDH) is a disorder of the development of the lung and diaphragm and is associated with pulmonary hypoplasia and pulmonary hypertension. Denys-Drash syndrome (DDS) is a well-known syndrome caused by several different germline mutations in the WT1-gene. CDH in DDS is rare. We present the third case of CDH with clinical features of DDS and the same, rare Arg366His mutation in the WT1-gene, as reported in the other two known cases. This report provides additional evidence that WT1 mutations can result in diaphragmatic hernia.

SummaryAim: In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, kidney uptake of radiolabelled compound is the major dose-limiting factor. We studied the effects of Gelofusine (20 mg) and lysine (100 mg) and the combination of both after injection of therapeutic doses of radiolabelled [DOTA0,Tyr3]octreotate (60 MBq 111In or 555 MBq 177Lu labelled to 15 μg peptide) in male Lewis rats. Methods: Kidney uptake was measured by single photon emission computed tomography (SPECT) scans with a four-headed multi-pinhole camera (NanoSPECT) at 24 h, 5 and 7 days p. i. and was quantified by volume of interest analysis. For validation the activity concentration in the dissected kidneys was also determined ex vivo using a gamma counter and a dose calibrator. Results: Gelofusine and lysine both reduced kidney uptake of [177Lu-DOTA0,Tyr3]octreotate significantly by about 40% at all time points. The combination of Gelo - fusine and lysine resulted in a 62% inhibition of kidney uptake (p < 0.01 vs. lysine alone). A weak but significant dose-response relationship for Gelofusine, but not for lysine, was found. In a study with [111In-DOTA0,Tyr3]octreotate, conclusions drawn from NanoSPECT data were confirmed by biodistribution data. Conclusions: We conclude that rat kidney uptake of radiolabelled somatostatin analogues can be monitored for a longer period in the same animal using animal SPECT. Gelofusine and lysine had equal potential to reduce kidney uptake of therapeutic doses of [177Lu-DOTA0,Tyr3]octreotate. The combination of these compounds caused a significantly larger reduction than lysine or Gelofusine alone and may therefore offer new possibilities in PRRT. The NanoSPECT data were validated by standard biodistribution experiments.

Purpose: Although metabolic changes make diagnosis of insulinoma relatively easy, surgical removal is hampered by difficulties in locating it, and there is no efficient treatment for malignant insulinoma. We have previously shown that the high density of glucagon-like peptide-1 receptors (GLP-1R) in human insulinoma cells provides an attractive target for molecular imaging and internal radiotherapy. In this study, we investigated the therapeutic potential of [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4, an 111In-labeled agonist of GLP-1, in a transgenic mouse model of human insulinoma. Experimental Design: [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 was assessed in the Rip1Tag2 mouse model of pancreatic β-cell carcinogenesis, which exhibits a GLP-1R expression comparable with human insulinoma. Mice were injected with 1.1, 5.6, or 28 MBq of the radiopeptide and sacrificed 7 days after injection. Tumor uptake and response, the mechanism of action of the radiopeptide, and therapy toxicity were investigated. Results: Tumor uptake was >200% injected activity per gram, with a dose deposition of 3 Gy/MBq at 40 pmol [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4. Other GLP-1R–positive organs showed ≥30 times lower dose deposition. A single injection of [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 resulted in a reduction of the tumor volume by up to 94% in a dose-dependent manner without significant acute organ toxicity. The therapeutic effect was due to increased tumor cell apoptosis and necrosis and decreased proliferation. Conclusions: The results suggest that [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a promising radiopeptide capable of selectively targeting insulinoma. Furthermore, Auger-emitting radiopharmaceuticals such as 111In are able to produce a marked therapeutic effect if a high tumor uptake is achieved.

Background: Insufficient cerebral O2 supply leads to cellular energy failure and loss of brain cell function. The relationship between the severity of cellular energy failure due to hemorrhagic hypotension and the loss of electrocortical brain activity (ECBA), as a measure of brain cell function, is not yet fully elucidated in near-term born lambs. Objectives: To study the relationship between cerebral purine and pyrimidine metabolism, as a measure of brain cell energy failure, and brain cell function after hemorrhagic hypotension in near-term born lambs. Methods: Eight near-term lambs (term 147 days) were delivered at 131 days of gestation. After a stabilization period, mean arterial blood pressure was reduced till 30% of baseline by withdrawal of blood. Cerebrospinal fluid (CSF) was obtained at the end of the hypotensive period (2.5 h). CSF from 8 siblings was used for comparison. HPLC was used to determine purine and pyrimidine metabolites in CSF, as a measure of cellular energy failure. ECBA was calculated as the root mean square value of a band-filtered (2–16 Hz) one-channel EEG. Results: Values of guanosine, inosine, hypoxanthine, xanthine and uridine were significantly higher, while ECBA was significantly lower after hemorrhagic hypotension than control values. The concentrations of inosine, hypoxanthine, xanthine and uridine were significantly negatively linearly related to ECBA. Conclusions: Brain cell function is negatively related to concentrations of inosine, hypoxanthine, xanthine and uridine in the CSF after hemorrhagic hypotension in near-term born lambs.

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.

Item does not contain fulltext 01 februari 2013

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 BACKGROUND: The aim of this study was to detect normal changes in fetal two-dimensional speckle-tracking echocardiography-derived values for global and regional longitudinal left and right ventricular strain, strain rate, and time to peak (T2P) global strain during pregnancy. METHODS: Forty-four healthy fetuses were examined prospectively during the second-trimester and third-trimester ultrasound examinations (20-24 and 30-34 weeks, respectively). Clips with high frame rates (mean, 120 frames/sec) of two-dimensional (B-mode) grayscale images of apical or basal four-chamber views of both ventricles were used for offline analyses of global and regional walls and segments (basal, mid, and apical) of myocardial strain and strain rate as well as T2P global strain in the longitudinal direction. RESULTS: There were statistically significant decreases in global and regional strain of the right ventricle between the second and third trimesters. No statistically significant changes were observed in global and regional strain of the left ventricle. Global and regional strain rates of both ventricles decreased in a similar way during pregnancy. The mean T2P longitudinal left ventricular global strain (adjusted for heart rate) increased mildly during fetal life. Whereas T2P longitudinal strain of the left ventricle at 20 to 24 weeks was statistically significantly shorter than that of the right ventricle, no difference in T2P longitudinal strain was found at 30 to 34 weeks of gestation between both ventricles. CONCLUSIONS: The establishment of these changes between the second-trimester and third-trimester two-dimensional speckle-tracking echocardiography-derived reference values is a mandatory prerequisite for its use in evaluating (pathologic) changes in both ventricular functions during pregnancy. 01 oktober 2013

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 : 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

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 PURPOSE: Congenital valvar aortic stenosis (VAS) causes a pressure overload to the left ventricle. In the clinical setting, the severity of stenosis is graded by the pressure drop over the stenotic valve (pressure gradient). This parameter is dependent on the hemodynamic status and does not provide information regarding myocardial performance. This study was undertaken to reveal the potential of two-dimensional strain echocardiography (2DSTE) for the detection of myocardial functional changes due to congenital VAS in children. MATERIALS AND METHODS: A total of 86 patients (aged from birth to 18 years) with various degrees of isolated congenital VAS were enrolled in this study. None of the patients had undergone any form of surgical or balloon intervention. 139 healthy children served as a control group. Two-dimensional cine-loop recordings of apical 4-chamber, mid-cavity short-axis and basal short-axis views were digitally stored for off-line analysis. Longitudinal, circumferential and radial peak systolic strain and strain rate values were determined as well as the time to peak systolic strain (T2P). Two-way analysis of variance was performed to assess the relationship between VAS severity and 2DSTE parameters. RESULTS: In all patients conventional echocardiographic findings did not indicate systolic left ventricular dysfunction. All strain parameters of the control group were significantly different from those of VAS patients. There was a statistically significant, inverse relationship between global peak systolic strain parameters in all three directions and the degree of VAS (p < 0.05). Local peak systolic strain (rate) in the interventricular septum was most affected. T 2P increased significantly with VAS severity (p < 0.05). The decline in LV longitudinal systolic performance preceded that in other directions. CONCLUSION: 2DSTE detects alterations in myocardial function in children diagnosed with congenital VAS, whose conventional echocardiographic findings did not indicate ventricular systolic dysfunction.

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 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

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.

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.

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.

Item does not contain fulltext In recent years, several attempts have been made to evaluate the activity of a corpus luteum by determining its sonographic echo texture. In all of these studies the values of the echo texture parameters depended on the type and settings of the ultrasound machine. Therefore, the aim of the study was to investigate if a quantitative analysis of ultrasound (US) images of the corpus luteum (CL) after calibration of the ultrasound machine enables the assessment of the peripheral plasma progesterone (P4) level. Ten Holstein Friesian cows were examined daily at Days 4 to 8, 10 to 16, and -5 to -1 (Day 1=ovulation) of the estrous cycle. B-mode sonography of the corpora lutea was performed and blood samples were taken for plasma P4 analysis. US images were calibrated and analyzed using a software package (CAUS) developed by the authors. In addition to the area of the CL (Total Area, TotA; Tissue Area interactive, TisAi; Tissue Area Automatic, TisAa), the following US parameters were calculated from the gray level histogram and from the size of the speckles: Mean, Standard Deviation (SD) and Signal-to-Noise Ratio (SNR=Mean/SD) of echo levels, Residual Attenuation (ResAtt), Axial and Lateral speckle size (Ax and Lat, respectively). The inter-individual variability of the P4 level was expressed by the coefficient of variability (CV), averaged over all days. It appeared that the CV of the absolute P4 was high (0.65) and the P4 relative to that at Day 4 and at Day 16 was of comparable magnitude. Correlations of US parameters with P4 were highest for the P4 relative to Day 16 (P4_rel_D16). This relative P4 measure was then used for further analysis. The correlations of P4_rel_D16 with TotA, TisAa (CL area after automatic segmentation of tissue) and ResAtt were found the highest (R=0.68, 0.74, and -0.42, respectively). Multiple linear regression analysis, incorporating all US parameters revealed the formula: P4_rel_D16(pred)=-0.315+0.225TisAa-0.023ResAtt, and a goodness of fit: R(2)=0.59 (p0.80 (corresponding to 0.95 times the average_P4_rel_D16 measured during the "static" phase of the luteal cycle) by ROC analysis was correctly made in 88% of cases. In conclusion the quantitative analysis of calibrated ultrasound images may yield a good prediction of cyclic changes of P4 levels and has potential for predicting the phase in the estrous cycle of a cow.

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.

Item does not contain fulltext BACKGROUND: The accurate evaluation of intrinsic myocardial contractility in children with or without congenital heart disease (CHD) has turned out to be a challenge. Two-dimensional strain echocardiographic (2DSTE) imaging or two-dimensional speckle-tracking echocardiographic imaging appears to hold significant promise as a tool to improve the assessment of ventricular myocardial function. The aim of this study was to estimate left ventricular myocardial systolic function using 2DSTE imaging in a large cohort consisting of healthy children and young adults to establish reference strain values. METHODS: Transthoracic echocardiograms were acquired in 195 healthy subjects (139 children, 56 young adults) and were retrospectively analyzed. Longitudinal, circumferential, and radial peak systolic strain values were determined by means of speckle tracking. Nonlinear regression analysis was performed to assess the effect of aging on these 2DSTE parameters. RESULTS: There was a strong, statistically significant second-order polynomial relation (P < .001) between global peak systolic strain parameters and age. Global peak systolic strain values were lowest in the youngest and oldest age groups. CONCLUSION: This is the first report to establish age-dependent reference values per cardiac segment for myocardial strain in all three directions assessed using 2DSTE imaging in a large pediatric and young adult cohort. There is a need to use age-specific reference values for the adequate interpretation of 2DSTE measurements.

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.

Purpose High-grade prostatic intraepithelial neoplasia (HGPIN) is a putative precursor of invasive prostate cancer (PCa). Preclinical evidence suggests vitamin E, selenium, and soy protein may prevent progression of HGPIN to PCa. This hypothesis was tested in a randomized phase III double-blind study of daily soy (40 g), vitamin E (800 U), and selenium (200 μg) versus placebo. Patients and Methods Three hundred three men in 12 Canadian centers were analyzed. The main eligibility criterion was confirmed HGPIN in at least one of two biopsies within 18 months of random assignment. Treatment was administered daily for 3 years. Follow-up prostate biopsies occurred at 6, 12, 24, and 36 months postrandomization. The primary end point was time to development of invasive PCa. Kaplan-Meier plots and log-rank tests were used to compare two treatment groups for this end point. Results For all patients, the median age was 62.8 years. The median baseline prostate-specific antigen (PSA; n = 302) was 5.41 ug/L; total testosterone (n = 291) was 13.4 nmol/L. Invasive PCa developed among 26.4% of patients. The hazard ratio for the nutritional supplement to prevent PCa was 1.03 (95% CI, 0.67 to 1.60; P = .88). Gleason score distribution was similar in both groups with 83.5% of cancers graded Gleason sum of 6. Baseline age, weight, PSA, and testosterone did not predict for development of PCa. The supplement was well tolerated with flatulence reported more frequently (27% v 17%) among men receiving micronutrients. Conclusion This trial does not support the hypothesis that combination vitamin E, selenium, and soy prevents progression from HGPIN to PCa.