Indications for cardiovascular magnetic resonance in children with congenital and acquired heart disease: an expert consensus paper of the Imaging Working Group of the AEPC and the Cardiovascular Magnetic Resonance Section of the EACVI.

This article provides expert opinion on the use of cardiovascular magnetic resonance (CMR) in young patients with congenital heart disease (CHD) and in specific clinical situations. As peculiar challenges apply to imaging children, paediatric aspects are repeatedly discussed. The first section of the paper addresses settings and techniques, including the basic sequences used in paediatric CMR, safety, and sedation. In the second section, the indication, application, and clinical relevance of CMR in the most frequent CHD are discussed in detail. In the current era of multimodality imaging, the strengths of CMR are compared with other imaging modalities. At the end of each chapter, a brief summary with expert consensus key points is provided. The recommendations provided are strongly clinically oriented. The paper addresses not only imagers performing CMR, but also clinical cardiologists who want to know which information can be obtained by CMR and how to integrate it in clinical decision-making.

Impact of Early-Life Exposures on Immune Maturation and Susceptibility to Disease.

Exiting from the largely sterile environment of the womb, the neonatal immune system is not fully mature, and thus neonatal immune cells must simultaneously mount responses against environmental stimuli while maturing. This dynamic process of immune maturation is driven by a variety of cell-intrinsic and extrinsic factors. Recent studies have focused on some of these factors and have shed light on the mechanisms by which they drive immune maturation. We review the interactions and consequences of immune maturation during the pre- and perinatal period. We discuss environmental signals in early life that are needed for healthy immune homeostasis, and highlight detrimental factors that can set an individual on a path towards disease. This early-life period of immune maturation could hold the key to strategies for setting individuals on trajectories towards health and reduced disease susceptibility.

On the interplay between Q^2 and t dependence in exclusive diffractive production of real photons and vector mesons in ep collisions

We show how the familiar phenomenological way of combining the Q2 (photon virtuality) and t (squared momentum transfer) dependences of the scattering amplitude in Deeply Virtual Compton Scattering (DVCS) [1, 2] and Vector Meson Production (VMP) [2] processes can be understood in an off-mass-shell generalization of dual amplitudes with Mandelstam analyticity [3]. By comparing different approaches, we managed also to constrain the numerical values of the free parameters.

Verbal learning in mild cognitive impairment and alzheimer's disease : behavioural and neural approaches

The main focus of the present thesis was at verbal episodic memory processes that are particularly vulnerable to preclinical and clinical Alzheimer’s disease (AD). Here these processes were studied by a word learning paradigm, cutting across the domains of memory and language learning studies. Moreover, the differentiation between normal aging, mild cognitive impairment (MCI) and AD was studied by the cognitive screening test CERAD. In study I, the aim was to examine how patients with amnestic MCI differ from healthy controls in the different CERAD subtests. Also, the sensitivity and specificity of the CERAD screening test to MCI and AD was examined, as previous studies on the sensitivity and specificity of the CERAD have not included MCI patients. The results indicated that MCI is characterized by an encoding deficit, as shown by the overall worse performance on the CERAD Wordlist learning test compared with controls. As a screening test, CERAD was not very sensitive to MCI. In study II, verbal learning and forgetting in amnestic MCI, AD and healthy elderly controls was investigated with an experimental word learning paradigm, where names of 40 unfamiliar objects (mainly archaic tools) were trained with or without semantic support. The object names were trained during a 4-day long period and a follow-up was conducted one week, 4 weeks and 8 weeks after the training period. Manipulation of semantic support was included in the paradigm because it was hypothesized that semantic support might have some beneficial effects in the present learning task especially for the MCI group, as semantic memory is quite well preserved in MCI in contrast to episodic memory. We found that word learning was significantly impaired in MCI and AD patients, whereas forgetting patterns were similar across groups. Semantic support showed a beneficial effect on object name retrieval in the MCI group 8 weeks after training, indicating that the MCI patients’ preserved semantic memory abilities compensated for their impaired episodic memory. The MCI group performed equally well as the controls in the tasks tapping incidental learning and recognition memory, whereas the AD group showed impairment. Both the MCI and the AD group benefited less from phonological cueing than the controls. Our findings indicate that acquisition is compromised in both MCI and AD, whereas long13 term retention is not affected to the same extent. Incidental learning and recognition memory seem to be well preserved in MCI. In studies III and IV, the neural correlates of naming newly learned objects were examined in healthy elderly subjects and in amnestic MCI patients by means of positron emission tomography (PET) right after the training period. The naming of newly learned objects by healthy elderly subjects recruited a left-lateralized network, including frontotemporal regions and the cerebellum, which was more extensive than the one related to the naming of familiar objects (study III). Semantic support showed no effects on the PET results for the healthy subjects. The observed activation increases may reflect lexicalsemantic and lexical-phonological retrieval, as well as more general associative memory mechanisms. In study IV, compared to the controls, the MCI patients showed increased anterior cingulate activation when naming newly learned objects that had been learned without semantic support. This suggests a recruitment of additional executive and attentional resources in the MCI group.

Vascular Function in Chronic Kidney Disease and in Renovascular Disease

Cardiovascular mortality is 15 to 30 times higher in patients with chronic kidney disease than in the age-adjusted general population. Even minor renal dysfunction predicts cardiovascular events and death in the general population. In patients with atherosclerotic renovascular disease the annual cardiovascular event and death rate is even higher. The abnormalities in coronary and peripheral artery function in the different stages of chronic kidney disease and in renovascular disease are still poorly understood, nor have the cardiac effects of renal artery revascularization been well characterized, although considered to be beneficial. This study was conducted to characterize myocardial perfusion and peripheral endothelial function in patients with chronic kidney disease and in patients with atherosclerotic renovascular disease. Myocardial perfusion was measured with positron emission tomography (PET) and peripheral endothelial function with brachial artery flow-mediated dilatation. It has been suggested that the poor renal outcomes after the renal artery revascularization could be due to damage in the stenotic kidney parenchyma; especially the reduction in the microvascular density, changes mainly evident at the cortical level which controls almost 80% of the total renal blood flow. This study was also performed to measure the effect of renal artery stenosis revascularization on renal perfusion in patients with renovascular disease. In order to do that a PET-based method for quantification of renal perfusion was developed. The coronary flow reserve of patients with chronic kidney disease was similar to the coronary flow reserve of healthy controls. In renovascular disease the coronary flow reserve was, however, markedly reduced. Flow-mediated dilatation of brachial artery was decreased in patients with chronic kidney disease compared to healthy controls, and even more so in patients with renovascular disease. After renal artery stenosis revascularization, coronary vascular function and renal perfusion did not improve in patients with atherosclerotic renovascular disease, but in patients with bilateral renal artery stenosis, flow-mediated dilatation improved. Chronic kidney disease does not significantly affect coronary vascular function. On the contrary, coronary vascular function was severely deteriorated in patients with atherosclerotic renovascular disease, possibly because of diffuse coronary artery disease and/or diffuse microvascular disease. The peripheral endothelial function was disturbed in patients with chronic kidney disease and even more so in patient with atherosclerotic renovascular disease. Renal artery stenosis dilatation does not seem to offer any benefits over medical treatment in patients with renovascular disease, since revascularization does not improve coronary vascular function or renal perfusion.

Lipotoxicity in Obesity and Coronary Artery Disease. Studies by PET, CT and MR

Lipotoxicity is a condition in which fatty acids (FAs) are not efficiently stored in adipose tissue and overflow to non-adipose tissue, causing organ damages. A defect of adipose tissue FA storage capability can be the primary culprit in the insulin resistance condition that characterizes many of the severe metabolic diseases that affect people nowadays. Obesity, in this regard, constitutes the gateway and risk factor of the major killers of modern society, such as cardiovascular disease and cancer. A deep understanding of the pathogenetic mechanisms that underlie obesity and the insulin resistance syndrome is a challenge for modern medicine. In the last twenty years of scientific research, FA metabolism and dysregulations have been the object of numerous studies. Development of more targeted and quantitative methodologies is required on one hand, to investigate and dissect organ metabolism, on the other hand to test the efficacy and mechanisms of action of novel drugs. The combination of functional and anatomical imaging is an answer to this need, since it provides more understanding and more information than we have ever had. The first purpose of this study was to investigate abnormalities of substrate organ metabolism, with special reference to the FA metabolism in obese drug-naïve subjects at an early stage of disease. Secondly, trimetazidine (TMZ), a metabolic drug supposed to inhibit FA oxidation (FAO), has been for the first time evaluated in obese subjects to test a whole body and organ metabolism improvement based on the hypothesis that FAO is increased at an early stage of the disease. A third objective was to investigate the relationship between ectopic fat accumulation surrounding heart and coronaries, and impaired myocardial perfusion in patients with risk of coronary artery disease (CAD). In the current study a new methodology has been developed with PET imaging with 11C-palmitate and compartmental modelling for the non-invasive in vivo study of liver FA metabolism, and a similar approach has been used to study FA metabolism in the skeletal muscle, the adipose tissue and the heart. The results of the different substudies point in the same direction. Obesity, at the an early stage, is associated with an impairment in the esterification of FAs in adipose tissue and skeletal muscle, which is accompanied by the upregulation in skeletal muscle, liver and heart FAO. The inability to store fat may initiate a cascade of events leading to FA oversupply to lean tissue, overload of the oxidative pathway, and accumulation of toxic lipid species and triglycerides, and it was paralleled by a proportional growth in insulin resistance. In subjects with CAD, the accumulation of ectopic fat inside the pericardium is associated with impaired myocardial perfusion, presumably via a paracrine/vasocrine effect. At the beginning of the disease, TMZ is not detrimental to health; on the contrary at the single organ level (heart, skeletal muscle and liver) it seems beneficial, while no relevant effects were found on adipose tissue function. Taken altogether these findings suggest that adipose tissue storage capability should be preserved, if it is not possible to prevent excessive fat intake in the first place.

Magnetic Resocance Imaging Methods in the Follow-up of Multiple Sclerosis and in Farby Disease

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disorder of the central nervous system. MS is the most common disabling central nervous system (CNS) disease of young adults in the Western world. In Finland, the prevalence of MS ranges between 1/1000 and 2/1000 in different areas. Fabry disease (FD) is a rare hereditary metabolic disease due to mutation in a single gene coding α-galactosidase A (alpha-gal A) enzyme. It leads to multi-organ pathology, including cerebrovascular disease. Currently there are 44 patients with diagnosed FD in Finland. Magnetic resonance imaging (MRI) is commonly used in the diagnostics and follow-up of these diseases. The disease activity can be demonstrated by occurrence of new or Gadolinium (Gd)-enhancing lesions in routine studies. Diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) are advanced MR sequences which can reveal pathologies in brain regions which appear normal on conventional MR images in several CNS diseases. The main focus in this study was to reveal whether whole brain apparent diffusion coefficient (ADC) analysis can be used to demonstrate MS disease activity. MS patients were investigated before and after delivery and before and after initiation of diseasemodifying treatment (DMT). In FD, DTI was used to reveal possible microstructural alterations at early timepoints when excessive signs of cerebrovascular disease are not yet visible in conventional MR sequences. Our clinical and MRI findings at 1.5T indicated that post-partum activation of the disease is an early and common phenomenon amongst mothers with MS. MRI seems to be a more sensitive method for assessing MS disease activity than the recording of relapses. However, whole brain ADC histogram analysis is of limited value in the follow-up of inflammatory conditions in a pregnancy-related setting because the pregnancy-related physiological effects on ADC overwhelm the alterations in ADC associated with MS pathology in brain tissue areas which appear normal on conventional MRI sequences. DTI reveals signs of microstructural damage in brain white matter of FD patients before excessive white matter lesion load can be observed on conventional MR scans. DTI could offer a valuable tool for monitoring the possible effects of enzyme replacement therapy in FD.

Regulation of intercellular coupling in acute and chronic heart disease

Effective pump function of the heart depends on the precise control of spatial and temporal patterns of electrical activation. Accordingly, the distribution and function of gap junction channels are important determinants of the conduction properties of myocardium and undoubtedly play other roles in intercellular communication crucial to normal cardiac function. Recent advances have begun to elucidate mechanisms by which the heart regulates intercellular electrical coupling at gap junctions in response to stress or injury. Although responses to increased load or injury are generally adaptive in nature, remodeling of intercellular junctions under conditions of severe stress creates anatomic substrates conducive to the development of lethal ventricular arrhythmias. Potential mechanisms controlling the level of intercellular communication in the heart include regulation of connexin turnover dynamics and phosphorylation.

Association of apolipoprotein E polymorphism with plasma lipids and Alzheimer's disease in a Southern Brazilian population

Apolipoprotein E (protein: apo E; gene: APOE) plays an important role in the multifactorial etiology of both Alzheimer's disease (AD) and lipid level concentrations. The polymerase chain reaction (PCR) was used to investigate the APOE gene polymorphism in 446 unrelated Caucasians, among them 23 AD patients, and 100 Afro-Brazilians living in Porto Alegre, Brazil. The frequencies of the APOE*2, APOE*3 and APOE*4 alleles were 0.075, 0.810 and 0.115 in Caucasians and 0.075, 0.700 and 0.225 in Afro-Brazilians, respectively (c2 = 8.72, P = 0.013). A highly significant association was observed between the APOE*4 allele and AD in this population-based sample. The APOE*4 frequency in AD patients (39%) was about four times higher than in the general Caucasian population (11.5%). The influence of each of the three common APOE alleles on lipid traits was evaluated by the use of the average excess statistic. The E*2 allele is associated with lower levels of triglycerides and of total and non-HDL cholesterol in both men and women. Conversely, the E*4 allele is associated with higher levels of these traits in women only. The effect of APOE alleles was of greater magnitude in women.

Association studies between -1185A/G von Willebrand factor gene polymorphism and coronary artery disease

High levels of von Willebrand factor (vWF) have been associated with cardiovascular disease. The A allele of the -1185A/G polymorphism in the 5'-regulatory region of the vWF gene was associated with the highest plasma vWF levels in a normal population. To examine the association between -1185A/G polymorphism and coronary artery disease (CAD), 173 Brazilian Caucasian subjects submitted to coronary angiography were studied. Of these, 57 (33%) had normal coronary arteries (control group) and 116 (67%) had CAD (patient group). Plasma vWF levels were higher in patients (145 U/dl) than in controls (130 U/dl), but the differences were significant only for O blood group subjects. Polymerase chain reaction amplification of the 864-bp vWF promoter region followed by AccII restriction digestion was used to identify the -1185A/G genotypes. The -1185A allele frequency was 43.1% in patients and 44.7% in controls. Allele and genotype frequencies were not significantly different between patients and controls. No association was observed between the -1185A/G genotypes and plasma vWF levels in patients or controls. These results suggest that -1185A/G polymorphism is not an independent risk factor for CAD.

One-year follow-up of the effects of sildenafil on pulmonary arterial hypertension and veno-occlusive disease

We hypothesized that chronic oral administration of the phosphodiesterase-5 inhibitor sildenafil could improve the exercise capacity and pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH) on the basis of previous short-term studies. We tested this hypothesis in 14 subjects with PAH, including seven patients with the idiopathic form and seven patients with atrial septal defects, but no other congenital heart abnormalities. Patients were subjected to a 6-min walk test and dyspnea was graded according to the Borg scale. Pulmonary flow and pressures were measured by Doppler echocardiography. Patients were given sildenafil, 75 mg orally three times a day, and followed up for 1 year. Sildenafil therapy resulted in the following changes: increase in the 6-min walk distance from a median value of 387 m (range 0 to 484 m) to 462 m (range 408 to 588 m; P < 0.01), improvement of the Borg dyspnea score from 4.0 (median value) to 3.0 (P < 0.01), and increased pulmonary flow (velocity-time integral) from a median value of 0.12 (range 0.08 to 0.25) to 0.23 (range 0.11 to 0.40; P < 0.01) with no changes in pulmonary pressures. In one patient with pulmonary veno-occlusive disease diagnosed by a lung biopsy, sildenafil had a better effect on the pulmonary wedge pressure than inhaled nitric oxide (15 and 29 mmHg, respectively, acute test). He walked 112 m at baseline and 408 m at one year. One patient died at 11 months of treatment. No other relevant events occurred. Thus, chronic administration of sildenafil improves the physical capacity of PAH patients and may be beneficial in selected cases of veno-occlusive disease.

Estrogen receptor 1 gene polymorphisms and coronary artery disease in the Brazilian population

We examined the association of three established single nucleotide polymorphisms, IVS1-397T>C, IVS1-351A>G, and +261G>C, in the ESR1 gene with the prevalence and severity of coronary atherosclerosis in a southern Brazilian population of European ancestry. Three hundred and forty-one subjects (127 women and 214 men) with coronary artery disease (CAD) were classified as having significant disease (CAD+ patient group) when they showed 60% or more luminal stenosis in at least one coronary artery or major branch segment at angiography; patients with 10% or less luminal stenosis were considered to have minimal CAD (CAD- patient group). The control sample consisted of 142 subjects (79 women and 63 men) without significant disease, in whom coronary angiography to rule out the presence of asymptomatic CAD was not performed. The polymorphisms were investigated by polymerase chain reaction followed by restriction analyses. In the male sample, the +261G>C*C allele was more frequent in CAD+ than CAD- subjects (8 versus 1%, P = 0.024). Homozygosity for the C allele of the IVS1-397T>C polymorphism was also significantly associated with increased CAD severity (OR: 2.99; 95% CI = 1.35-6.63; P = 0.007). In agreement with previous findings, these results suggest that the IVS1-397T>C*C allele was associated with CAD severity independent of gender, whereas the association of the +261G>C variant with CAD was observed in males only. The relation between ESR1 variation and CAD may influence clinical decisions such as the use of hormone therapy, and additionally will be helpful to identify the genetic susceptibility determinants of cardiovascular disease development.

Relationship of macrophage migration inhibitory factor levels in PBMCs, lesional skin and serum with disease severity and activity in vitiligo vulgaris

Melanocyte loss in vitiligo vulgaris is believed to be an autoimmune process. Macrophage migration inhibitory factor (MIF) is involved in many autoimmune skin diseases. We determined the possible role of MIF in the pathogenesis of vitiligo vulgaris, and describe the relationship between MIF expressions and disease severity and activity. Serum MIF concentrations and mRNA levels in PBMCs were measured in 44 vitiligo vulgaris patients and 32 normal controls, using ELISA and real-time RT-PCR. Skin biopsies from 15 patients and 6 controls were analyzed by real-time RT-PCR. Values are reported as median (25th-75th percentile). Serum MIF concentrations were significantly increased in patients [35.81 (10.98-43.66) ng/mL] compared to controls [7.69 (6.01-9.03) ng/mL]. MIF mRNA levels were significantly higher in PBMCs from patients [7.17 (3.59-8.87)] than controls [1.67 (1.23-2.42)]. There was also a significant difference in MIF mRNA levels in PBMCs between progressive and stable patients [7.86 (5.85-9.13)vs 4.33 (2.23-8.39)] and in serum MIF concentrations [40.47 (27.71-46.79) vs 26.80 (10.55-36.07) ng/mL]. In addition, the vitiligo area severity index scores of patients correlated positively with changes of both serum MIF concentrations (r = 0.488) and MIF mRNA levels in PBMCs (r = 0.426). MIF mRNA levels were significantly higher in lesional than in normal skin [2.43 (2.13-7.59)vs 1.18 (0.94-1.83)] and in patients in the progressive stage than in the stable stage [7.52 (2.43-8.84)vs 2.13 (1.98-2.64)]. These correlations suggest that MIF participates in the pathogenesis of vitiligo vulgaris and may be useful as an index of disease severity and activity.

The value of the exchange rate and the Dutch disease

This paper revisits the original (2008) paper on the Dutch disease, which defined it by the existence of two exchange rate equilibriums (the current and the industrial exchange rate equilibriums). Its novelty is in claiming that, as we have a value and a market price for each good or service, we also have a value and a market price for foreign money. The value is the cost plus reasonable profit corresponding to the exchange rate that makes competitive the country's competent business enterprises; the nominal exchange rates floats around the value according to the demand and supply of foreign money. This basic distinction of the exchange rate in terms of value and in terms of price allows us to understand that the two equilibriums are defined in value terms, and opens room for a clear distinction of the policies that affect the value from the ones that affect the market price of the exchange rate.