Ectopia Cordis

A Case Report of Cor Triatriatum Sinister (CTS) in an Asymptomatic Adult with Chronic Adhesive Pericarditis

Introduction: Cor Triatriatum Sinister (CTS) is a rare congenital anomaly, accounting for 0.1%- 0.4% of congenital heart diseases. While often diagnosed and treated in infancy, some cases remain asymptomatic until adulthood due to large fenestrations. This report presents a unique case of CTS in an adult coexisting with chronic adhesive pericarditis, which may have contributed to chronic atrial dilatation, a condition not previously documented.

Case Presentation: A 60-year-old asymptomatic Taiwanese male underwent a routine medical examination. Coronary computed tomography angiography revealed a fenestrated septum dividing the left atrium, consistent with CTS. Virtual endoscopy confirmed two wide fenestrations. Notably, chronic adhesive pericarditis, evidenced by curvilinear calcifications, was diagnosed. This condition likely exacerbated the hemodynamic impact of CTS, contributing to left atrial dilation and atrial fibrillation. Atrial fibrillation was identified, and the patient was treated with an anticoagulant for stroke prevention.

Conclusion: This is the first reported case of CTS coexisting with chronic adhesive pericarditis. Advanced imaging modalities, including cardiac computed tomography, angiography, and virtual endoscopy, are crucial for diagnosis and anatomical evaluation. Chronic adhesive pericarditis may amplify the effects of CTS, leading to complications, including atrial fibrillation. Anticoagulation is essential for stroke prevention in such cases.

Submaximal Field Walking Tests Applied in the Cardiopulmonary Assessment in Congenital Heart Diseases: A Systematic Review

Introduction: Submaximal field walking tests are easy to apply and low cost, but it is necessary to standardize their application, especially in the pediatric population. The feasibility and its use in patients with congenital heart disease have been studied. The goal of this study was to verify which are the submaximal field walking tests applied in the cardiopulmonary assessment of children and adolescents with CHD and to verify if they are being performed as recommended by the standardization protocols/guidelines.

Methods: Literature review through a search in six electronic databases, structured in PICO format, without date restrictions. Looking for studies that used submaximal field walking tests in children and adolescents with congenital heart disease aged 5 to 18 years. Methodological quality, effectiveness and safety and risk of bias were assessed.

Results: Five studies met the eligibility criteria with a sample of 160 individuals with congenital heart disease, and all used the six-minute walk test. Note that different methodologies and modifications are used. Only the clinical trial showed good methodological quality.Four studies had low risk of bias and one study had moderate risk.

Conclusion: Although the six-minute walk test is the only test used as a field test found in our research, there is no standardization in the application of the test, making it difficult to compare the results. In this sense, reducing the limitations and heterogeneity in the application of the test will enable more concrete outcomes and facilitate their reproduction in clinical practice.

Cardiovascular Diseases in Pregnancy - A Brief Overview

Even though, there have been many advances in maternal medical care and fertility treatments, the presence of cardiovascular disease has a significant impact on pregnancy. In pregnant women, several heart conditions, such as valvular heart disease, chronic hypertension, congenital heart defects and non-ischemic cardiomyopathies are linked to increased risk of fetal as well as maternal morbidity and mortality. To date, the management of the co-existing conditions of pregnancy and heart disease has been challenging. Therefore, in-depth information may be beneficial to tackle a difficult case scenario. Towards this end, this paper provides an overview of the recent updated knowledge of pregnancy-related cardiovascular diseases in women.

Maternal Sodium Valproate Exposure Alters Neuroendocrine-Cytokines and Oxido-inflammatory Axes in Neonatal Albino Rats

Objective: The aim of the study was to determine the influence of maternal sodium valproate (SVP) on neonatal neuroendocrine (hypothalamic-pituitary-adrenal; HPA)-cytokines and oxido-inflammatory axes.

Methods: Pregnant rats (Rattus norvegicus) were orally administered (by gavage) SVP (50 mg/kg) from gestation day (GD) 8 to lactation day (LD) 21.

Results: The elevation in serum corticotropin-releasing hormone (CRH), corticosterone, and adrenocorticotropic hormone (ACTH) levels was highly significant at postnatal days (PNDs) 14 and 21 in both dams and neonates of the maternal SVP-treated group relative to those in the control group. However, hypercortisolism (cortisolemia) was highly significant in neonates at both PNDs 14 and 21, while in dams, it was not significantly increased at LD 14 but was at LD 21. This disruption caused adverse effects on maternal food consumption and maternal/neonatal body weight. The maternal SVP treatment resulted in higher levels of neonatal serum adrenaline, noradrenaline, neuropeptide Y (NPY), tumor necrosis factor-alpha (TNF-α), leptin, interleukins (IL-1β, IL-17, IL-4, IL-6 & IL-2), transforming growth factor-beta (TGF-β), and prostaglandin E2 (PGE2), and lower levels of neonatal serum growth hormone (GH), insulin growth factor-1 (IGF-1) and adiponectin at both PNDs. This administration also induced the oxidative stress in neonatal cerebrum and cerebellum at both tested PNDs via the production of free radicals (malondialdehyde; MDA & nitric oxide; NO) and reduction of antioxidant parameters (glutathione; GSH, superoxide dismutase; SOD & catalase; CAT).

Conclusion: Maternal SVP treatment stimulated the neonatal stress-brain (HPA) axis, resulted in an oxido-inflammatory state, and disrupted the neuroendocrine-cytokines axis, and generally neonatal health.

The Vectorcardiogram and the Main Dromotropic Disturbances

Until the mid-1980s, it was believed that the vectorcardiogram (VCG) presented a greater specificity, sensitivity and accuracy in comparison to the 12-lead electrocardiogram (ECG), in the cardiology diagnosis. Currently, the VCG still is superior to the ECG in specific situations, such as in the evaluation of myocardial infarctions when associated with intraventricular conduction disturbances, in the identification and location of accessory pathways in ventricular preexcitation, in the differential diagnosis of patterns varying from normal of electrical axis deviation, in the evaluation of particular aspects of Brugada syndrome, Brugada phenocopies, concealed form of arrhythmogenic right ventricular cardiomyopathy and zonal or fascicular blocks of the right bundle branch on right ventricular free wall.VCG allows us to analyze the presence of left septal fascicular block more accurately than ECG and in the diagnosis of the interatrial blocks and severity of some chambers enlargements. The three-dimensional spatial orientation of both the atrial and the ventricular activity provides a far more complete observation tool than the linear ECG. We believe that the ECG/VCG binomial simultaneously obtained by the technique called electro-vectorcardiography (ECG/VCG) brought a significant gain for the differential diagnosis of several pathologies. Finally, in the field of education and research, VCG provided a better and more rational tridimensional insight into the electrical phenomena that occurs spatially, and represented an important impact on the progress of electrocardiography.

Modeling Neuronal Diseases in Zebrafish in the Era of CRISPR

Background: Danio rerio is a powerful experimental model for studies in genetics and development. Recently, CRISPR technology has been applied in this species to mimic various human diseases, including those affecting the nervous system. Zebrafish offer multiple experimental advantages: external embryogenesis, rapid development, transparent embryos, short life cycle, and basic neurobiological processes shared with humans. This animal model, together with the CRISPR system, emerging imaging technologies, and novel behavioral approaches, lay the basis for a prominent future in neuropathology and will undoubtedly accelerate our understanding of brain function and its disorders.

Objective: Gather relevant findings from studies that have used CRISPR technologies in zebrafish to explore basic neuronal function and model human diseases.

Methods: We systematically reviewed the most recent literature about CRISPR technology applications for understanding brain function and neurological disorders in D. rerio. We highlighted the key role of CRISPR in driving forward our understanding of particular topics in neuroscience.

Results: We show specific advances in neurobiology when the CRISPR system has been applied in zebrafish and describe how CRISPR is accelerating our understanding of brain organization.

Conclusion: Today, CRISPR is the preferred method to modify genomes of practically any living organism. Despite the rapid development of CRISPR technologies to generate disease models in zebrafish, more efforts are needed to efficiently combine different disciplines to find the etiology and treatments for many brain diseases.

Adaptive Behavior in Williams-Beuren Syndrome, Down Syndrome, and Autism Spectrum Disorder

Adaptive behavior (AB) is defined as the skills acquired in response to everyday life demands. AB profiles of genetic syndromes have been proposed, but the literature on them has not been conclusive, mainly due to the large number of these syndromes and marked within-profile variability. The aim of the present study was to analyze the different ABs observed in subjects with Williams-Beuren Syndrome (WBS), Down Syndrome (DS) and Autistic Spectrum Disorder (ASD) through a literature review using the PubMed and Scopus database. The results indicated that Socialization strongly affects WBS; however, this group demonstrated the greatest amount of difficulty in the domain of daily living. The DS group demonstrated better performance in Socialization and Daily Living compared to Communication. The ASD group displayed better performance in Daily Living and Communication and the worst performance in socialization. Although the reviewed studies appear to demonstrate controversial results related to how ABs occur in each group, the main skills and shortages remained similar to each corresponding diagnostic behavioral characteristic. We conclude that it is possible to build AB profiles in the analyzed diagnostic groups, and we believe that these profiles may facilitate the construction of intervention plans.

Human Induced Pluripotent Stem Cells for Inherited Cardiovascular Diseases Modeling

Cardiovascular cells derived from patient specific induced Pluripotent Stem Cell (iPSC) harbor gene mutations associated with the pathogenesis of inherited cardiac diseases and congenital heart diseases (CHD). Numerous reports have demonstrated the utilization of human induced Pluripotent Stem Cell (hiPSC) to model cardiac diseases as a means of investigating their underlying mechanisms. So far, they have been shown to investigate the molecular mechanisms of many cardiac disorders, such as long-QT syndrome (LQT), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), LEOPARD syndrome (LS), arrhythmogenic cardiomyopathy (ACM), Friedreich ataxia (FRDA), Barth syndrome (BTHS), hypoplastic left heart syndrome (HLHS), Marfan syndrome (MFS) and other CHD. This article summarizes the growing body of research related to modeling various cardiac diseases using hiPSCs. Moreover, by reviewing the methods used in previous studies, we propose multiple novel applications of hiPSCs to investigate comprehensive cardiovascular disorders and facilitate drug discovery.

Diagnostic Cardiac Catheterization in the Pediatric Population

Although the utility of diagnostic cardiac catheterization in the clinical setting has diminished over the last years, due to the emergence of noninvasive imaging modalities, such as echocardiography, magnetic resonance imaging and computed tomography, catheterization for diagnostic reasons still constitutes a valuable tool in certain parts in the workup of pediatric heart disease. As a result, awareness of the main aspects of diagnostic catheterization is of great importance for the clinical cardiologist. In this article, the main variables measured and the main actions performed during diagnostic cardiac catheterization in children are discussed.

Atrial Macroreentry in Congenital Heart Disease

Macroreentrant atrial tachycardia is a common complication following surgery for congenital heart disease (CHD), and is often highly symptomatic with potentially significant hamodynamic consequences. Medical management is often unsuccessful, requiring the use of invasive procedures. Cavotricuspid isthmus dependent flutter is the most common circuit but atypical circuits also exist, involving sites of surgical intervention or areas of scar related to abnormal hemodynamics. Ablation can be technically challenging, due to complex anatomy, and difficulty with catheter stability. A thorough assessment of the patients status and pre-catheter ablation planning is critical to successfully managing these patients.

Atrial Tachycardias Occurring Late After Open Heart Surgery

Atrial tachycardias are common after open heart surgery. Most commonly these are macro-reentrant including cavotricuspid isthmus dependent atrial flutter, incisional right atrial flutter and left atrial flutter. Focal atrial tachycardias occur less frequently. The specific type of atrial tachycardia highly depends on the type of surgical incision. Catheter ablation can be very effective, however requires a thorough understanding of anatomy and surgical technique.

Fragmented ECG as a Risk Marker in Cardiovascular Diseases

Various noninvasive tests for risk stratification of sudden cardiac death (SCD) were studied, mostly in the context of structural heart disease such as coronary artery disease (CAD), cardiomyopathy and heart failure but have low positive predictive value for SCD. Fragmented QRS complexes (fQRS) on a 12-lead ECG is a marker of depolarization abnormality. fQRS include presence of various morphologies of the QRS wave with or without a Q wave and includes the presence of an additional R wave (R’) or notching in the nadir of the R’ (fragmentation) in two contiguous leads, corresponding to a major coronary artery territory. fQRS represents conduction delay from inhomogeneous activation of the ventricles due to myocardial scar. It has a high predictive value for myocardial scar and mortality in patients CAD. fQRS also predicts arrhythmic events and mortality in patients with implantable cardioverter defibrillator. It also signifies poor prognosis in patients with nonischemic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and Brugada syndrome. However, fQRS is a nonspecific finding and its diagnostic prognostic should only be interpreted in the presence of pertinent clinical evidence and type of myocardial involvement (structural vs. structurally normal heart).

Patent on Biomarkers in Medical Research: A Focus on Neuropsychiatric Disorders

Identification of putative biomarkers is a need of modern society today. Biomarker measures a biological or pathogenic process that can predict disease prognosis. It is important for monitoring drug safety, identification of individuals who are most likely to respond to specific treatments, stratification of presymptomatic patients and quantification of treatment benefits. The peripheral blood based identification of biomarkers or disease signatures from psychiatric patients possesses an immense potential towards drug developmental process. Biomarkers have been used as an early diagnostic tool for neuropsychiatric disorders. Identification of potential biomarkers of psychiatric disorders has become most important when it comes to biological psychiatry related research area. Patent provides a legal protection given to a new invention which gives the holder exclusive right to use or sell the patented product. Hence, deep understanding towards patent system is important as it protects novel research outputs that may lead to invention of new drugs. The present review describes patents, its methods and validations focused on peripheral biomarkers including cerebrospinal fluid (CSF), plasma, serum and various neuropsychiatric disorders.

Advanced Echocardiographic Imaging of the Congenitally Malformed Heart

There have been significant advancements in the ability of echocardiography to provide both morphological and functional information in children with congenitally malformed hearts. This progress has come through the development of improved technology such as matrix array probes and software which allows for the off line analysis of images to a high standard. This article focuses on these developments and discusses some newer concepts in advanced echocardiography such is multi-planar reformatting [MPR] and tissue motion annular displacement [TMAD].

Our aim is to discuss important aspects related to the quality and reproducibility of data, to review the most recent published data regarding advanced echocardiography in the malformed heart and to guide the reader to appropriate text for overcoming the technical challenges of using these methods. Many of the technical aspects of image acquisition and post processing have been discussed in recent reviews by the authors and we would urge readers to study these texts to gain a greater understanding [1]. The quality of the two dimensional image is paramount in both strain analysis and three dimensional echocardiography. An awareness of how to improve image quality is vital to acquiring accurate and usable data.

Three dimensional echocardiography (3DE) is an attempt to visualise the dynamic morphology of the heart. Although published media is the basis for theoretical knowledge of how to practically acquire images, electronic media [eg.www.3dechocardiography.com] is the only way of visualising the advantages of this technology in real time.

It is important to be aware of the limitations of this technology and that much of the data gleaned from using these methods is at a research stage and not yet in regular clinical practice.

Perinatal and Neonatal Outcomes of Lithium-Treated and Untreated Bipolar Women During Pregnancy: A Review of Present Literature

Many women with a bipolar disorder are in their reproductive age and will need to continue their psychopharmacological treatment during pregnancy, being abrupt discontinuation of these medications associated with an increase of the probability of relapse, high-risk behaviours, significant family dysfunction, and suicide. Lithium is a first line drug for acute and maintenance treatment of bipolar disorder. Its teratogenic and perinatal effects are controversial, so as its longterm effects on neurodevelopment of the children. Our purpose is to review the most up-to-date literature dealing with growth, neurological, cognitive and behavioural development of children exposed to Lithium in utero. A PubMed search was performed with the following keywords: bipolar disorder, Lithium, pregnancy, lactation, perinatal disease, child development. Studies were included in the review if they investigated one or more of the adverse events of interest. Of the 26 studies included in our review, some show an association between Lithium treatment and several grades of malformations (most commonly minor), both cardiac and involving other organs, and dysfunctions which are often reversible. Some studies reported no collateral effects due to in utero exposure to Lithium. Even though literature points out a slightly increased risk of major malformations due to Lithium therapy during pregnancy, the drug should not be discontinued, yet monitoring of serum Lithium levels and foetal echocardiography are recommended.

From Bortezomib to other Inhibitors of the Proteasome and Beyond

The cancer drug discovery field has placed much emphasis on the identification of novel and cancer-specific molecular targets. A rich source of such targets for the design of novel anti-tumor agents is the ubiqutin-proteasome system (UP-S), a tightly regulated, highly specific pathway responsible for the vast majority of protein turnover within the cell. Because of its critical role in almost all cell processes that ensure normal cellular function, its inhibition at one point in time was deemed non-specific and therefore not worth further investigation as a molecular drug target. However, today the proteasome is one of the most promising anti-cancer drug targets of the century. The discovery that tumor cells are in fact more sensitive to proteasome inhibitors than normal cells indeed paved the way for the design of its inhibitors. Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma. Though successful in improving clinical outcomes for patients with hematological malignancies, relapse often occurs in those who initially responded to bortezomib. Therefore, the acquisition of bortezomib resistance is a major issue with its therapy. Furthermore, some neuro-toxicities have been associated with bortezomib treatment and its efficacy in solid tumors is lacking. These observations have encouraged researchers to pursue the next generation of proteasome inhibitors, which would ideally overcome bortezomib resistance, have reduced toxicities and a broader range of anti-cancer activity. This review summarizes the success and limitations of bortezomib, and describes recent advances in the field, including, and most notably, the most recent FDA approval of carfilzomib in July, 2012, a second generation proteasome inhibitor. Other proteasome inhibitors currently in clinical trials and those that are currently experimental grade will also be discussed.

Clinical and Pharmacological Aspects of Immunoprophylaxis for Respiratory Syncytial Virus Infection in High-Risk Infants

Respiratory syncytial virus (RSV) is the leading cause of respiratory tract infection in infants and young children throughout the world. Although preterm birth has been considered for years the major risk factor for severe disease and hospitalization, recent findings indicate that prematurity is not a necessary condition, but one of the independent risk factors for severe RSV infection, together with chronic lung diseases, congenital heart disease and immunodeficiency. Furthermore, over 50% of infants hospitalized for RSV infections during the first year of life are healthy, full-term newborns, suggesting that other environmental and individual factors may be involved. Unfortunately, there is still no specific therapy against RSV infection and therefore prophylactic measures seem to be the only intervention to avoid disease complications. No safe and effective RSV vaccine is available for the prevention of serious RSV infection. Therefore, in addition to hygienic measures, the only approach is passive immunoprophylaxis with humanized monoclonal anti-RSV antibodies, such as palivizumab that have been developed for clinical use. Because of the high cost of these antibodies, a better definition of the individual risk profile for severe RSV infection and timing of administration is needed for optimal effectiveness and careful use of limited health care resources.

In this article, we have reviewed the clinical and pharmacological aspects of immunoprophylaxis with monoclonal antibodies for preventing RSV infection in high-risk infants.

Heart Transplantation in Biventricular Congenital Heart Disease: Indications, Techniques, and Outcomes

Heart transplantation is an accepted therapeutic modality for end-stage congenital heart disease for both biventricular and univentricular anomalies. Many transplant centers have pushed the limits of transplantation to include patients with high pulmonary vascular resistance, high panel reactive antibodies, positive cross-matches, and ABOincompatibility. Excellent results have been possible, particularly with the development of improved diagnostic and therapeutic algorithms to prevent and treat rejection, infection, and post-transplant lymphoproliferative disease. Late graft failure and chronic rejection remain vexing problems. The vast majority of patients with biventricular congenital heart disease have undergone prior cardiac surgical procedures. Indications for transplantation in this subgroup are primarily progressive refractory heart failure following prior cardiac surgical reconstructive procedures. Contraindications to transplantation mimic those for other forms of end-stage heart disease. A determination of pulmonary vascular resistance is important in listing patients with biventricular congenital heart disease for heart transplantation. Modifications in the implant technique are necessary and vary depending on underlying recipient anatomy. Risk factors for perioperative outcomes in patients with biventricular congenital heart disease include the need for reoperation, the degree of anatomic reconstruction necessary during the implant procedure, and the degree of antibody sensitization, in addition to a number of other recipient and donor factors. Postoperative outcomes and survival are very good but remain inferior to those with cardiomyopathy in most series. In conclusion, patients with end-stage biventricular congenital heart disease represent a complex group of patients for heart transplantation, and require careful evaluation and management to ensure optimal outcomes.

Heart Transplantation for Congenital Heart Disease in the First Year of Life

Successful infant heart transplantation has now been performed for over 25 years. Assessment of long term outcomes is now possible. We report clinical outcomes for322 patients who received their heart transplant during infancy. Actuarial graft survival for newborn recipients is 59% at 25 years. Survival has improved in the most recent era. Cardiac allograft vasculopathy is the most important late cause of death with an actuarial incidence at 25 years of 35%. Posttransplant lymphoma is estimated to occur in 20% of infant recipients by25 years. Chronic kidney disease grade 3 or worse is present in 31% of survivors. The epidemiology of infant heart transplantation has changed through the years as the results for staged repair improved and donor resources remained stagnant. Most centers now employ staged repair for hypoplastic left heart syndrome and similar extreme forms of congenital heart disease. Techniques for staged repair, including the hybrid procedure, are described. The lack of donors is described with particular note regarding decreased donors due to newer programs for appropriate infant sleep positioning and infant car seats. ABO incompatible donors are a newer resource for maximizing donor resources, as is donation after circulatory determination of death and techniques to properly utilize more donors by expanding the criteria for what is an acceptable donor. An immunological advantage for the youngest recipients has long been postulated, and evaluation of this phenomenon may provide clues to the development of accommodation and/or tolerance.

Lithium Use During Early, Late Pregnancy, and Breastfeeding

Lithium salts are regularly used in the treatment for bipolar disorder, both as a prophylactic and as an episodic treatment agent. Bipolar affective disorder is most common in women of childbearing age. The available evidence indicate that lithium at therapeutic dose levels poses only a small but measurable teratogenic hazard to human reproduction being the main teratogenic target the cardiovascular system. The specific defect associated with lithium exposure, the Ebstein anomaly, may be serious or life threatening. In addition, the continuous use throughout gestation is associated with perinatal complications including toxicity and transient neurodevelopment deficits in the neonatal period. Since there is no controlled data in human pregnancy, lithium should only be given during pregnancy when there are no alternatives and benefit outweighs risk. Whenever lithium is the drug of choice in women with bipolar disorder it may be continued during pregnancy although these lithium-treated women should be considered high risk and need to be monitored during pregnancy including fetal echocardiography and serum Li levels throughout pregnancy.

Arrhythmias and Left Ventricular Hypertrabeculation/Noncompaction

Arrhythmias in left ventricular hypertrabeculation/noncompaction (LVHT) comprise sustained or non-sustained ventricular tachycardia (VT) (n=135), atrial fibrillation (AF) (n=96) AV block (n=55) and QT prolongation (n=47). The prevalence differs between children and adults. In children most frequent are WPW-syndrome (n=24), AV block (n=24), VT (n=17) and bradycardia (n=15). In adults most frequent arrhythmias are VT (n=118), AF (n=95), QT prolongation (n=42) and AV block (n=31). Some arrhythmias are more frequently reported in children than in adults like WPW-syndrome (24 vs. 17 patients), second-degree AV block (4 vs. 0 patients), bradycardia (15 vs. 3 patients) and ventricular fibrillation (VF) (9 vs. 5 patients). There are nearly no pediatric cases with AF (1 vs. 95 patients). In 120 patients implantable cardioverters/defibrillators have been implanted for primary or secondary prevention of sudden cardiac death. The pathomechanisms of arrhythmias in LVHT are largely unknown, especially if patients with LVHT and neuromuscular disorders are more prone to arrhythmias than patients without. There is a need to clarify risk factors for VT or VF because 19% of LVHT patients with VT or VF have a normal systolic function and demonstration of systolic dysfunction is no reliable risk marker. Data about long-term follow- up of LVHT patients with implanted cardioverters/defibrillators are necessary since the indication for prophylactic implantation is still unclear. AF in LVHT increases the embolic risk, thus it would be useful to know which LVHT patients who have sinusrhythm at baseline are prone to develop AF in order to start early with anticoagulant therapy.

Somatic Genomic Variations in Early Human Prenatal Development

Only 25 to 30% of conceptions result in a live birth. There is mounting evidence that the cause for this low fecundity is an extremely high incidence of chromosomal rearrangements occurring in the cleavage stage embryo. In this review, we gather all recent evidence for an extraordinary degree of mosaicisms in early embryogenesis. The presence of the rearrangements seen in the cleavage stage embryos can explain the origins of the placental mosaicisms seen during chorion villi sampling as well as the chromosomal anomalies seen in early miscarriages. Whereas these rearrangements often lead to implantation failure and early miscarriages, natural selection of the fittest cells in the embryo is the likely mechanism leading to healthy fetuses.

Arterial Duct Stenting in Congenital Heart Disease with Duct-Dependent Pulmonary Circulation

Background: Despite current trends toward early primary repair, surgical systemic-to-pulmonary artery shunt is still an invaluable palliative option in some high-risk patients with congenital heart disease and duct-dependent pulmonary blood flow. However, maintaining arterial duct patency by stent implantation has been proposed as an effective alternative to surgical palliation in neonates who are unsuitable for primary repair or in whom there is anticipated spontaneous improvement of oxygen saturation as the pulmonary vascular resistance decreases. Recent advances in technology has made arterial duct stenting a safe and feasible tool for short-term palliation of newborns and young infants with this pathophysiologic arrangement. This option might be even more advisable in low-weight newborns, who are at higher risk for surgical palliation or repair and in whom repeat stent dilatations could be effective in tailoring the pulmonary flow to the patients growth. This paper highlights history, methodology and results of this innovative and minimally-invasive palliative option. Methods and Results: Following duct morphology evaluation, the stent is chosen to completely cover the entire ductal length and is dilated to about 75% of the proposed surgical shunt. The procedure can be performed from arterial or venous approach and is successfully completed in the vast majority of cases. Procedural failure mainly depends on ductal tortuosity, typically found in complex conotruncal anomalies such as tetralogy of Fallot or pulmonary atresia with ventricular septal defect. The morbidity rate ranges from 8 to 11% and mainly consists in stent embolization or thrombosis as well as vascular access injury. The mid-term fate of the stented duct is spontaneous, slow and progressive closure within a few months. However, the stented arterial duct promotes similar and more balanced pulmonary artery growth than surgical shunt over a mid-term follow-up. Conclusions: Arterial duct stenting is a technically feasible, safe and effective palliation in congenital heart disease with duct-dependent pulmonary circulation. The stented arterial duct is less durable than conventional surgical shunt but is highly effective in promoting global and balanced pulmonary artery growth.

Novel Therapies for Schizophrenia: Understanding the Glutamatergic Synapse and Potential Targets for Altering N-methyl-D-aspartate Neurotransmission

For over fifteen years, N-methyl-D-aspartate receptor (NMDAR) mediated glutamatergic neurotransmission has generated interest because of its putative role in the pathophysiology of schizophrenia. Thus far, all antipsychotic medications have centered on manipulating the dopamine receptor to treat psychosis. These medications have limited efficacy, especially in treating the cognitive and negative symptoms of schizophrenia, and serious side effects. The NMDAR now provides an entirely new array of targets around which to focus new drug development. This paper first examines components of the glutamatergic synapse and discusses the relationship between decreased NMDAR function and schizophrenia. Then, human trials that have been conducted with agents that enhance NMDAR function, whether by molecules that activate the glycine co-agonist site (GCS), or by positive allosteric modulators (PAMs) that act on non- NMDAR are reviewed. In examining patents granted in the United States for treatment of schizophrenia based on normalizing glutamatergic neurotransmission, it seems academic researchers have focused primarily on GCS agents, and pharmaceutical industries have concentrated on synthesizing PAMs. The 21st century holds promise as the era in which an entirely new type of medication for schizophrenia may be created, one with more success at treating the debilitating negative and cognitive symptoms of this disease.

Staged Starnes Operation Preserving Patent Ductus Arteriosus for Neonates with Ebsteins Anomaly and Pulmonary Atresia

We herein reported 2 successful neonates with Ebsteins anomaly and small pulmonary arteries undergoing Starnes operation preserving the patent ductus arteriosus. Subsequent Blalock-Taussig shunt was carried out 1 or 2 months after the first surgery. One case had already undergone a successful Fontan operation, and the other had a successful bidirectional Glenn shunt so far. This staged Starnes strategy might be a safe and simple choice for neonates with Ebsteins anomaly and small pulmonary arteries.

Supraventricular Tachycardia in Fetus: How Can We Treat ?

The normal fetal cardiac rhythm is characterized by a regular heart rate ranging between 100 and 160 -180 beats/min with a normal 1: 1 atrioventricular electromechanical relationship during each cardiac cycle. Fetal tachycardia occurring in approximately 0.5% of all pregnancies and it is an important cause of fetal morbidity and mortality. A fetal tachycardic heart is at risk for developing low cardiac output, hydrops and ultimately fetal death or significant neurological morbidity. Different conditions can play a role to determine the natural history of tachycardic fetus as gestational age, underlying pathophysiology of the arrhythmia, fetal heart rate, duration of the tachyarrhythmia, and presence or absence of cardiac dysfunction. Reliable diagnosis in utero of fetal arrhythmia is possible by ultrasound examination of the fetal heart. In fact pulsed wave Doppler guided by two-dimensional echocardiography provided important information on cardiac rhythm as it study the blood flow from different chambers. With the introduction of the latest myocardial deformation methodology, the fetal tachyarrhythmias can be diagnosed more accurately. Precise diagnosis of cardiac arrhythmias in the fetus is crucial for a managed therapeutic approach. The choice of management is correlated to many factors: gestational age, underlying pathophysiology of the arrhythmia, fetal heart rate, duration of the tachyarrhythmia, and presence or absence of cardiac dysfunction. A large review of fetal arrhythmias was been reported in our work.

Characterization of Supraventricular Tachycardia in Infants: Clinical and Instrumental Diagnosis

Supraventricular tachycardia (SVT) is the most common symptomatic arrhythmias in children. Re-entry tachycardias are the most common form, on the contrary automatic tachycardias are relatively rare. There are four types or re-entry: along anomalous pathway with bi-directional (Wolff-Parkinson-White) or unidirectional conduction, intranodal re-entry, intra-atrial re-entry that is common after surgical procedure, and finally the uncommon sinus node re-entry. Automatic tachycardias may be atrial or junctional. The different types of tachycardia have a different incidence according to the age: in the first year of age re-entry along anomalous pathway is the dominant form, while intranodal reentry becomes common during adolescence. The age at the beginning of tachycardia is important for long term prognosis. When SVT starts in the first months of life it disappears in 80% of cases within the first year of life; on the contrary, if tachycardia starts later spontaneous remission is detected in only 15%-20% of patients. In infancy heart failure is the more common presenting symptom, thereafter palpitations become the principal cause of recognition of SVT. Syncope is reported in about 8% of cases and in another 15% usually neonates and infants, the SVT has an occasional detection. Electrocardiogram (ecg) usually allows the precise diagnosis of various types of SVT, and every effort should be made to record ecg during tachycardia. The parameters that should be evaluated are: heart rate, P wave axis, PR and RP interval, and finally presence or absence of AV block. Short lasting episodes should be difficult to be recorded; in these cases cardio-call and trans-telephonic transmission represent useful techniques to obtain SVT demonstration. Patients with SVT require a complete evaluation with others diagnostic techniques: echocardiogram, Holter monitoring, stress test, that should be chosen according the type of tachycardia. Electrophysiologic evaluation is now rarely performed for diagnostic purpose; trans-esophageal atrial stimulation being less invasive than intracardiac evaluation is more extensively employed when diagnosis of SVT is uncertain. Transesophageal stimulation is useful in the following situations: 1) evaluation of patients with symptoms suggestive of paroxistic tachycardia but without ecg documentation, 2) to assess the mechanism responsible for re-entry tachycardia: macro re-entry versus intranodal re-entry 3) to evaluate characteristics of anomalous pathway with bi-directional conduction, and 4)to terminate re-entrant SVT.

Genetic and Environmental Factors in Complex Neurodevelopmental Disorders

Complex neurodevelopmental disorders, such as schizophrenia, autism, attention deficit (hyperactivity) disorder, (manic) depressive illness and addiction, are thought to result from an interaction between genetic and environmental factors. Association studies on candidate genes and genome-wide linkage analyses have identified many susceptibility chromosomal regions and genes, but considerable efforts to replicate association have been surprisingly often disappointing. Here, we summarize the current knowledge of the genetic contribution to complex neurodevelopmental disorders, focusing on the findings from association and linkage studies. Furthermore, the contribution of the interaction of the genetic with environmental and epigenetic factors to the aetiology of complex neurodevelopmental disorders as well as suggestions for future research are discussed.

From the Oxygen to the Organ Protection: Erythropoietin as Protagonist in Internal Medicine

Erythropoietin (EPO), already known as the stimulating hormone for erythropoiesis, has shown different and interesting pleiotropic actions. It does not only affect erythroid cells, but also myeloid cells, lymphocytes and megakaryocytes. This hormone can also enhance phagocytic function of the polymorphonuclear cells and reduce the activation of macrophages, thus modulating the inflammatory process.Moreover, hematopoietic and endothelial cells probably have the same cellular origin, and the discovery of erythropoietin receptors (EPO-R) also on mesangial and myocardial cells, smooth muscle fibrocells and neurons has prompted the study of the non-erythropoietic functions of this hormone.The interaction between EPO and VEGF may be of particular importance in neovascularization and wound healing.Different studies have demonstrated that EPO has an important direct hemodynamic and vasoactive action, which does not depend exclusively on any increase in hematocrit and viscosity. Moreover EPO showed protective effects on myocardial cells against apoptosis induced by ischemia/repefusion injury, but it could negatively affect pulmonary hypertension in patient with chronic cor pulmonale.This review aims to stress the importance of the increasing interest in EPO applications and the necessity of further studies to gain a deeper knowledge of this hormone and its pleiotropic and complex actions.

Teratogenic and Developmental Effects of Lithium

A review is presented on the effects of lithium in therapeutic doses on the outcome of human pregnancy. The results of various studies including cohort, prospective, retrospective and small number case reports indicate that lithium is a \"weak\" teratogen in humans. The main effects attributable to lithium are, cardiac malformations and babies with increased birth weight. There is a possibility that, in particular, lithium may be associated with the Ebstein anomaly but present evidence cannot definitely affirm or deny this association. Animal studies with lithium using doses comparable to human therapeutic serum levels have not reported any abnormalities. However, higher doses have produced exencephaly, skeletal and craniofacial defects and abnormalities of blood vessel development. Experiments with other vertebrates have shown that lithium affects dorsoventral specification and inhibition of vasculogenesis. Both these effects can be prevented by pretreatment with myo-inositol indicating that lithium interferes with the phosphatidyl inositol cycle. More recent findings have shown that the effects of lithium on invertebrates may be mediated through inhibition of GSK-3β in the Wnt-GSK-3 pathway.

Aetiology, Diagnosis and Treatment of Hydrops Foetalis

Hydrops foetalis is defined as a state of excessive fluid accumulation in the extravascular compartment of the foetus, leading to widespread soft tissue oedema and / or accumulation of fluid in the foetal body cavities. The prognosis of hydrops foetalis is highly dependent on the underlying pathology and early diagnosis is essential to identify treatable cases. The classification of immune and non-immune hydrops foetalis describes the difference between Rhesus haemolytic disease of the newborn and other aetiologies leading to hydrops foetalis. With improved diagnosis and treatment of Rhesus iso-immunisation, non-immune factors have become more frequent. Distinction between anaemic and non-anaemic hydrops foetalis provides a far more useful differentiation between aetiologies. This approach is used to discuss differential diagnosis, work-up and therapeutic options in hydrops foetalis. A structured multidisciplinary work-up will facilitate early diagnosis and assist in making treatment decisions.

Molecular Cytogenetics of Autism

Autism is a neurodevelopmental disorder characterized by clinical, etiologic and genetic heterogeneity. It is often associated with other conditions, such as disorders of the CNS (tuberous sclerosis), developmental delay, attention deficit, epilepsy, and anxiety and mood disorders. Our survey found cytogenetically visible chromosomal anomalies in ∼7.4% (129 / 1749) of autistic patients documented as well as several sub-microscopic variants. Almost every chromosome is affected by numeric or structural aberrations. Among the most consistent cytogenetics findings are fragile X and duplication of maternal 15q11-q13. Molecular cytogenetics, together with genome scans and linkage / association studies, point to ≥22 chromosome regions harbouring putative autism susceptibility genes, such as 2q32, 3q25-q27, 7q31-q35, 15q11-q13, 16p13, Xp22, and Xq13. We hypothesize that there might be at least three types of autism susceptibility genes / mutations that can be (i) specific to an individual patient or family, (ii) in a genetically isolated sub-population and (iii) a common factor shared amongst different populations. The genes / mutations could act alone or interact with other genetic and / or epigenetic or environmental factors, causing autism or related disorders. This review emphasizes the potential of analysing chromosomal rearrangements as a means to rapidly define candidate disease loci for further investigation. To facilitate ongoing research we have established a new database of autism-associated chromosomal anomalies (http: / / tcag.bioinfo. sickkids.on.ca / autism).