Tetralogy Of Fallot

Medical and Social Outcomes in the Management of Cardiac Diseases in Children

Children with cardiovascular diseases, especially congenital heart diseases are exposed to socioeconomic burdens ranging from poverty, economic difficulties, and emotional breakdown to parental schism. There are various ways by which cardiac diseases affect children. These include the effect of the disease on the child, the family and the nation as a whole. Management of cardiovascular diseases in children comprises diagnosis, investigations, medical and surgical rehabilitation/ergonomics and follow-up. All these steps in management have both medical and social implications on the child. The effects of cardiovascular diseases are not limited to health, but can seep into social life, as well. Affected individuals tend to forgo a lot of things, including restrictions in their life, depression and even family structure disintegration, decrease life expectancy and family disharmony in some cultures. The socio-economic burden of pediatric cardiovascular diseases is quite huge both for the individual, household and society. The impact includes loss in financial resources, productivity, increased disability-adjusted life years, decreased quality of life, catastrophic expenditure and premature death. These burdens are more in the low and middle-income countries. This chapter aims at eliciting the various social and economic burdens that children with heart diseases encounter in the course of their illness.

Congenital Heart Disease

Anesthesia for Pediatric Patients with Common Comorbidities Part III

There have been dramatic improvements in the survival of neonates and children with many diseases and disorders due to advancements in medicine over the past several decades. These advances are attributed to the better understanding of these disease processes, the advent of multidrug combinations, molecularly targeted therapies, critical care and various surgical interventions. In the wake of this rapidly developing wide range of treatment protocols, the anesthesiologist needs to have a clear understanding of these disorders and their comorbidities, and stay abreast of the various treatment modalities, including their safety and toxicity profiles. This review attempts to emphasize some of the clinical conditions unique to these patients and special considerations for the conduct of anesthesia in this population. Some of the disease processes and comorbidities discussed here include anesthetic considerations for ex-premature infants, diabetes mellitus, obesity, childhood cancer, and children with congenital heart disease who present for non-cardiac surgery. The objective of this discussion is to provide an updated and comprehensive review of current perioperative anesthetic management of pediatric patients with these conditions. We also delineate the effects of anesthesia during the perioperative course, including major metabolic changes that may result in increased morbidity. We provide guidelines for any anesthesia provider involved in the care of these vulnerable patients. Special considerations need to be taken to promote the physical and mental wellbeing of these children and their families. Collaborative coordination with all providers involved in care is essential to provide safe and effective anesthesia to this subset of patients.

Anesthesia for Pediatric Patients with Common Comorbidities Part I

Children undergoing anesthesia have many considerations of disease processes that require careful attention to details and addressing specific needs. There are several comorbidities that are frequently encountered in a pediatric setting. A common scenario is a child with an upper respiratory tract infection presenting for elective surgery. We will discuss the criteria to be considered regarding when it is safe to proceed with elective surgery and when the risk is high. Asthma is common among children, and exacerbation can occur during an anesthetic. Anesthetic management of children with these respiratory illnesses is discussed. Children with Down syndrome frequently present for various cardiac and non-cardiac surgical interventions. Anesthetic issues relating to their non-cardiac surgeries will be discussed. Children with sickle cell disease is yet another group of patients frequently admitted to the hospital with sickle cell crisis. They warrant attention to specific details to ensure getting through surgery safely and require optimal pain management. Obstructive sleep apnea is increasingly encountered in children presenting for surgical procedures. Anesthetic challenges and risks they pose will be discussed.

Postnatal Surgical Approach of Congenital Heart Disease

The advances in neonatal care and pediatric cardiac surgery have allowed repairing of complex congenital heart disease in the newborn and young infants with excellent results. The most common congenital heart defects that may need early surgical treatment are tetralogy of Fallot (TOF), transposition of the great arteries (TGA), univentricular heart, total anomalous pulmonary veins connection, hypoplastic left heart syndrome, critical aortic stenosis, and truncus arteriosus. TGA, characterized by atrioventricular concordance with ventriculoarterial discordance, is the most common cyanogenic cardiopathy, which requires treatment in the neonatal period. Atrioseptostomy with Raskind balloon must be performed in the newborn with TGA, who presents significant hypoxia and restrictive atrial septal defect. Surgical treatment of TGA depends on the gestational age diagnosis, associated defects and evaluation of the left ventricle anatomy and function. TOF is the cyanogenic cardiopathy that requires therapy more frequently within the first year of life. Those newborns with TOF who present severe cyanoses and or hypoxic crises may become ductus dependent, requiring surgical shunting procedure, percutaneous ductal stenting or total repair. Currently, there is a trend to perform neonatal total surgical repair in the centers of excellence, based in the low surgical risk. In univentricular hearts, medical decision depends on some anatomical aspects. While in case of significant pulmonary flow obstruction, it will require shunting procedure, in case of pulmonary overflow, it may need pulmonary banding. Total anomalous pulmonary venous return, critical aortic valve stenosis, and pulmonary atresia patients will require surgical or interventional heart catheterization procedures as a newborn. While, newborns with Ebstein’s anomaly have about 60% chance of requiring early surgical intervention.

Genetics and Congenital Heart Disease

Congenital defects are frequent, occurring in 2-3% of live births, with high morbidity and mortality. Congenital heart defects are the most frequent, occurring in 1% of all live births. Most occur as isolated malformations, but approximately 1/3 are part of a syndrome, usually of genetic etiology. The correct etiological diagnosis is important for useful clinical follow-up and genetic counseling. Children born with congenital heart defects should be carefully examined for other malformations and dysmorphia.

Extra Cardiac Defects in Fetuses with Congenital Heart Diseases

Extracardiac malformations (ECMs) and chromosomal abnormalities are common in fetuses with some congenital heart defects (CHD). The frequency and type of ECMs and chromosomal abnormalities vary according to the type of CHD and the studied population. The detection rate of CHD and ECMs depends on the first-trimester screening through nuchal translucence (NT) measurement, second trimester anomaly scan, and fetal echocardiography. The CHDs most frequently associated with ECMs are atrioventricular septal defect (AVSD), ventricular septal defect (VSD), tetralogy of Fallot (TOF), hypoplastic left heart syndrome (HLHS), tricuspid atresia (TA), aortic arch, coarctation of the aorta (CoA) and interruption of the aortic arch (IAA). Conversely, the association of ECMs and chromosomal abnormalities with the transposition of the great arteries (TGA) is low. CHD such as: Ebstein's anomaly, left ventricular outflow tract obstruction (aortic stenosis) and obstruction of the right ventricular outflow tract (atresia and pulmonary stenosis) are associated with extremely low ECMs and chromosomal abnormalities, and are limited to a few sporadic cases.

Fetal Cardiac Tumors

Fetal cardiac tumors (FCT) are rare anomalies (about 1% among prenatal cardiac problems). There are more frequent multiple FCT and less frequent single FCT. The FCT occur in the population of healthy young mothers and risk factors are not easily detectable, but environmental factors (benzapirin?) could play a role. Basic ultrasound (US) anatomy in the 1st and 2nd trimester usually is normal and FCT are usually detected in the second half of pregnancy. In the majority of cases the fetus’s growth is normal. In each case, targeted fetal echocardiography should be performed in a fetal cardiology center. The very first problem is to discriminate between normal heart anatomy and congenital heart defect. The second goal of fetal echocardiography in FCT is to make an assessment of the hemodynamic status of the fetus. Extracardiac and additional anomalies coexisting in cases of FTC can be divided into two types i.e., frequent and rare. An experienced fetal cardiologist can not only make a proper diagnosis but also should counsel parents about the short-term prognosis for the fetus (about his future during prenatal life) as well as long term prognosis (after birth and later on). In cases of maternal decision to continue the pregnancy, fetal echocardiography monitoring should be offered to evaluate possible hemodynamic changes, to prepare both fetus and pregnant woman for optimal time for delivery and perinatal care. The main goal would be to avoid prematurity and to confirm fetal wellbeing, despite the cardiac abnormality. Details of echocardiography and postnatal outcome are presented in rhabdomyoma, teratoma, fibroma, myxoma and hemangioma. The way of delivery in surgical resection of cardiac tumors in newborns is discussed. In differential diagnosis, “bright spot” is discussed. Suggested management – algorithm of perinatal care in cases of FCT is presented with emphasis on cooperation of a perinatal team. FCT can be diagnosed at 20 weeks of pregnancy, which allows to start echocardiographic monitoring, taking into consideration the potential risk of hemodynamic progression. FCT (both multiple and single) can be the first sign of tuberous sclerosis complex in later prenatal or postnatal life. Single FCT other than rhabdomyoma can be asymptomatic in newborns, but may require an early surgical resection, therefore delivery in tertiary centers is recommended. FCT are a good example of the practical value of prenatal cardiology development.

Fetal Conotruncal Anomalies

Conotruncal anomalies are characterized by abnormalities of the great vessels of the heart. There are five types of conotruncal anomalies named as tetralogy of Fallot, double outlet of the right ventricle, transposition of the great arteries, truncus arteriosus and corrected transposition of the great arteries. These lesions known as “conotruncal anomalies” are caused by aberrant development of the conotruncal region of the embryonic heart. Prenatal diagnosis of congenital heart disease optimizes obstetric and neonatal care. Identification of these anomalies in prenatal life allows a variety of treatment with options to be considered, including delivery at a tertiary center, termination of pregnancy in some cases and in utero therapy. Majority of fetuses with conotruncal anomalies will undergo surgery in the neonatal period or in the first year of life. This chapter will discuss the fetal echocardiographic findings, extracardiac and chromosomal anomalies associations, prenatal and postnatal outcomes of conotruncal anomalies.

Fetal Left Cardiac Malformations

Congenital heart defects (CHDs) represent the most common congenital malformations, especially those affecting the left side of the fetal heart. During fetal life, the presence of the ductus arteriosus is responsible for the low intrauterine mortality rate if compared with the postnatal life. Prenatal diagnosis of CHDs has improved over the past 20 years and diagnostic enhancement has been obtained with the introduction of standardized examination of the fetal heart together with the technological advancement of the ultrasound equipment, particularly with the introduction of the four-dimensional (4D) ultrasound technique based on spatiotemporal- image correlation (STIC) or the application of the three-vessels and trachea view (3VT). The chapter describes and reports the evolution of the antenatal detection of left cardiac malformations, with emphasis regarding the echocardiographic characteristics that need to be evaluated in order to assess the hemodynamic state of the fetus. An extending search and analysis of the medical literature has been sought and describe in relation to the prenatal ultrasound diagnosis of aortic coarctation (CoA), aortic stenosis (AS), interrupted aortic arch (IAA), hypoplastic left heart syndrome (HLHS), aortic arch abnormalities and aorto-pulmonary window (APW). Understanding the cardiac performance of the fertus is of vital and critical importance to plan appropriate management and prognosis. Cardiac defect as critical aortic stenosis (CAS), IAA and HLHS are described as a potential emerging pathogenetic continuum. Attention has been paid to the latest improvement of in utero surgery and technique such as fetal aortic valvuloplasty in case of CAS or severe CoA and the use of multiple scoring system to predict postnatal biventricular circulation are described in great details. Notewithstanding, the chapter is enriched by a series of 2D- as well as 3D/4D ultrasound imaging and videos for each type of left cardiac malformation.

Fetal Septal Defects

The frequency of the different fetal septal defects and their presentation prenatally is described, including atrial septum defects (ASDs), ventricular septum defects (VSDs) and atrioventricular septum defects (AVSDs). Embryology of the defects and the association with underlying aneuploidy and genetic syndromes are discussed. Image findings in the fetal period are presented alongside diagrams to aide comprehension of the ultrasound views. A brief summary of prognosis and postnatal course of these conditions is also included.

Utero-Placental Circulation Development

With increasing obesity and diabetes in our population, and alcohol, marijuana, and tobacco use among women of child-bearing years, there is a high probability of embryonic exposure to risk factors before pregnancy is recognized. These metabolic changes and environmental factors are known in animals to induce birth defects and specifically, congenital heart defects (CHDs). This study discusses an interrelationship between placental and heart development in which blood flow between these developing organs needs to be maintained at specific levels. When blood flow is altered in the mouse by embryonic exposure to environmental factors, dysmorphogenesis occurs. Additionally, with gene expression analysis of the embryonic heart it was demonstrated that with elevated homocysteine (HCy) a natural metabolite, and alcohol exposures, numerous Gene Ontology classifications relating to lipid metabolism were altered. As for example, relative to the female embryo, significantly more alterations occurred in the male embryonic heart transcriptome with homocysteine exposure. That lipid metabolism was altered was validated by staining for localization of neutral lipids in the embryonic mouse embryos. We demonstrated that lipid droplet amount and the localization patterning were changed with exposures in both the fetal four-chambered heart and in the placenta. More changes occurred, however, in the placental tissue. We have demonstrated that a regimen of high folic acid supplementation of the pregnant mouse diet started with the morning after conception prevented the environmentally induced alterations. The importance of lipids in trophoblast and placental development, the relationship to gender, and how folate supplementation normalizes development through epigenetic programming is reviewed.

Cardiovascular Development

An understanding of normal cardiovascular development is essential to appreciating the abnormalities seen in congenital heart disease. The cardiovascular system develops within the mesoderm and through the process of folding, and establishment of the body axis, patterning and laterality it transforms from blood islands into the primitive heart tube and then the complex cardiac structures that supply the fetus. This chapter will discuss the embryological formation of the cardiovascular system and how deviations from normal development result in common cardiac defects.

Classification of Prenatal Congenital Heart Diseases

The in utero progression of congenital heart diseases (CHDs) can be observed in almost all CHDs during the first, second, and third trimesters of pregnancy. The progression of a cardiac disease can be associated with worsening of structural defects, new onset of foramen ovale restriction, decreased ventricular inflow or outflow, or worsening arch obstruction. The role of contemporary fetal cardiologists is to not only diagnose CHDs but also foresee the condition of the newborn after delivery and plan potential treatment in the first hours-or even minutes-of life. For this reason, pregnancy and delivery management of newborns with a prenatal diagnosis of CHD requires a multidisciplinary team composed of fetal and pediatric cardiologists, obstetricians and maternal–fetal specialists, neonatologists, and other pediatric specialists. The potential progression of CHD severity in utero and changes occurring during the transition from fetal life to infancy led to the creation of new classifications of CHDs dedicated to fetuses only. Severest heart defects are defined as CHDs in fetuses whose treatment results in death in nearly all cases, and potential treatment is needed immediately after birth; severe urgent heart defects are defined as CHDs in fetuses who need to undergo an invasive cardiologic treatment or cardiologic surgery within the first hours of postnatal life; severe planned heart defects are defined as CHDs in fetuses who need to undergo cardiologic surgery within the first month after birth, usually with ductal-dependent circulation and prostaglandin infusion to prolong prenatal physiology; and planned heart defects are defined as CHDs in fetuses who do not need to undergo cardiologic surgery within the first month after birth (usually surgery may be postponed to infancy). The only tool for the proper qualification of fetuses to one of the groups in the new classification system is fetal echocardiography.

Chemometrics as a Powerful and Complementary Tool for Mass Spectrometry Applications in Life Sciences

Because of its unique capabilities, mass spectrometry is an indispensable part of life science research. In this chapter, a review is made on aids of chemometrics in life sciences applications of mass spectrometry. Because of the increasing complexity of biological samples and ongoing technological enhancements of mass spectrometers, huge sum of data are provided for each biological sample. If the routine exploratory tools are used for data exploration, much of the information is not extractable and hence it gets lost. However, chemometrics helps to explore data thoroughly and extract maximum amount of information. The most common aids of chemometrics in bio-based mass spectrometry data is for experimental design, noise reduction, classification, library search, identification of biomolecules, finding the biomarkers, data compression and data mining.

This chapter is focused on the different aspects of using chemometrics for the analysis of mass spectrometry data in omics and biomedical images. In the first part, chemometrics applications for mass data in omics sciences (metabolomics and proteomics) are revealed. The mass data in omics are mainly provided by hyphenation of mass spectrometry with chromatographic techniques, i.e., gas chromatography (GC), liquid chromatography (LC) and electrophoretic techniques. In the second part of the chapter, the benefits of using chemometrics for mass spectrometry images are revealed. The data of these images are gathered by mass spectrometer itself or hyphenation with chromatographic techniques. Since, hyphenated methods are used for both omics and biomedical imaging, some of the chemometrics methodologies used in these two disciplines may be the same.

Qualitative and Quantitative LC-MS Analysis in Food Proteins and Peptides

LC-MS combines high separation ability of liquid chromatography with strong mass spectrometric structure identification. The advantages of LC-MS include high sensitivity and selectivity, minimal sample throughput, fast analysis speed and extensive structural information. It has been widely used in many fields, such as natural product analysis, pharmaceutical and food analysis, and environmental analysis.

In recent years, a great deal of researches have been conducted on the qualitative and quantitative aspects of food proteins and peptides. A variety of qualitative analyses of food proteins and peptides have been performed by LC-MS, such as accurate analysis of relative molecular weight, primary structural sequence, disulfide bond position, post-translational modifications (PTMs), etc. The quantitative analysis of proteins and peptides by LC-MS has been mainly achieved by two methods, i.e., label-free methods (peak intensities approach and spectral counting approach) and labeled methods (chemical labeling, metabolic labeling and enzymatic labeling methods). This chapter focuses on the application of qualitative and quantitative analysis of proteins and peptides in food sources.

Applications of Mass Spectrometry for the Determination of Microbial Crude Protein Synthesis in Ruminants

The importance of quantifying ruminal microbial crude protein synthesis has promoted the development and comparison of several different methods for precise determination of both the amount and rate of synthesis. One major challenge is in estimating and differentiating protein in the rumen between microbial, dietary, and endogenous fractions, and to correctly isolate the solid and liquid microbial fraction of the rumen contents. This is further complicated by the goal of using non-invasive methods as much as is feasible, such as avoiding the use of fistulated animals; the selection of an appropriate microbial marker, specifically one that behaves similarly in the solid-associated and liquid-associated microbial fractions. It is also vital to be able to accurately estimate the contribution of microbial protein to overall nitrogen used by the animal, which can be accomplished by the use of 15N labeled, as assimilated by ruminal bacteria, and by the quantification of labeled nitrogen via mass spectrometry (15N/14N). This review focuses on challenges regarding accurate quantification of microbial crude protein synthesis in the rumen, as well as providing the methodology for quantification using the 15N marker. This review is based on the collection of scientific papers from the main research groups in feed and animal nutrition in ruminants.

The Advance of the Intelligent Instrument Applied in an Online Equipment Monitoring System

In this chapter, we will introduce the state-of-the-art instruments of online equipment monitoring system. Meanwhile, the technology of fault tolerance, fault analysis and the fault identify problem will be discussed.

The Data Processing Technology of Intelligent Instruments

In this chapter, we will discuss the measurement uncertainty in intelligent instruments; the data processing algorithms in industrial intelligent instruments; the inverse problem and its processing method; the intelligent computing includes the deep learning and machine learning arithmetic in the intelligent instrument design.

The Signal Detection and Analysis Technology in Intelligent Instrument

The fundamental modern intelligent instrument is signal detection and analysis technology. Although it is the classic content of intelligent instruments, the noise analysis technology, the weak signal detection technology developed largely in many test fields. Therefore, in Chapter 2, the structure principle of data acquired system, the noise analysis technology, and the weak signal detection technology are introduced.

The Concept of Intelligent Instrument

One of the most fundamental principles in science and technology is that the discovery can be reproduced or the results can be measured. So, at the beginning of the book “modern intelligent instruments-theory and application”, the introduction of measurement, the intelligent instrument and its composition, and the example of an intelligent instrument are present.

Subject Index

Heart Failure in Pediatric Patients with Congenital Heart Disease

Heart failure may occur in structurally normal heart or in congenitally diseased heart. Some congenital heart diseases may predispose to heart failure, in different mechanisms and different pictures, as Fallot tetralogy, single ventricle, muscular dystrophy associated cardiomyopathy and left ventricular non compaction. The etiology of heart failure in those patients may be due to volume overload, pressure overload or valve insufficiency. The medical treatment for such patients includes diuretics, B blockers, ACE inhibitors, digoxin and anticoagulations.

Traditional Indian Therapeutic Herbal Agent for the Treatment of Ischemic Myocardial Disorders: Promises and Precautions

Cardiovascular disorders (CVD) like ischemic heart disease, hypertension, dysrhythmia and cerebrovascular complications account for maximum mortality in developed and developing world. According to World Bank health review, estimated deaths in all age groups due to CVD may mount up to 33% by 2015. In addition, ever increasing healthcare costs to the society are also becoming a huge social liability. Especially, ischemic heart diseases (IHD) are leading cause of mortalities and morbidities encountered by almost all CVD patients around the world. Till now there are a few approved therapeutic agents, one of them is tissue plasminogen activator (tPA), for the treatment of ischemic disorders. Moreover, use of thrombolytic agents and surgical interventions involve high interventional costs both economically and physiologically. Prevention of IHD can significantly add on to the quality of life of the vulnerable section of population than its therapeutic management. It has been established that injury and ensuing necrosis to cardiomyocytes can result from sudden reperfusion of the ischemic core which is pathognomonic of myocardial ischemic reperfusion injury. The underlying mechanisms viz. exacerbated generation of reactive oxygen species (ROS), inflammatory reactivity and uncontrollable necrosis are responsible for massive cellular injury during IHD. An ideal treatment should address most of these mechanisms without disturbing other vital physiological systems. Traditional herbal therapy has been shown to provide almost all of these benefits. The clinical evaluation of active constituents of many ayurvedic medicines like Terminalia arjuna greatly reinforces these centuries’ old beliefs. However, the increasing concomitant use of herbal therapeutic agents with modern medicines by patients with CVD poses a grave clinical challenge to physicians. In addition to this, less than 50% of the patients inform the use of alternative medicines to their physicians. Even if patients report it, many times physicians himself is unaware of the knowledge about the activity and the toxicity potentials of active constituents. Hence, a physician sometimes finds himself grossly unequipped to handle possible alterations in the actions of modern medicines used for the treatment of CVDs.

To highlight the advances in traditional herbal medicines, their potential therapeutic effects, possible drug-herb interactions and precautions to be taken are discussed in this chapter. Patients commonly use These scientifically validated herbs as an alternative therapy for the prevention and management of cardiovascular disorders.

Spatial Geostatistical Analysis Applied To The Barroso-Alvao Rare-Elements Pegmatite Field (Northern Portugal)

The geological science has been in recent years an excellent playground for GIS applied studies, especially regarding the mineral deposits prospectivity. Other fields of study in the geological science (e.g. soil risk management, mining exploitation, geothermal resources…) also took advantages of this geocomputing methodology to extract spatial information. The geoscientist community fairly agrees that interrelations between mineral deposits and certain geological features are observed in the terrain, presenting also a non-random spatial regional distribution pattern in a vast majority of cases. This is where the spatial analysis using geocomputational techniques, in this particular case for rare-elements pegmatites, can be used as a great analytical tool to produce a mapping of mineral potential, or unveil the regional zonation patterns for this type of mineralization. In this study, statistical spatial analyses were performed for the pegmatites to highlight any possible relationship, or lack of it, between them and the surrounding granitic plutons, shear zones or schistose foliations. To accomplish our proposed objectives, the geocomputational method of Distance to Nearest Neighbours (DNN), Ripley’s L’- function and pegmatites orientations families were employed to study the spatial distribution pattern of the pegmatites, whereas Euclidean distance and Kernel density distributions aimed the spatial association between these same pegmatites to the various geological features within the study area. The obtained results show: i) Pegmatites spatial distribution following a clustering pattern, presenting the Lienriched pegmatites a higher rate and extent compared to the total pegmatites, as well as a spatial association with moderate to high pegmatites density; ii) Three distinct families of pegmatites orientation; iii) No statistically significant spatial relationship for the total pegmatites or Li-enriched relatively to the granitic pluton; iv) A regime of deformation within the study area, suggesting the presence of corridors of deformation with NW to NNW orientations; and v) Pegmatites spatial emplacement suggesting shear-zones control.

Anatomy of Intraoral Techniques

Anatomy (from the ancient Greek anatom

Integral-Balance Solution to Nonlinear Subdiffusion Equation

Improved double-integration technique to approximate integral-balance solutions of non-linear fractional subdiffusion equations has been conceived. The time-fraction subdiffusion equation with Dirichlet boundary condition and a powerlaw fractional diffusivity has been chosen as a test example. Problems pertinent to approximation of time-fractional Riemann-Liouville derivative when the distribution is expressed as a parabolic profile with unspecified exponent and accuracy of the solutions have been analyzed. The final solution is a closed-form can be presented with either a similarity variable of a fractional order as independent variable or by an effective similarity variable incorporating the effects of both the fractional order and the nonlinearity of the diffusion coefficient. Optimization problem pertinent to determination of the optimal exponent of the parabolic profile, dependent on both the fractional order and the nonlinearity parameter of the diffusion coefficient, has been developed by a modified technique transforming the time-varying domain of integration into one with fixed boundaries. It was clearly defined that the approximate profile can exhibit a concave behaviour, typical for subdiffusion relaxation processes when the non-linearity of the diffusion coefficient is low and the fractional order is high. Otherwise, the increase in the nonlinearity of the diffusion coefficient results in convex profiles typical for the degenerate diffusion behaviour.

The Contrivance of General Theory of Relativity: Unification of Abraham, Einstein and Nordström’s Hybrid Theoretical Models

The aim of the chapter is to amend the received view on the general theory of relativity (GTR) genesis and advancement by taking into account common scientific practice of its functioning, the history of science data and certain philosophy of science arguments. The inter-theoretical aspect of the GTR genesis as an instance of perspicuous epistemological model of mature theory change that hinges upon ‘old’ theories encounter and interaction is scrutinized. I strengthen arguments in favour of the tenet that the dynamic creation of GTR had been continually governed by internal tensions between two research traditions, that of special relativity and Newton’s gravity. The encounter of the traditions, their interpenetration and intertwinement engendered the rival programmes of relativistic theory of gravity construction: the programmes of Abraham and Nordstrӧm – on the one hand – and Einstein’s programme – on the other. The encounter created the hybrid realm at first with an irregular set of theoretical models. The rival approaches of Einstein, Abraham and Nordström grew closer and eventually were transformed by Einstein into complementary ‘mathematical’ and ‘physical’ strategies of a general synthetic research programme that put forward the Entwurf and the GTR. Step by step, on eliminating the contradictions between the models contrived, the hybrid set was put into order by Einstein via the principle of equivalence. As in the STR case, Einstein was able to freely juxtapose Nordstrӧm, Abraham’s and his own non-metric theoretical schemes without reducing one to the others. It is contended that the main reason for the GTR ‘victory’ over the rival programmes of Abraham and Nordström was a synthetic character of Einstein’s programme. Einstein’s programme did supersede the rival ones because it did ingeniously assimilate some ideas of the Nordström programme as well as some presuppositions of the programme of Abraham. Einstein had put forward as a basic synthetic principle the principle of equivalence that radically differed from that of rival approaches by its open, flexible and regulative character. As a result of reconciling and amalgamating the ‘physical’ and ‘mathematical’ approaches, embodied in Abraham, Einstein and Nordström’s crossbred theoretical models , Einstein was able to explain the anomalous motion of Mercury.

Clinical Trials of Curcumin, Camptothecin, Astaxanthin and Biochanin

Use of natural products as therapeutics, has been in practice even before the advent of modern medicine. Traditional medicinal systems like Ayurveda, Siddha and Unani which prescribe medicines based on natural products have been in practice for centuries, authenticating the medicinal efficacy of these drugs. However, with the advent of modern medicine, the focus shifted from medicines based on formulations to mostly single component drugs. Also, norms were established to standardize methodologies for clinical trials that will establish safety and efficacy of the drugs before human use. These stringent norms meant that most of the traditional medicines could not be used in the current medicinal system of treatment as drugs. Nevertheless, researchers have repeatedly mined these traditional natural sources and other similar materials for compounds with potential therapeutic value. Such research has yielded compounds like acetylsalicylic acid (aspirin), morphine, quinine and even Nobel prize winning natural products like artemisinin (anti-malarial agent) and avermectin (antibiotic). In fact, more than half of the drugs approved by FDA have either direct or indirect inspiration from natural products. Apart from these, several interesting natural products are also under various stages of clinical trials varying from inflammation, infection to dietary supplements. The present chapter reviews some of these attractive natural products namely curcumin, camptothecin, astaxanthin, and biochanin that are currently under various stages of clinical trials for their application as therapeutics in various diseases. The chapter also deals with challenges such as lead optimization, formulations and delivery systems that should be addressed by researchers to move the natural product from the realm of nutraceuticals to the area of clinical medicine.

Syndromes with Characteristic Facies

A wide array of syndromes reported in the literature have significant impact on the craniofacial complex, with great influence on the facial aspect, which is usually typical of each syndrome. For this reason, this chapter refers to these disorders as “syndromes with unusual facies”, as described in the classical book of Gorlin et al.,. Affecting the craniofacial complex, these syndromes also often have significant implications for dental treatment and affected individuals may have peculiar dental needs.

Syndromes with Orofacial Clefts

Orofacial clefts are among the commonest malformations affecting mankind; even though most cases of orofacial clefts are non-syndromic, they may also manifest concomitantly with a wide array of syndromes. These syndromes with orofacial clefts often also cause diverse tooth abnormalities; knowledge on these peculiarities is fundamental for professionals to allow proper dental care for affected individuals.

Anesthesia in Down Syndrome Children

Down syndrome (DS) Children are more liable for frequent sedation and anesthesia either for imaging procedure or for surgical intervention. They have many risk factors that increase the anesthesia related complications. These risk factors include cardiac, esophageal, gastrointestinal or urinary tracts, eyes, ears, and joints anomalies. There is also an increased risk of infection due to immune deficiency. Proper preoperative, operative and post operative management are mandatory to decrease the anesthesia-related complications. In this chapter; these co morbidities and the factors that increase the risk of complications during anesthesia will be addressed, as well as pre-operative, intraoperative and post-operative management will be discussed.

Neurological Manifestations of Down Syndrome

Down syndrome is the most common chromosomal abnormality. A variety of neurological manifestations including stroke, epilepsy, cervical spinal cord compression, and basal ganglia damage may complicate the syndrome. As the neurologists have little chance to see a good number of DS patients and hence their expertise in this field is lesser than psychiatrists, it is suggested that cooperation between both neurologists and psychiatrists especially the learning disability might lead to better outcome of neurological complications of DS. This chapter reviews the commonest neurological complications associated with DS.

Neonates with Down Syndrome

Neonates with DS have many co morbidities that jeopardize this critical period of life with increased morbidity and mortality. They have more incidences of congenital heart diseases, pulmonary disorders, epilepsies, gastrointestinal anomalies, hematological problems as well as feeding disorders. They need to recognize their problems and for early intervention that could improve their medical conditions as well as their quality of life.

Surgeons and Cardiologist Working Together in Interventions in Congenital Heart Disease

Hybrid therapy is an emerging field of cardiology in which the skills of surgeons and cardiologists (both interventional and imaging experts) are co-operatively combined during a procedure to improve patient outcome. A hybrid approach is defined as a combined intervention performed in a single setting or in a planned close sequential fashion. Hybrid therapies aim to “play to the strengths and minimize the weaknesses” of the different disciplines in order to tackle lesions otherwise inaccessible without a combined procedure or with suboptimal outcomes when tackled using a single approach. Inevitably this philosophy has been used to extend the boundaries of therapy in patients at or beyond the limits of traditional surgery or transcatheter treatment for example very small infants with hypoplastic heart syndrome and patients with large and potentially inaccessible muscular ventricular defects. Hybrid therapy has the potential to reduce patient morbidity and systemic stress and can offer a bridge to definitive treatment in vulnerable patients.

In addition to the more “traditional” and accepted hybrid treatments for hypoplastic left heart syndrome, ventricular septal defect closure and intra-operative stenting a number of other techniques have been described including intra-operative valvoplasty, coarctation stenting and atrial septal defect closure.

Ideally hybrid therapy requires a dedicated operating facility although many procedures can be adequately performed in ordinary catheter laboratories or operating suites with relatively minor modifications.

Given that the majority of hybrid techniques are novel the precise indications and limitations of procedures require further definition.

New Approach in Congenital Heart Diseases with Duct- Dependent Pulmonary Circulation: Trans-Catheter Arterial Duct Stenting

Despite current trends toward primary repair, surgical systemic-to-pulmonary shunt is still an invaluable palliative option in some patients with congenital heart defects and duct-dependent pulmonary circulation. However, arterial duct stabilization with high-flexibility coronary stent could be an effective alternative in high-risk surgical candidates or whenever a short-term pulmonary blood flow support is anticipated. This paper highlights history, methods and results of this attractive mini-invasive palliative approach to cardiac malformation with duct-dependent pulmonary circulation. Based on ductal origin and morphology, stenting procedure can be perfomed from arterial or venous route. Following arterial duct angiographic imaging, the stabilizing stent is chosen to completely cover the entire ductal length and dilated slightly less than the proposed surgical shunt. Procedural failure mainly depends on ductal tortuosity and ranges around 10% of cases. Morbidity and mortality are 8-11% and less than 1%, respectively. Mid-term fate of the stented duct is spontaneous, slow and progressive closure within a few months. Compared to Blalock-Taussig shunt, stented duct result in similar but more uniform pulmonary artery growth over a mid-term follow-up.

In conclusion, arterial duct stenting is a technically feasible, safe and effective palliation in congenital heart disease with duct-dependent pulmonary circulation. It is advisable either in high-risk neonates or whenever a short-term pulmonary blood flow support is anticipated. The stented duct appears less durable than a conventional surgical shunt although it is highly effective in promoting a global and uniform pulmonary artery growth.

Magnetic Resonance Imaging in Congenital Heart Disease

Magnetic Resonance Imaging (MRI) has emerged as a valuable non-invasive diagnostic tool in congenital heart malformations providing anatomical and functional data regardless of patient’s size and quality of thoracic window. This technique is particularly indicated to avoid cardiac catheterization in post-surgical adult patients in whom the echocardiographic window is often poor. MRI is able to provide both accurate 3-dimensional images of the cardiovascular system as well as precisely quantify volumes and mass of the cardiac chambers and functional data of any single segment of the heart. MRI is now considered a Class I indication in pediatric or adult patients with congenital heart malformations. It is able to define morphological data of cardiac malformation and its functional consequences at the same time. This paper summarizes the most relevant technical aspects of MRI in congenital heart disease and reports on useful protocols to evaluate the most common malformations.

Genetics of Structural Congenital Heart Defects

Epidemiological studies, clinical observations and recent advances in molecular genetics are shedding increasing light on the genetic origin of congenital heart disease (CHD). Chromosomal anomalies, Mendelian syndromes or associations account for nearly 30% of all congenital cardiac malformations. These developmental anomalies may be part of well-defined syndromes due to chromosomal or submicroscopic genomic anomalies or may be non-syndromic as a consequence of still unidentified genes with sporadic occurrence in families. This paper summarizes the available findings from literature on the inference of genetics on cardiac development by classifying the congenital heart diseases as cono-truncal defects, atrio-ventricular canal and septal defects, right-sided obstruction and left-sided obstruction.

Cono-truncal defects represent an anatomically heterogeneous group of CHDs affecting the outflow tract of the ventricles and the arterial pole of the heart. The most common malformations of this group are tetralogy of Fallot, pulmonary atresia with ventricular septal defect, truncus arteriosus and interrupted aortic arch. These CHDs are associated with genetic syndromes in 25-40% of cases and even in non-syndromic forms show a high incidence of mono-genic abnormalities.

Atrio-ventricular canal is a complex malformation due to abnormal septation of the “crux cordis” resulting in ostium primum atrial septal defect, inlet ventricular septal defect and common atrio-ventricular valve. It is almost always associated with genetic syndromes, being non-syndromic in only 25% of cases. However, septal defects other than atrio-ventricular canal are rarely due to genetic syndromes, ranging from 3% to 25% of cases, yet with a high rate of segregation in some families.

Valvular or vascular-elicited right sided obstructions, are due to genetic syndromes in about 10% of cases and this association results in difficult treatment due to the ineffectiveness of any percutaneous treatment and extent of the lesions along the pulmonary trunk.

Among left heart obstructions, supra-valvular stenosis is a well-know malformation due to disruption of the elastin gene associated with Williams syndrome in many cases.

Conversely, aortic coarctation and other left-sided heart stenosis or hypoplastic malformation are often non-syndromic, being associated with genetic syndromes in less than 10% of cases.

In conclusion, improved molecular genetic technologies has led to the discovery of several causes of syndromic and non-syndromic CHDs. Nevertheless, much work remains in identifying in etiology of non-syndromic CHDs, since the number of genes known to be involved is still limited.

Appendix B: 2008 ACC/AHA Guidelines for the Management of Adults with Congenital Heart Disease

Cyanotic Heart Diseases

Tetralogy of Fallot, Transposition of the Great Arteries, and the Fontan circulation comprise some of the most common congenital cyanotic lesions encountered in practice. Tetralogy can be repaired initially, if the lesion is severe enough, with a systemic-to-pulmonary shunt to augment pulmonary blood flow. Then the definitive repair closes the VSD and enlarges the RV outflow tract. TTE is the initial imaging study of choice for Tetralogy, however, MRI and sometimes CT complement to assess conduits and post-op pulmonary valve insufficiency. d-TGA is characterized by ventriculoarterial discordance and initially was repaired by an atrial switch and is now repaired by an arterial switch. CCTGA has atrioventricular in addition to ventriculoarterial discordance and therefore does not usually necessitate surgical repair. Initial imaging is done with TTE, but TEE, MRI, and CT are frequently required to image the baffle from an atrial switch repair. Contrast angiography is used during percutaneous intervention to repair baffle stenosis. The Fontan circulation is the result of a series of surgeries to repair single ventricle anatomies. TTE is the initial imaging moda lity, but MRI is usually needed to visualize the entire Fontan circuit. CT and TEE are sometimes used as alternatives.

Conotruncal Anomalies

In the chapter, the 2D, color Doppler and 4D features of major conotruncal abnormalities will be described. In particular, the echocardiographic views on which the various lesions are detected will be described. In addition, the role of color Doppler in the recognition of valve stenosis or insufficiency will be illustrated. Finally, the diagnostic role of 4D echocardiography will be described, only in those cases in which it has additional clinical value. Videos of major diagnostic features are also provided, to facilitate the understanding of the text.