\r\n\tEqually important are the consequences deriving from the extraordinary nature of the present times. The COVID-19 pandemic and the restrictive measures to contain the infection (lockdown and "physical distancing" in primis) have revolutionized the lives, and a distortion/modification of habits, rhythms, arrangements will continue to be necessary.
\r\n\tGovernments have implemented a series of actions to mitigate the spread of infections and alleviate the consequent pressure on the hospital system. On the other hand, the Covid-19 pandemic has caused a series of other cascading effects that will probably be much more difficult to mitigate and which expose to complex consequences. The past two years have brought many challenges, particularly for healthcare professionals, students, family members of COVID-19 patients, people with mental disorders, the frail, the elderly, and more generally those in disadvantaged socio-economic conditions, and workers whose livelihoods have been threatened. Indeed, the substantial economic impact of the pandemic may hinder progress towards economic growth as well as progress towards social inclusion and mental well-being.
\r\n\t
\r\n\tAlthough in all countries the knowledge on the impact of the pandemic on mental health is still limited and mostly derived from experiences only partially comparable to the current epidemic, such as those referring to the SARS or Ebola epidemics, it is likely that the demand for intervention it will increase significantly in the coming months and years. The extraordinary growth of scientific research in the field of neuroscience now offers the possibility of a new perspective on the relationship between mind and brain and generates new scenarios in understanding the long wave of the pandemic and in the prospects for treatment. Moreover, the pandemic also has led to opportunities to implement remote monitoring and management interventions.
\r\n\t
\r\n\tOverall this volume will address the complex relationship existing between COVID-19, mental health, acquired knowledge, and possible interventions taking a highly multidisciplinary approach; from physiological and psychobiological mechanisms, and neuromodulation through medical treatment, psychosocial interventions, and self-management.
Cryopreservation is emerging as one of the most promising techniques for the long-term conservation of plant germplasm; it is also considered as an alternative method to safeguard plant species preserved by conventional conservation practices such as in vitro techniques and ex situ methods, i.e., seed and field collections, including vegetatively propagated crop species.
This conservation technique is based on the freezing of tissues (e.g., organs and shoots tips) from in vitro plantlets or field collections at extremely low temperatures, with the aim of reducing metabolic activity while at the same time maintaining the vitality of the tissue. The main principle of the method is based on cooling plant tissues at an ultralow temperature, usually by the use of liquid nitrogen (LN) which has a constant temperature of −196°C. The frozen tissue after the desired period in ultralow temperature after rewarming is able to regenerate to healthy plants. However, this method is not as straightforward as it seems; freezing plant tissue can result in intracellular ice nucleation and subsequent ice crystallization leading to cell damage during cooling and/or rewarming of the samples.
Low water content minimizes ice crystallization. Hence, the objective status for cryopreservation is to reduce the water content in the plant tissue. By this procedure it obtains a glassy state to avoid the formation of lethal intracellular ice crystals in order to obtain optimal recovery and regeneration after cryopreservation. This can be achieved by the induction of vitrification status which is a glass induction by dehydration, the addition of cryoprotectants, and a very fast decrease in temperature.
Methods based on dehydration include osmotic dehydration, air desiccation, and freeze dehydration [1, 2, 3]. The state of the water in the plant during cooling/warming cycles is shown in Figure 1 with highlighted thermally colored and its possible detection and quantification by DSC techniques.
State of water in biological objects for cryopreservation. Those highlighted in a black frame are possible to quantify by DSC.
Various plant vitrification solutions (PVS) are used for osmotic dehydration; these are usually labeled with a number according to the specific mixture of basic cryoprotectants and their concentrations. The main PVS are Luyet [4], Fahy [5], Steponkus [6], PVS1 [7, 8], PVS2 [9], PVS3, PVS4, PVS5 [10], VS6 [11], PVSL [12], and VSL [9]. These are composed of different concentrations and combinations of four main cryoprotectants: dimethyl sulfoxide, sucrose, glycerol, and ethylene glycol.
Each cryopreservation protocol is species- and genotype-specific and needs to be optimized accordingly. Hence, the standardization of the protocol is necessary to ensure and facilitate an effective cryo-storage of the plant germplasm. To achieve this, it is necessary to determine the optimal water content during dehydration, freezing in LN and thawing to avoid ice crystallization. Additionally, assessing the amount of freezable water and verifying if the tissue being used has reached glass transition as well as analyzing the thermal events during cooling and freezing are key factors in order to develop and standardize a reliable protocol. This can be determined by the use of thermal analysis such as differential scanning calorimetry (DSC).
The use of DSC for checking the content of freezable water (or first-order water transitions freezing and melting) is applied for the cryopreservation of shoot tips [13, 14, 15], dormant buds/winter-hardy buds [16, 17, 18], pollen [19, 20, 21], and seeds [15, 22, 23, 24]. The development of cryopreservation protocols using DSC has been used for a number of plant species, i.e., potato [25],
DSC is a thermal method that can be used to measure and determine the phase transitions for cryopreservation. Using a function of time and temperature, the main principle of this method is to measure the temperatures and heat flows associated with thermal transitions in plant material providing information on the endothermic or exothermic events or changes in heat capacity. This information can be used to determine the glass transition, the temperature of ice nucleation, melting, boiling, crystallization time, and kinetic reaction which are the most important characteristics useful for cryopreservation [16].
This method is based on applying a regulated decrease and increase in temperature while measuring the heat flow and temperature corresponding to the tested sample. The heat flux-type DSC measures differences of temperature between reference and sample and recalculates the differential heat flux. The most common cooling/heating rate of the sample is 10°C min−1. There are three different temperature modifications of the heat flux-type DSC: standard DSC gives a basic information about exothermic and endothermic signals and about glass transition presence, temperature-modulated DSC (TMDSC) separates kinetic and thermodynamic events in tested samples, and quasi-isothermal temperature-modulated DSC (QITMDSC) determines the exact measurement of heat capacity at equilibrium conditions. The principle, application, and use of each of these DSC modifications will be demonstrated within this chapter through a series of experiments carried out on vegetatively propagated species and cryoprotectants.
Thermal characteristics as melting point temperature, glass transition temperature, and proportion of freezable water content (percent of the fresh weight) were determined using a differential scanning calorimeters TA2920 (TA Instruments, USA) with refrigerated cooling system (RCS) in the temperature range from −60 to +20°C and Q2000 (TA Instruments, USA) with RCS or liquid nitrogen cooling system (LNCS) in the temperature range from −90 to +20°C or from −140 to +20°C, respectively. The cooling and heating rates were 10°C/min. or 1°C/min. For standard DSC or TMDSC, respectively. Temperature modulation was performed at 1°C amplitude of modulation and 60-second period. Aluminum, hermetically sealed pans were used for all samples to avoid water evaporation before and during measurement cycles. Sample size ranged from 5 to 20 mg. The purge gas was either nitrogen or helium.
Standard DSC is a thermal analysis method used to carry out a total heat flow measurement of the sample in order to determine phase transitions such as crystallization, melting, and glass transition (Figure 2).
Thermogram from differential scanning calorimeter during warming. The glass transition is characterized by the beginning of the heat flow change (onset), midpoint (in some cases inflection point), and finish of heat flow change (endset), characterized by change of heat capacity (ΔCp). Crystallization of supercooled water is an exothermic reaction, followed by the thawing of crystalized water. These events can be characterized by onset, midpoint, and endset temperatures and by event heat flow change. Based on analysis of the exothermic or endothermic events, the freezable water content can be calculated also in dehydrated samples. Additionally, this thermal analysis method is a powerful tool in the assessment of the sample’s water behavior during cooling and warming; this includes supercooling, freezing, glass transition, cold crystallization, and melting which influence the sample’s cryopreservation success.
In terms of cryopreservation of plant tissue, this method of thermal analysis can help to improve the development of a more reliable protocol. It can be applied in the phase of optimization of the sample’s preculture, acclimation, or dehydration to decrease the amount of freezable water content within the sample and in the risk of sample injury (Figure 3). The quality of cryo-sample preparation can be checked and modified to avoid the presence of cold crystallization in the sample during its thawing after cryo- storage for its recovery (Figure 4). This method can also be used to assess the Tg (glass transition temperature) and to determine safe storage temperatures for the samples.
Area of the melting peaks represents the heat of fusion needed for melting of the sample, related to the amount of frozen water in potato shoot tips (cv. “Arnika”) after 1 h air dehydration (Q2000 + LNCA).
Cold crystallization during the warming cycle in potato shoot tips (cv. “Arnika”) in diluted PVS3 solution (Q2000 + LNCA).
Freezable water content is probably the most important parameter which influences the injury of plant tissue during cryopreservation using cryoprotocol avoiding controlled freeze dehydration. The proper decrease in freezable water content is hence prerequisite for successful cryopreservation. Standard DSC method measures the endothermic and exothermic signal related to water freezing and thawing. Based on the knowledge of heat of fusion specific for water at 0°C (334 J/g/K) and total amount of energy used for the phase transition of water melting (ice crystals thawing), the total amount of frozen water can be calculated, and based on this finding, the optimal time of PVS3 treatment can be adjusted. Freezable water was detected in garlic shoot tips during PVS3 dehydration for a period up to 90 min (Figure 5a). After ice nucleation this water fraction can cause cell damage by ice crystal growth. Intracellular ice formation is in any case lethal for the plant cell. There was no freezable water in plants after 90 min of dehydration. The appropriate level of dehydration by PVS3 has to be controlled due to the decrease of survival and regeneration of shoot tips by excessive dehydration (Figure 5b). For successful cryopreservation with high regeneration rate, samples in narrow dehydration window of PVS3 must be used: with neglected or no freezable water (Figure 5a) and high regeneration rate due to dehydration (Figure 5b) after warming from ultralow temperatures.
(a) Frozen water content after different time of shoot tips of
Safety and stability of plant sample stored at ultralow temperature are influenced by the temperature of glass transition. Throughout the period of cryopreservation, the sample has to be kept below the sample glass transition temperature. In case of increase of storage above the sample glassy state temperature, the risk of sample damage by ice crystals occurs. Different cryopreservation methods resulted in different sample glass transition temperature. Thus, the selection of the cryopreservation method or cryoprotectant used can influence safe storage temperature. The most frequently used cryoprotectants for plant cryopreservation PVS2 and PVS3 are characterized by Tg of −114 and −90°C, respectively. When the 80%PVS3 solutions were used, the glass transition temperature was approximately −88°C in potato shoot tips dehydrated for 2 h (Figure 6).
Glass transition of potato shoot tips (cv. “Désirée”) after 2 h dehydration in 80%PVS3 (Q2000 + LNCA).
Some cryoprotective solutions with a higher glass transition temperature can be used to increase the safe storage temperature and sample stability. Standard cryopreservation methods used in CRI is based on sucrose loading the shoot tips and subsequent air dehydration. This dehydration resulted in increased sucrose concentration and as a result increased in glass transition temperature. Thus, the glass transition temperature of potato shoot tips increased to approximately −23°C after 0.7 M sucrose loading and following air dehydration for 5 h (Figure 7).
Glass transition of potato shoot tips (cv. “Désirée”) loaded in 2 M sucrose solution and subsequently dehydrated by air for 5 h (Q2000 + RCS).
Though this method of thermal analysis is easy and simple to use (most standard programs use simple methods with cooling/warming rates of 10°C min−1) and provides a relatively fast real-time measurement of thermal characteristics in the course of dehydration of the sample (e.g., 30-min DSC program allows to perform measurements in every 30 min of dehydration), there are some limitations. One of these limitations is the measurement of the total heat flow signals which include both thermodynamic and kinetic signals; hence, the evaluation of thermodynamic signals may not be exact. Additionally, kinetic events like relaxation or crystallization make thermogram evaluation and event identification difficult and can mask the thermodynamic component of the total heat flow signal (Figure 8). The overlapping signals may not be identified. In such cases, there is the need to carry out a more detailed analysis of the specific thermal events by the use of TMDSC or QITMDSC.
Complex thermogram of 60% sucrose solutions including thermodynamic (glass transition, melting) and kinetic (crystallization) events (Q2000 + LNCA).
TMDSC is the thermal analysis method (Figure 9) used to separate the total heat flow signal into thermodynamic and kinetic components. Hence, through this method, thermodynamic events such as melting, glass transition temperatures, and kinetic events such as crystallization and relaxations can be analyzed separately. Additionally, the freezable water content and the water behavior in the sample during cooling/warming cycles, like supercooling, freezing, glass transition, cold crystallization, and melting can be determined. This method also determines the Cp (specific heat capacity) and allows to specify its reversible Cp (thermodynamic) component.
The example of TMDSC result of thawing thermal event in Allium shoot tips. Note the reversing heat capacity (rev Cp) opposite to heat flux (TA 2920 + RCS).
This method of thermal analysis can help to improve the development of a cryopreservation protocol by improving the quality of the cryo-sample preparation. The method can identify kinetic events, which mask the thermodynamic events and which reveal unstable sample conditions. Due to the identification of the thermodynamic component of the heat flow signal by this method, the exact determination of freezable water content and the Tg in the sample is possible.
This method of thermal analysis can help to improve the development of a cryopreservation protocol by improving the quality of the cryo-sample preparation. The method can identify kinetic events, which mask the thermodynamic events and which reveal unstable sample conditions. Due to the identification of the thermodynamic component of the heat flow signal by this method, the exact determination of freezable water content and the Tg in the sample is possible.
The total heat flow signal includes both thermodynamic and kinetic signals. That is why exact analysis in complex thermogram is difficult (Figure 10). Total heat flow showed some changes in the region from −61 to −12°C in 64% sucrose solution (from left to right): flat-shaped curve, high s-shaped curve, and peak. It is difficult to solve if the second event is a glass transition of melting. The TMDSC separated total heat flow into reversing and non-reversing signals. The only two events were detected on reversing curve: glass transition and melting. The second event detected by standard DSC represents just kinetic event related to the crystallization of free water which is released before from glassy state during warming.
Separation of total heat flow (HF) signal (upper) to non-reversing kinetic signal (middle) and reversing thermodynamic signal (bottom) in 64% sucrose solution (Q2000 + LNCA).
The TMDSC can be also used for direct measurement of specific heat capacity (Cp). It changes with the change of the state of matter. The liquid state is characterized by a higher value of Cp than solid (crystal or ice) states. Phase changes, glass transition, and melting are characterized by a specific shape of Cp curve. The glassy state is characterized by an S-shaped curve of Cp baseline; on the other hand, melting is characterized by a peak (Figure 11).
Changes in reversible Cp during warming with detection of glass transition and melting in 20% sucrose solution by TM DSC (Q2000 + LNCA).
Proper sample preparation for its successful cryopreservation is characterized by low-temperature glass transition curve but without melting peak presence. A decrease in the melting peak on the Cp curve is therefore necessary during sample preparation. An appropriate way of dehydration has to be applied to avoid plant tissue injury by excessive dehydration. Tolerance to dehydration is influenced by species, genotype, and by plant tissue or cells’ physiological status. Pollen, besides orthodox seeds, is a plant material that can be dehydrated to very low water content without decrease of plant material vitality. Dehydrated pollen is characterized by the absence of a melting peak but the presence of glass transition s-shaped curve (Figure 12). Due to very low water content, the glass transition temperature is at high temperature (−18°C), which strongly increases the safe storage temperature of the material during cryopreservation.
Changes in reversible Cp during warming with detection of the glass transition in hop pollen (Q2000 + RCS).
Though if properly applied and analyzed, the method can be advantageous because of its exact measurement of thermodynamic events due to the separation of thermodynamic and kinetic signals and can also be useful in the identification of the overlapping events.
TMDSC solved the limits of standard DSC method, but it has some limits too. It is time-consuming due to slower cooling/warming ramp rates. This can be partially solved by temperature modulation in narrower temperature range, which could be previously identified by a standard DSC measurement. TMDSC is sensitive to specific parameter measurement settings, which may result in failure to determine the events due to inadequate parameters of measure. Additionally, the interpretation of the results obtained can be difficult as it carries out a more detailed analysis which provides detailed results that are difficult to interpret (e.g., kinetic events).
QITMDSC is a specific variant of TMDSC. This method of thermal analysis is used for the direct measurement of complex Cp at given temperatures in equilibrium conditions, at zero ramp cooling/warming rates (Figure 13). Hence, it is used to determine the Cp, more specifically, the thermodynamic events such as melting and glass transition.
Temperature modulation at a constant temperature until heat capacity equilibrates. After equilibration of heat capacity, the temperature jumps to higher temperature and modulation starts again (TA 2920 + RCS).
The QITMDSC measures sample heat capacity (Cp) similarly like in the case of MDSC. That is why similar achievements can be obtained. This method can be used together with a method of matter relaxation during annealing at increasing temperature. The advantage of this method is the following measurement of the sample at stable conditions because all processes can be finished during modulation at equilibrium conditions (temperature). The glassy state is also characterized by an S-shaped curve of Cp baseline; on the other hand, melting is characterized by a peak (Figure 14).
Changes in Cp revealed the glass transition and the melting peak in 20% sucrose solution analyzed by QITMDSC after relaxation at −6°C (Q2000 + RCS).
This method is applied in the development of a cryopreservation protocol as it is useful in the determination of the state of matter and exact measurement of glass transition and melting. Additionally, it is adventitious in obtaining a more exact measurement of Cp as the Cp equilibrium conditions avoid the effects of kinetic events.
However, there are a few limitations in using QITMDSC as it is also very time-consuming, though this can be partially solved by analysis in limited temperature range, which was previously analyzed by a standard DSC or TMDSC analysis. The method is also sensitive to the parameters of measurement settings which may result in failure to determine the events due to inadequate parameters of measure. Nevertheless, as is the case with TMDSC if applied correctly, this method represents a useful tool when developing a cryopreservation protocol for vegetatively propagated plant species.
Understanding the dynamics of water content in plant tissues during cooling and heating is crucial in developing a reliable cryopreservation protocol. Differential scanning calorimetry thermal analysis methods such as standard DSC, temperature-modulated DSC, and quasi-isothermal temperature-modulated DSC play a key role when cryopreserving plant material as they not only broaden the knowledge of thermal events but can also help to overcome the freezing injury during cryopreservation. The standard DSC method is recommended for routine work with known thermal properties of the sample and nonoverlapping thermal events. The MDSC method is recommended to use for plant samples with overlapping thermal events or for exact measurement of thermodynamic events. The hidden thermal events can be arisen and be separated by temperature modulation. The MDSC is also recommended to distinguish between reversing and non-reversing thermal events. The measurement of heat flow and heat capacity can be done in a single experiment. The QITMDSC is recommended to use for exact measurement of heat capacity in equilibrated conditions which can help a state of matter identification.
The authors would like to thank Mrs. Zdena Hybnerova and MS. Adrijana Cajkova for their technical help. This work is partially supported by projects QK1910277, QK1910476, and RO0418 from the Czech Ministry of Agriculture.
Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease (CHD) involving hypoplasia of the left ventricle (LV), aorta (Ao), and mitral valve (MV). While HLHS is relatively rare (prevalence 0.02%) [1], it accounts for 25% of CHD infant deaths [2]. The great surgical advancement in HLHS led to a transition from the only option of comfort care in the 1980s to a three-stage cardiac surgical palliation procedure offering a 50–70% five-year survival [2]. However, about 25% of HLHS patients either died or had a heart transplant within 1 year of their Norwood operation [3]. Most HLHS survivors suffer ongoing morbidity, with a substantial portion of these patients developing heart failure over time, as well as neurodevelopmental delay and neurocognitive impairment that can significantly degrade the health-related quality of life. The causes for such high morbidity and mortality are not well understood, but the majority of deaths are directly or indirectly related to cardiovascular causes [4]. While the causes for the poor cardiac outcomes are multifactorial, our study in a mouse model of HLHS uncovers important contributing factors related to mitochondrial dysfunction [5].
Dr. Maurice Lev first described the hypoplastic left heart as hypoplasia of the aortic tract in 1952 [6]. However, the term HLHS was initially used by Noonan and Nadas in 1958 [7]. HLHS is a diagnosis that incorporates a spectrum of left ventricular inlet, ventricular and outlet obstructions that may include: aortic atresia or stenosis; mitral stenosis, atresia or agenesis (Figure 1); hypoplasia of the ascending aorta that may extend to the entire aortic arch; a non-apex forming left ventricle with variable degrees of left ventricular hypoplasia; commonly, a discrete coarctation of the aorta; and an intact ventricular septum in most patients [6, 7, 8].
Illustration of 4 types of HLHS and Norwood procedure with modified BTT shunt (e) and Sano shunt (f). AA: aortic atresia, AS: aortic stenosis, BTT: Blalock-Taussig-Thomas shunt, MA: mitral atresia, MS: Mitral stenosis (graphic illustration by Dr. Raymond Morales).
A normal left ventricle has a mitral valve and gives rise to the aorta. Furthermore, the apical portion of a left ventricular septal surface shows finer trabeculations than a morphologic right ventricle, and the subarterial septal surface is smooth (Figure 2a). Hearts with HLHS show variability in the size of the left ventricle (Figure 2b–d), and the types of mitral valve malformations (Figure 3b–e) and aortic valve obstruction (Figure 4b and c) along with the varying degrees of hypoplasia of the ascending aorta and aortic arch (Figure 5a and b) with or without coarctation.
Variations in the degree of left ventricular hypoplasia in hearts with HLHS. (a) Septal view of a normal left ventricle, (b) hypoplastic left ventricle with a stenotic and dysplastic aortic valve and endocardial fibroelastosis, and (c) three-chamber view showing the muscle bound, non-apex forming hypoplastic left ventricle with endocardial fibroelastosis, mitral valve stenosis and aortic valvar atresia, (d) diminutive and atretic (no inlet or outlet) left ventricular chamber in a heart with aortic and mitral atresia, and the muscle bound left ventricular segment of the heart bulges on the epicardial surface, and the position of the left ventricle is outlined by the anterior and posterior descending coronary arteries.
Variations in the condition of the mitral valve in hearts with HLHS. (a) Normal mitral valve, (b) normally configured but miniaturized mitral valve with slightly shortened and mildly thickened tension apparatus and mild diffuse endocardial fibroelastosis, (c) stenotic and dysplastic mitral valve in a heart with severe hypoplasia of the left ventricle and prominent endocardial fibroelastosis, (d) floor of the left atrium and an imperforate mitral valve, and (e) completely muscular floor of the left atrium without evidence of a mitral valve in a heart with mitral valve agenesis.
Aortic valve stenosis and atresia in the setting of HLHS. (a) Normal aortic valve, (b) tricuspid, stenotic and dysplastic aortic valve, and c) aortic valvar membranous atresia, mitral valve stenosis, and thick endocardial fibroelastosis.
Supracardiac great arteries and the right side of specimens with HLHS. (a) Mildly hypoplastic ascending aorta and large arterial duct, (b) hypoplastic ascending aorta and proximal aortic arch, coarctation of the aorta at the level of a large arterial duct, (c) enlarged right heart with hypertrophy of the right ventricle and an atrial septal defect.
In classical HLHS, the left ventricle has an intact ventricular septum. Ventricular size may vary from a mild degree of hypoplasia to being morphologically absent with no discernible inlet or outlet. The hypoplastic ventricle is commonly muscle bound with a thick myocardial wall causing the hypoplastic left ventricle to bulge on the epicardial surface. The hypoplastic left ventricle almost universally shows endocardial fibroelastosis that, at times, can be quite prominent (Figure 2b–d). Additionally, the left atrium will demonstrate varying degrees of hypoplasia.
A normal mitral valve consists of an anterior and posterior leaflet with tension apparatus attached to papillary muscles (Figure 3a), and the anterior leaflet is in fibrous continuity with the aortic valve. In the setting of HLHS, mitral valve can vary from well-formed but miniature to dysplastic and stenotic to imperforate or congenitally absent (Figure 3b–e).
The normal aortic valve consists of three semilunar cusps (Figure 4a) and the aorta consists of the ascending aorta, aortic arch, isthmus, and descending aorta. Aortic valves in hearts with HLHS can vary from having three cusps to bicuspid and are dysplastic and stenotic or atretic. Hearts with HLHS can have ascending aortas that may uncommonly be mildly hypoplastic (Figure 5a), but most of the time they vary from moderately to extremely hypoplastic with an almost thread-like appearance (Figure 5b). The hypoplastic ascending aorta serves as a conduit to perfuse both coronary arteries in a retrograde manner. In addition, the aortic arch may be hypoplastic. Coarctation of the aorta - a shelf-like, circumferential, paraductal lesion - is common in the setting of HLHS and may be mild to severe. Furthermore, HLHS is ductal-dependent condition, and the arterial duct is usually widely patent and large (Figure 5b). The right heart is enlarged and shows right ventricular hypertrophy. A patent oval fossa or atrial septal defect (Figure 5c) is present. Sometimes, the flap valve of the oval fossa can show aneurysmal dilatation bulging into the right atrium.
Hearts with premature closure of the oval fossa at an early gestational age result in malformations such as mitral atresia or stenosis and/or aortic atresia or stenosis, variable degrees of hypoplasia of the left ventricle, and endocardial fibroelastosis. The severity of the impact on the heart depends on the gestational timing of the closure or restriction of the oval fossa [9]. Figure 6a–c are images of a heart with premature closure of the oval fossa. Rarely, in patients born with premature closure of the oval fossa and inflow obstruction such as mitral atresia and in cases of typical HLHS with inflow obstruction, an escape channel for the pulmonary venous return may be present [10]. This escape channel may be a levoatriocardinal vein that allows pulmonary blood to egress from the left atrium or a pulmonary vein and reaches the right atrium via the left innominate/superior caval veins (Figure 6d) [11]. Rarely the escape of pulmonary venous blood from the left atrium may be accomplished by partial or total anomalous pulmonary venous return [12].
Right and left heart anatomy of a heart with premature closure of the oval fossa, and a specimen with a levoatriocardinal vein. (a) Septal surface of the right atrium illustrating the prematurely closed oval fossa, (b) dysplastic and stenotic mitral valve, (c) non-apex forming hypoplastic left ventricle with pronounced endocardial fibroelastosis, (d levoatriocardinal vein connecting the left atrium to the left innominate vein.
A hypoplastic left ventricle with aortic stenosis and an intact ventricular septum (Figure 7a) is not classified as an HLHS. Furthermore, isolated cardiac malformations such as a right-dominant unbalanced atrioventricular septal defect (AVSD) (Figure 7b) or a heart with double outlet right ventricle (DORV) with its ventricular septal defect and mitral valve stenosis (Figure 7c and d), both of which have interventricular communications and a hypoplastic left ventricle are arguably not categorized as having HLHS because they do not meet the traditional definition. However, these types of hearts (right-dominant unbalanced AVSD and DORV) have been described as
Specimens with hypoplastic left ventricles that do not meet the criteria of HLHS. (a) Aortic stenosis and intact ventricular septum, (b) right-dominant, unbalanced AVSD, and an atrial septal defect, (c) right ventricle view, DORV and a ventricular septal defect, (d) left ventricular view of C showing the hypoplastic left ventricle, ventricular septal defect, and the stenotic mitral valve.
The surgical palliation of HLHS consists of three, staged procedures: the Norwood, the Glenn, and the Fontan procedures.
The goal of the first two procedures is to prepare the heart for the final Fontan procedure. The ventricular function must be preserved by avoiding a pressure load (avoiding a pressure gradient in the aortic arch) or excessive load (correct-sized shunt), minimizing pulmonary vascular resistance (good-sized atrial communication), maintaining optimal pulmonary artery growth, and preserving the tricuspid valve function by avoiding ventricular dilatation associated with excessive volume work by the ventricle.
The first report of an attempted palliative operation for HLHS was in 1977 by Doty and Knott [14]. All the patients described died of poor right ventricular function or coronary ischemia. Norwood and associates reported the first successful palliative procedure that is still performed today [15].
The crucial components of this procedure can be divided into 3 steps:
Anastomosis of the main pulmonary artery with the ascending aorta to provide unobstructed right (systemic) ventricle outflow.
Atrial septectomy to allow unobstructed pulmonary venous drainage.
Systemic-to-pulmonary shunt as the source of controlled pulmonary blood flow using a Blalock-Taussing Shunt or Sano shunt (right ventricle to pulmonary artery conduit) [16, 17, 18].
The Norwood procedure is performed through median sternotomy; under moderate or deep hypothermia, using circulatory arrest or selective cerebral perfusion; the latter is currently the preferred option. Different materials are used for arch reconstruction; homograft is the most common material used, but there are other options including bovine pericardium, core-matrix, and femoral vein graft.
The systemic-to-pulmonary shunt can be performed by using the modified Blalock-Taussing-Thomas shunt (MBTT) (Figure 1e) or the right ventricle to pulmonary artery shunt (RVPA) which is named the Sano Shunt (Figure 1f).
MBTT shunt is made of polytetrafluoroethylene (PTFE, Gore-Tex): generally 3.5 mm for infants of 2.5–3.5 kg and 4 mm for larger infants.
The 5 mm RVPA shunt is used for neonates between approximately 2.3 and 3.5 kg. If PVR is high, a 6 mm RVPA shunt may be considered.
A randomized clinical trial comparing MBTT and RVPA at 15 North American Centers was performed which includes 275 patients with MBTT and 274 patients with RVPA shunt [16]. Compared with the MBTT group, the patients with RVPA shunt were associated with higher rates of transplantation-free survival at 12 months. By 14 months, the right ventricular end-diastolic volumes were similar in 2 groups [16], however, the RVPA shunt group had more unintended interventions and complications. Data collected over the follow-up period of 32 months showed a nonsignificant difference in transplantation-free survival between the two groups [16].
The second stage procedure is the bidirectional Glenn procedure that consists of a Cavo-pulmonary anastomosis which is usually is performed between 3 and 6 months of age. Viegas et al. reviewed 14 years of experience on 36 patients younger than 90-day-old and reported no mortality, but 90% of patients required Glenn patch augmentation. The indications to perform a Glenn procedure within the first 90 days of life are persistent hypoxemia, signs of ventricular dysfunction, and atrioventricular valve regurgitation [19].
Finally, the third stage procedure is total cavopulmonary connection or the modified Fontan procedure. There are two different surgical techniques for this procedure, namely, the lateral tunnel with intra-atrial PTFE graft and the extracardiac PTFE conduit; these procedures were popularized in an attempt to avoid late supraventricular arrhythmias [20]. The expandable Gore-Tex graft (Peca-labs) allows for dilatation of the Fontan conduit in the cardiac catheterization suite [21].
In 2002, Akintuerk et al. from Giessen, Germany were the first to describe the hybrid approach to HLHS, which is a combination of surgical intervention (application of bilateral branch pulmonary artery bands) and catheter intervention (placement of ductal stent) as primary palliation for neonates with HLHS [22]. In the United States, Galantowicz and Cheatham reported the results of this procedure in 2005 [23].
The results of the Norwood procedure have improved over the last few decades to where it is unethical not to offer this procedure to all newborns with HLHS; cardiac transplant is considered if there is any contraindication for the Norwood operation or Hybrid procedure.
Adequate pre-operative management of HLHS requires knowledge of the fetal circulation in this disorder. In patients with aortic atresia and very severe aortic stenosis—in general, there is a lower pO2 to the fetal brain with probably decreased blood flow to the brain as well. There is retrograde flow into coronaries in these instances and the ascending aorta is quite small. Normally the lungs will receive only 11% of the combined ventricular output [24], but the blood flow that the lungs see in HLHS fetus is usually higher [25]. In HLHS, it is conceivable that the relatively higher oxygen saturation could impact the normal microvascular development in the pulmonary artery and veins [26].
Postnatally, pulmonary venous return (normally fully saturated blood) must be routed to the right atrium. This mixes with desaturated blood in the right atrium and is ejected by the right ventricle. By default, the right ventricle supplies both systemic (through the PDA) and pulmonic circulations. Blood may need to flow retrograde to supply head and neck vessels and coronaries arteries. The delicate balance between systemic vascular resistance and pulmonic vascular resistance plays a major role. As suggested in the above section, ischemia of the brain and coronaries may occur.
In the postnatal period, we need an adequate interatrial communication, widely patent ductus arteriosus and a balanced pulmonary vascular resistance (PVR) to systemic vascular resistance (SVR). There is an inherent tendency for high pulmonary blood flow—in otherwise uncomplicated cases, with concurrent systemic steal. The right ventricle is volume overloaded at baseline. So, the immediate goals of pre-op care rest on preserving ductal patency and balancing PVR and SVR. One needs to be able to diagnose a high pulmonary to systemic flow ratio (Qp:Qs) state. Some of the clinical manifestations include hypotension, decreased urine output, delayed capillary refill, and lactic acidosis. Patients may also present with tachypnea, increased work of breathing, and respiratory distress.
The ductus arteriosus can be kept patent via the use of prostaglandin E1 (PGE1). The previously described starting dose range of 0.05–0.10 mcg/kg/min [27] has fallen out of favor to a lower starting dose of 0.01 mcg/kg/min [28]. It is most probable that these previously higher doses were the starting doses for patients who had not been prenatally diagnosed; and who came to medical attention later in the neonatal period. The risk of precipitating apnea is higher at higher starting doses. The recommended maintenance dose of PGE is 0.01–0.04 mcg/kg/min. At our institution, we will use doses as low as 0.003 mcg/kg/min–0.005 mcg/kg/min while patients await surgical repair. There are still institutions that will maintain their patients on PGE1 for prolonged periods of time.
The other means by which the ductus arteriosus can be maintained patent is through stenting of the ductus arteriosus. For patients with HLHS, this is generally done as part of the Hybrid procedure.
Pulmonary blood flow may be limited by manipulating pulmonary vascular resistance. This may be done by the use of sub-ambient oxygen otherwise called hypoxemic mixture [29]. The literature on this is sparse; particularly there are no randomized controlled trials. There has been hesitation to use this widely due to concerns about the cellular effect of hypoxemic mixture on tissue oxygenation. The other concern is that a non-intubated patient receiving a hypoxic mixture may hypo-ventilate or become apneic due to prostaglandin administration; therefore, the PaO2 levels may fall drastically [30]. The use of a hypoxemic mixture requires vigilance in terms of frequent checking of blood gases—to look at PaO2 and base deficit. Attempts to maintain Qp:Qs of approximately 1:1, with an ideal goal for PaO2 of 35–45 mmHg should be made. A useful thing to be aware of is that a central line placed in the right atrium of a patient with HLHS and aortic atresia is generally representative of an arterial gas in such patients. Hypoxemic mixture can be administered via high flow nasal cannula or via oxy-hood or a combination of both or through the endotracheal tube of an intubated patient.
Adjusting the ventilator settings of an intubated patient to allow for higher PaCO2 will also restrict pulmonary blood flow, as well as blending CO2 into the circuit [31, 32]. The latter is also not commonly practiced.
One can increase systemic circulation by use of afterload reduction agents such as milrinone—which can be titrated to effect as we monitor saturations; clinical cardiac output, base deficit, lactate levels, and PaO2 [2]. Optimization of oxygen-carrying capacity by keeping hematocrit >40% is also ideal. Ultimately, if all these maneuvers fail and one still needs to wait for intervention, then muscle relaxation of the patient may need to be considered in order to decrease metabolic demand, fully take over respiratory support and manipulated PaCO2.
Some of the maneuvers to limit pulmonary blood flow and increase systemic circulation are listed in the table below.
Limiting pulmonary blood flow | Augmenting systemic blood flow |
Hypoxemic mixture | Good intravascular volume |
PaCO2 | Increasing oxygen-carrying capacity |
Intubation and mechanical ventilation | Milrinone (afterload reduction) |
Muscle relaxation | Muscle relaxation |
Neonates with a restrictive atrial septum are usually quite ill-appearing with hypoxia and heart failure. The keys to management prior to cardiac catheterization intervention are intubation; ventilation; maintaining good blood volume; inotropic support in the form of a dopamine infusion or epinephrine infusion and continuing prostaglandin. It should be noted that increasing the PGE may worsen the clinical picture as there may be a transient increase in the blood return to the left atrium with no egress. Administration of sodium bicarbonate to mitigate the acidotic milieu and alerting the cardiac catheterization team as well as the surgical team are crucial. The atrial level communication in a patient with HLHS is superior in position and often times the tissue is very thick. As such, the cardiac catheterization intervention to establish atrial level patency can be challenging. If a balloon atrial septostomy cannot be effectively performed, then static ballooning may be done (alternatively stent implantation across the restrictive PFO) and if that fails, the surgical opening of the atrial septum is indicated. Blalock-Hanlon procedure (described in 1948 by Alfred Blalock and C. Rollins Hanlon) [33] is not usually performed for HLHS patients.
Infants with moderate-to-severe tricuspid valve insufficiency and/or poor right ventricular function from the very beginning pose an especially high degree of challenge for the cardiac intensive care physician. Some considerations in their management include ventilation; institution of diuretics; inotropic support; heart failure/cardiac transplant evaluation and supportive care/palliation team care involvement.
The patient with HLHS and severe pulmonary venous obstruction will develop marked hypoxemia over time. This hypoxemia may progress after a period of apparent well-being. The goal for these patients until surgical intervention—is to intubate, provide hyper-ventilation, increase FiO2, and increase SVR using inotropic support. A severe degree of pulmonary venous obstruction is a surgical emergency and may require rescue via extracorporeal membrane oxygenation (ECMO).
Genetic evaluation should include chromosome microarray and whole-exome sequencing, if indicated. A screening renal and head ultrasound is also recommended. Feeding the patient with HLHS pre-operatively is also important. Those with relatively balanced circulations—should feed by mouth. For those in whom we may be concerned about their systemic circulation—total parenteral nutrition may be the judicious approach to avoid complications such as necrotizing enterocolitis [2].
The post-operative management of the HLHS patient is dependent on which initial procedure is undertaken. In general, there are three first-stage palliation procedures—Norwood procedure with MBTT shunt; Norwood procedure with Sano shunt; and the Hybrid procedure as mentioned in the above section.
The initial management of patients with Norwood MBTT shunt revolves again around achieving that fine balance between pulmonary and systemic flows. If the shunt is relatively large, the patient may have too much pulmonary blood flow and all the maneuvers to limit those as described in the prior section may be instituted. If the shunt placed is long or narrow and relatively resistive and or patient has high pulmonary artery pressure or PVR, then one may find oneself in the situation where there is a need to increase the SVR (use of epinephrine, norepinephrine, vasopressin, calcium) to drive flow through the shunt; to administer volume; and, in extreme cases, to Administrator pulmonary vasodilators in the form of inhaled nitric oxide. These maneuvers are intended to be temporary as the infant’s circulation adapts. The management of these patients post-operatively requires great skill and expertise. One also needs to ensure patency of the shunt by administering anticoagulation—usually in the form of heparin drip—which could later be transitioned to Enoxaparin or Aspirin or both. The regimen of anticoagulation is institution-dependent.
The patients who undergo the Norwood procedure and Sano modification are, in general, less cerebrally challenging to care for. Their cardiac output is highly dependent on pre-load and single ventricular function and less so on a potentially tenuous balance between Qp and Qs. Volume administration and inotropic support generally are sufficient.
Both procedures require judicious monitoring and aggressive treatment of dysrhythmias.
The Hybrid procedure involves placement of a PDA stent and bilateral PA bands and, if needed, atrial septostomy [22, 23]. The management of patients post-operatively after a Hybrid procedure can be very similar to the way we manage patients post a Norwood procedure and MBTT shunt. Balancing Qp:Qs is important. Keen attention should be paid to the maintenance of duct patency with anticoagulation and/or anti-platelet therapies.
Patients should be observed closely for signs of stent migration either into the pulmonary artery or the aorta as well as for the possibility of PA band migration. Retrograde arch obstruction from the migration of the stent can be screened through daily 4-limb blood pressure measurements. Intermittent echocardiographic assessment can assist in early diagnosis.
The Glenn procedure is the second stage in the HLHS palliation. By far, it is much less challenging to manage these patients post-operatively. The expectation is that these patients will exit the operating room extubated. If the patient had a reassuring pre-Glenn catheterization study, then the hope is that this would have translated into a successful procedure.
In terms of the respiratory system, post-operative care lies in the avoidance of high positive end-expiratory pressure (PEEP) and high PVR states. Through avoidance of hyperventilation, one may manipulate PaCO2 to optimize flow in the Glenn circulation should the patient be intubated. Augment cardiac inotropy, if necessary. Oftentimes, a combination of milrinone and epinephrine drips post-operatively works well. Pain control and, later, effective diuresis are also important. Cerebral congestion from the new passive circulation to the pulmonary arteries can be a source of significant patient discomfort. Simple maneuvers such as elevating the head of the bed can contribute to great patient comfort by using gravity to promote anterograde blood flow from the cerebral to the pulmonary circulation.
Monitoring these patients for desaturation relative to their physiology is also important; and assessing for the common causes of a desaturated Glenn patient is crucial. The desaturated Glenn patient may pose a serious dilemma for the ICU team. The use of 100% FiO2 and inhaled nitric oxide can be employed. Ultimately, the patient may need to be intubated. In such instances, cardiac catheterization procedure should be pursued to investigate the possible causes. Ensuring adequate hemoglobin levels for Glenn’s physiology is important. If the patient requires additional pulmonary blood flow, then an aortopulmonary shunt may be added to the system [34].
These patients require monitoring for high chest tube output and pleural effusions/chylothorax.
The third stage of palliation is called the Fontan procedure or total cavo-pulmonary anastomosis. Similar to the Glenn procedure, acute post-operative management includes avoidance of high PEEP, and high PVR triggers. The majority of Fontan patients will return from the operating room extubated. Typically, the saturations in a patient post Fontan procedure will be around 92–95%—barring the presence of collaterals or pulmonary vein desaturations. They are preload dependent—at some institutions, the initial post-operative fluid management involves giving patient one and half times maintenance fluid volume. After the first 24–36 h, effective diuresis is then initiated.
Inotropic support may involve the use of epinephrine, milrinone, and/or dopamine. Most recently, the potential beneficial use of vasopressin post-operatively has been explored [35].
Arrhythmias are not infrequent. Postoperatively Fontan patients should be observed for supraventricular tachyarrhythmias of all forms (atrial tachyarrhythmias, re-entry tachyarrhythmias, and junctional arrhythmias).
Like in the Glenn patients, the post-operative Fontan patients require monitoring for high chest tube output and pleural effusions/chylothorax.
Any evidence of an acutely failing Fontan physiology [36, 37] should be anticipated and acted upon expeditiously. If there is evidence of an acutely failed Fontan physiology—serious consideration should be given to taking down the Fontan circuit [38].
Reduced blood flow through the left side of the developing heart is the most prevalent hypothesis in the causation of HLHS. Abnormal blood flow has a negative effect on the shear forces applied to the developing heart which in turn impacts the growth of the left ventricle. Any experimental manipulation to decrease left ventricular preload during embryonic development by either obstructing the left atrioventricular canal flow [39], inserting a balloon in the left atrium [25], or by placing an occluder in the foramen ovale [40] resulted in cardiac phenotypes of HLHS in chick embryos and fetal lambs. This hypothesis is further supported by the observation of the HLHS phenotypes in human fetuses with foramen ovale restriction [41] and premature closure of foramen ovale (Figure 6).
A group of fetuses with aortic valve stenosis with dilated or normal-sized left ventricles in mid-gestation were found to develop into HLHS [42, 43]. In this group of patients, the aortic stenosis in the developing heart resulted in left ventricular dysfunction, myocardial damage, and decreased left ventricular flow which led to HLHS after birth [43, 44]. However, after successful aortic valvuloplasty for aortic stenosis in human fetus, some patients did not have an improvement in their left ventricle growth and ended up with single ventricle palliation [42]. Therefore, intrinsic defects of left ventricular cardiomyocytes cannot be excluded.
Strong evidence of the genetic etiology of HLHS came from the observation that HLHS has a high recurrence risk [45] and is associated with various chromosomal abnormalities [46, 47]. Identifying the genetic causes of HLHS may yield deeper insights into the molecular mechanism driving the pathogenesis of HLHS. In families with HLHS, often bicuspid aortic valve (BAV) is also observed, indicating a genetic link between these two congenital heart lesions [48]. Paradoxically, BAV is the most common CHD (prevalence 1–2%) and is clinically important because of the morbidity and mortality of associated phenotypes, specifically aortic valve disease and aortic aneurysm/dissection (aortopathy). Indeed, BAV underlies aortic valve disease in >50% of patients of all ages undergoing valve surgery [49]. The recurrence of left-sided congenital heart defects in first-degree relatives of a proband of HLHS is about 10–15%, suggestive of a strong but heterogeneous genetic component [45, 47, 50, 51, 52]. In addition, there are approximately 30% of fetuses with HLHS that have extracardiac abnormalities [53]. Analysis from the Society of Thoracic Surgeons database from 2002 to 2006 demonstrated mortality after Norwood procedure was significantly worse in HLHS neonates with non-cardiac abnormalities and/or syndromes with higher unfavorable results in patients with chromosomal defects [54].
Syndromes with HLHS as a cardiac phenotype: Holt-Oram syndrome caused by TBX 5 mutations [55], Rubinstein Taybi syndrome caused by CREB binding protein mutation [56, 57], Smith-Lemli-Opitz syndrome [58], and Noonan syndrome [59, 60].
Chromosomal abnormalities: chromosomal abnormalities were noted in 10% of HLHS including trisomy 13 [61, 62], trisomy 18 [62, 63], trisomy 21 [62, 64], Turner syndrome [62, 65], and DiGeorge syndrome [62, 64]. Turner syndrome with HLHS is associated with significant mortality [54, 66].
Copy number variants: Jacobsen syndrome (11q24-qter deletion) [67], Alagille syndrome (20p12.2-p12.3 deletion) [68], dup 1q21.1, dup 16p13.11, dup 15q11.2-13, dup 22q11.2, and del 2q23.1 [69], del14q23.3 [70]. Copy number variants were reported to be associated with more than 10% of single ventricle lesions including HLHS [71, 72, 73]. However, copy number variants of undetermined significance in neonates with HLHS are not associated with worse clinical outcomes [73].
Gene mutations: Notch1 [72, 74, 75], Nkx2.5 [72, 75, 76], HAND1 [72, 75, 77], GJA1 [78], Lrp2 [79], SMAD3 [80], ERBB4 [81], PROX1 [82]. Pathological mutations in cardiomyopathy-associated genes-MYBPC3, RYR2 and MYH6 were noted in HLHS patients with cardiomyopathy which suggests a shared clinical and genetic pathway between HLHS and cardiomyopathy [83].
The complex genetics of HLHS is further supported by analysis of HLHS mutant mice through the usage of a large-forward genetic screen [5]. Lo et al. recovered 8 HLHS mutant lines with exome sequencing demonstrating no shared mutations among the 8 HLHS lines [5, 84] (Figure 8). The results indicate that HLHS is genetically heterogeneous with a multi-genetic etiology. Through extensive analysis of one HLHS mutant line,
Oxygen consumption rate (OCR) from peripheral blood mononuclear cells in 16 biventricular-CHD (BV-CHD) patients, 20 single ventricle-CHD (SV-CHD) patients, and 22 healthy controls without CHD demonstrated higher respiratory maximum and reserve in single ventricle patients with poor cardiac outcome (death or cardiac death) [87]. Apart from that, we observed a lower OCR in HLHS patients with cardiac dysfunction compared with normal controls [87]. Of the 8 SV-CHD patients with Fontan completion, we observed significantly higher OCR in 4 patients with poor cardiac outcomes (death or cardiac death) (Figure 9a and b). These changes were observed in two related respiratory parameters—respiratory maximum and respiratory reserve. In contrast, SV-CHD patients with normal cardiac function showed significantly lower OCR when compared to either SV-CHD patients with HF, BV-CHD patients, or healthy controls (Figure 9a and b). Given SV-CHD with systemic RV are known to have worse clinical outcomes than SV-CHD patients with systemic LV [88, 89, 90], we reanalyzed the data focusing on only SV patients with HLHS (systemic RV), either with or without HF. This analysis yielded similar findings with significantly higher respiratory maximum and reserve observed in the post-Fontan HLHS patients with HF. However, we observed a lower OCR in HLHS patients without HF (Figure 9c and d). In addition, there is no difference between post-Fontan SV or HLHS patients either with or without HF when compared to BV-CHD patients or control subjects in basal glycolysis by measurement ECAR. Heart tissue from
Mitochondrial respiration in SV-CHD patients and
Many studies have shown patients with complex CHD, especially those with HLHS, have impaired neurodevelopment associated with developmental delay, learning disabilities, behavioral deficits, and cognitive impairment [92, 93, 94, 95, 96, 97]. The etiology of the cognitive impairment in HLHS had been generally assumed to arise from hypoxic injury (prior to palliation) and/or complications from medical/surgical management. Clinical studies analyzing various risk elements (cardiopulmonary bypass time, hypothermia, etc) in the Single Ventricle Reconstruction Trial showed such factors can explain some of variance in HLHS outcomes which suggests patient intrinsic factors may contribute to the cause of the poor neurodevelopmental outcomes in SV-CHD patients [92]. A shared genetic etiology for CHD and brain abnormalities has been indicated by a large-scale human genomic study [98] as well as studies of HLHS mutant mouse models. Mouse models of HLHS were also observed to exhibit brain abnormalities, suggesting that mutations causing the cardiac lesion in HLHS can also cause brain defects that could contribute to the poor neurodevelopmental outcome in HLHS patients [99, 100, 101]. The brain phenotypes observed in the HLHS mice included microcephaly, which has also been reported in HLHS patients [99, 101]. Also seen were other brain abnormalities largely confined to forebrain structures, including the cerebral cortex, hippocampus, corpus callosum, cerebellum, and olfactory bulbs. In contrast, the midbrain and hindbrain structures were mostly spared. These findings suggest abnormal brain development with regional brain dysplasia may drive the neurodevelopmental delay and neurocognitive impairment associated with HLHS.
A diagnosis of HLHS was once uniformly lethal, but now survivable with multi-stage surgical palliation. However, it is still associated with significant morbidity and mortality. Through clinical research and animal models, our understanding of the pathophysiology and underlying mechanisms is actively evolving to improve outcomes for this vulnerable population of patients.
We thank Miss Olivia Phillips for her computer assistance in preparing the figures.
The contributing authors declare no competing interests in this article.
Edited by Jan Oxholm Gordeladze, ISBN 978-953-51-3020-8, Print ISBN 978-953-51-3019-2, 336 pages,
\nPublisher: IntechOpen
\nChapters published March 22, 2017 under CC BY 3.0 license
\nDOI: 10.5772/61430
\nEdited Volume
This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\\n\\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\\n\\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\\n\\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\\n\\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\\n\\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\\n\\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\\n\\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\\n\\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\\n\\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\\n\\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\\n\\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
\\n"}]'},components:[{type:"htmlEditorComponent",content:'This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\n\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\n\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\n\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\n\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\n\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\n\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\n\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\n\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\n\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\n\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\n\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
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Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1394",title:"Applied Physics",slug:"applied-physics",parent:{id:"20",title:"Physics",slug:"physics"},numberOfBooks:4,numberOfSeries:0,numberOfAuthorsAndEditors:57,numberOfWosCitations:15,numberOfCrossrefCitations:12,numberOfDimensionsCitations:22,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"1394",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"10082",title:"Accelerators and Colliders",subtitle:null,isOpenForSubmission:!1,hash:"7774bddf707cc21601de7051625e30b6",slug:"accelerators-and-colliders",bookSignature:"Ozan Artun",coverURL:"https://cdn.intechopen.com/books/images_new/10082.jpg",editedByType:"Edited by",editors:[{id:"255462",title:"Associate Prof.",name:"Ozan",middleName:null,surname:"Artun",slug:"ozan-artun",fullName:"Ozan Artun"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8434",title:"Modern Applications of Electrostatics and Dielectrics",subtitle:null,isOpenForSubmission:!1,hash:"de3cc628456ab823927d4c8b640eee7f",slug:"modern-applications-of-electrostatics-and-dielectrics",bookSignature:"Dengming Xiao and Krishnaswamy Sankaran",coverURL:"https://cdn.intechopen.com/books/images_new/8434.jpg",editedByType:"Edited by",editors:[{id:"18115",title:"Dr.",name:"Dengming",middleName:null,surname:"Xiao",slug:"dengming-xiao",fullName:"Dengming Xiao"}],equalEditorOne:{id:"266293",title:"Dr.",name:"Krishnaswamy",middleName:null,surname:"Sankaran",slug:"krishnaswamy-sankaran",fullName:"Krishnaswamy Sankaran",profilePictureURL:"https://mts.intechopen.com/storage/users/266293/images/system/266293.jpeg",biography:"Dr. Krishnaswamy Sankaran is the Chief Executive Officer of Radical Innovations Group AB, a clean energy and circular economy infrastructure development company based in Finland. He is the winner of the 2020 Mission Innovation Champion Award under the flagship of 24 countries around the world plus European Commission for his pioneering work in Clean Energy and Circular Economy. He is an established industrialist and entrepreneur with several years of demonstrated track record in energy, utilities, infrastructure, manufacturing, and recycling industries. He has served in various operational and leadership roles in industries, the World Economic Forum, and the European Commission in more than sixteen countries and four continents. He is nominated by the Government of Finland for the prestigious 2020 Mission Innovation Champion Award, a global recognition for clean energy innovation (http://mission-innovation.net/)\n\nDr. Sankaran received a doctorate in Engineering Sciences from the Swiss Federal Institute of Technology ETH Zurich, Switzerland, a master’s degree from Karlsruhe Institute of Technology KIT, Germany, and a joint executive master’s degree in Organisational Development and Leadership from Wharton School, Columbia University, INSEAD, and London Business School. 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Since the KP method yields an eigenfunction expansion of the present geometry, the solution satisfies the proper edge condition as well as all the boundary conditions, and therefore we can obtain highly accurate and fast-convergent results. Many numerical results, which are useful for scientists and engineers, are provided for various physical quantities, such as the far-field diffracted pattern, transmission coefficients (normalized transmitted power), and aperture electric field distributions, and by using these numerical results, we examine the convergent property of the KP solution and discuss the effect of the hole size and shape, screen thickness, and incident polarization on the transmission property of the rectangular hole.",book:{id:"9202",slug:"novel-imaging-and-spectroscopy",title:"Novel Imaging and Spectroscopy",fullTitle:"Novel Imaging and Spectroscopy"},signatures:"Hirohide Serizawa",authors:[{id:"301504",title:"Prof.",name:"Hirohide",middleName:null,surname:"Serizawa",slug:"hirohide-serizawa",fullName:"Hirohide Serizawa"}]},{id:"72188",doi:"10.5772/intechopen.92545",title:"Investigation of the Production of Medical Ir-192 Used in Cancer Therapy via Particle Accelerator",slug:"investigation-of-the-production-of-medical-ir-192-used-in-cancer-therapy-via-particle-accelerator",totalDownloads:556,totalCrossrefCites:0,totalDimensionsCites:3,abstract:"To investigate the production of medical Ir-192 radionuclide used in brachytherapy on Os targets in the energy range of Eparticle = 100 → 1 MeV, we calculated the cross-section results for charged particle-induced reactions. The calculation was done via TALYS code and simulated activity and yield of product of each reaction process in the irradiation time of 1 h with constant beam current of 1 μA. The calculated results were compared with experimental data in the literature. Moreover, based on the calculated cross-section data and the mass stopping powers obtained from X-PMSP program, the integral yield results of all the reaction processes to produce Ir-192 on Os targets were presented as a function of incident particle energy. The obtained results were discussed to recommend appropriate reaction processes and targets for the production of Ir-192.",book:{id:"10082",slug:"accelerators-and-colliders",title:"Accelerators and Colliders",fullTitle:"Accelerators and Colliders"},signatures:"Ozan Artun",authors:[{id:"255462",title:"Associate Prof.",name:"Ozan",middleName:null,surname:"Artun",slug:"ozan-artun",fullName:"Ozan Artun"}]},{id:"68360",doi:"10.5772/intechopen.88352",title:"Development of a Corona Discharge Ionizer Utilizing High-Voltage AC Power Supply Driven by PWM Inverter for Highly Efficient Electrostatic Elimination",slug:"development-of-a-corona-discharge-ionizer-utilizing-high-voltage-ac-power-supply-driven-by-pwm-inver",totalDownloads:1238,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"The corona discharge ionizer has been widely used to eliminate electrostatic charges on insulators in a variety of manufacturing industries for the prevention of electrostatic discharge (ESD) problems. High-speed electrostatic elimination is conventionally required for ionizer performance. Because of the high sensitivity of recent electronic devices to ESD damage, an extremely low-offset voltage (ion balance) is required for the performance of electrostatic eliminators. Long-term performance stability is required to maintain the quality of the products, but the short cleaning interval of the unit increases the operating cost. The efficiency is also affected by the waveform of the applied voltage. The optimization of the applied voltage is an important factor in achieving long-term performance stability. In this study, an intermittent pulse voltage AC power supply was developed to achieve a highly efficient electrostatic elimination with long-term stability high-speed electrostatic elimination and an excellent ion balance.",book:{id:"8434",slug:"modern-applications-of-electrostatics-and-dielectrics",title:"Modern Applications of Electrostatics and Dielectrics",fullTitle:"Modern Applications of Electrostatics and Dielectrics"},signatures:"Katsuyuki Takahashi, Koichi Takaki, Isao Hiyoshi, Yosuke Enomoto, Shinichi Yamaguchi and Hidemi Nagata",authors:[{id:"11890",title:"Prof.",name:"Koichi",middleName:null,surname:"Takaki",slug:"koichi-takaki",fullName:"Koichi Takaki"},{id:"211922",title:"Dr.",name:"Katsuyuki",middleName:null,surname:"Takahashi",slug:"katsuyuki-takahashi",fullName:"Katsuyuki Takahashi"},{id:"298263",title:"Dr.",name:"Isao",middleName:null,surname:"Hiyoshi",slug:"isao-hiyoshi",fullName:"Isao Hiyoshi"},{id:"298264",title:"Mr.",name:"Yosuke",middleName:null,surname:"Enomoto",slug:"yosuke-enomoto",fullName:"Yosuke Enomoto"},{id:"298265",title:"Mr.",name:"Shinichi",middleName:null,surname:"Yamaguchi",slug:"shinichi-yamaguchi",fullName:"Shinichi Yamaguchi"},{id:"298266",title:"Mr.",name:"Hidemi",middleName:null,surname:"Nagata",slug:"hidemi-nagata",fullName:"Hidemi Nagata"}]},{id:"58023",doi:"10.5772/intechopen.71022",title:"X-Ray Diffraction Detects D-Periodic Location of Native Collagen Crosslinks In Situ and Those Resulting from Non- Enzymatic Glycation",slug:"x-ray-diffraction-detects-d-periodic-location-of-native-collagen-crosslinks-in-situ-and-those-result",totalDownloads:1377,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Synchrotron based X-ray diffraction experiments can be highly effective in the study of mammalian connective tissues and related disease. It has been employed here to observe changes in the structure of Extra-Cellular Matrix (ECM), induced in an ex vivo tissue based model of the disease process underlying diabetes. Pathological changes to the structure and organization of the fibrillar collagens within the ECM, such as the formation of non-enzymatic crosslinks in diabetes and normal aging, have been shown to play an important role in the progression of such maladies. However, without direct, quantified and specific knowledge of where in the molecular packing these changes occur, development of therapeutic interventions has been impeded. In vivo, the result of non-enzymatic glycosylation i.e. glycation, is the formation of sugar-mediated crosslinks, aka advanced glycation end-products (AGEs), within the native D-periodic structure of type I collagen. The locations for the formation of these crosslinks have, until now, been inferred from indirect or comparatively low resolution data under conditions likely to induce experimental artifacts. We present here X-ray diffraction derived data, collected from whole hydrated and intact isomorphously derivatized tendons, that indicate the location of both native (existing) and AGE crosslinks in situ of D-periodic fibrillar collagen.",book:{id:"6140",slug:"accelerator-physics-radiation-safety-and-applications",title:"Accelerator Physics",fullTitle:"Accelerator Physics - Radiation Safety and Applications"},signatures:"Rama Sashank Madhurapantula and Joseph P.R.O. Orgel",authors:[{id:"212413",title:"Prof.",name:"Joseph",middleName:null,surname:"Orgel P.R.O.",slug:"joseph-orgel-p.r.o.",fullName:"Joseph Orgel P.R.O."},{id:"212416",title:"Dr.",name:"Rama Sashank",middleName:null,surname:"Madhurapantula",slug:"rama-sashank-madhurapantula",fullName:"Rama Sashank Madhurapantula"}]},{id:"71156",doi:"10.5772/intechopen.91215",title:"Surface Plasmons and Optical Dynamics on Vanadium Dioxide",slug:"surface-plasmons-and-optical-dynamics-on-vanadium-dioxide",totalDownloads:887,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"We report on plasmonic resonances on VO2 nanodot arrays and associated optical dynamics. The plasmon excitations based on electric field interactions lead to red shifts of the plasmon resonances to lower photon energy with increasing nanodot size. The spectral linewidths of plasmon peaks gradually become narrow with increasing nanodot size. This is related to a reduction in plasmon damping with respect to the electronic band structure of VO2. This specific band structure of VO2 affects the optical dynamics of plasmon resonances at the sub-picosecond scale. The optical excitations of VO2 comprise intraband and interband transitions. The existence of plasmon bands induces long-lived lifetimes on decay processes. Intraband transitions in the conduction band (C.B.) play an important role in producing long lifetimes, attributing to free carriers in the C.B. By contrast, interband transitions related to bound electrons contribute to plasmon damping. The dynamic optical responses are closely related to the electronic band structures of VO2.",book:{id:"9202",slug:"novel-imaging-and-spectroscopy",title:"Novel Imaging and Spectroscopy",fullTitle:"Novel Imaging and Spectroscopy"},signatures:"Hiroaki Matsui",authors:[{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui"}]}],mostDownloadedChaptersLast30Days:[{id:"68360",title:"Development of a Corona Discharge Ionizer Utilizing High-Voltage AC Power Supply Driven by PWM Inverter for Highly Efficient Electrostatic Elimination",slug:"development-of-a-corona-discharge-ionizer-utilizing-high-voltage-ac-power-supply-driven-by-pwm-inver",totalDownloads:1238,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"The corona discharge ionizer has been widely used to eliminate electrostatic charges on insulators in a variety of manufacturing industries for the prevention of electrostatic discharge (ESD) problems. High-speed electrostatic elimination is conventionally required for ionizer performance. Because of the high sensitivity of recent electronic devices to ESD damage, an extremely low-offset voltage (ion balance) is required for the performance of electrostatic eliminators. Long-term performance stability is required to maintain the quality of the products, but the short cleaning interval of the unit increases the operating cost. The efficiency is also affected by the waveform of the applied voltage. The optimization of the applied voltage is an important factor in achieving long-term performance stability. In this study, an intermittent pulse voltage AC power supply was developed to achieve a highly efficient electrostatic elimination with long-term stability high-speed electrostatic elimination and an excellent ion balance.",book:{id:"8434",slug:"modern-applications-of-electrostatics-and-dielectrics",title:"Modern Applications of Electrostatics and Dielectrics",fullTitle:"Modern Applications of Electrostatics and Dielectrics"},signatures:"Katsuyuki Takahashi, Koichi Takaki, Isao Hiyoshi, Yosuke Enomoto, Shinichi Yamaguchi and Hidemi Nagata",authors:[{id:"11890",title:"Prof.",name:"Koichi",middleName:null,surname:"Takaki",slug:"koichi-takaki",fullName:"Koichi Takaki"},{id:"211922",title:"Dr.",name:"Katsuyuki",middleName:null,surname:"Takahashi",slug:"katsuyuki-takahashi",fullName:"Katsuyuki Takahashi"},{id:"298263",title:"Dr.",name:"Isao",middleName:null,surname:"Hiyoshi",slug:"isao-hiyoshi",fullName:"Isao Hiyoshi"},{id:"298264",title:"Mr.",name:"Yosuke",middleName:null,surname:"Enomoto",slug:"yosuke-enomoto",fullName:"Yosuke Enomoto"},{id:"298265",title:"Mr.",name:"Shinichi",middleName:null,surname:"Yamaguchi",slug:"shinichi-yamaguchi",fullName:"Shinichi Yamaguchi"},{id:"298266",title:"Mr.",name:"Hidemi",middleName:null,surname:"Nagata",slug:"hidemi-nagata",fullName:"Hidemi Nagata"}]},{id:"71156",title:"Surface Plasmons and Optical Dynamics on Vanadium Dioxide",slug:"surface-plasmons-and-optical-dynamics-on-vanadium-dioxide",totalDownloads:887,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"We report on plasmonic resonances on VO2 nanodot arrays and associated optical dynamics. The plasmon excitations based on electric field interactions lead to red shifts of the plasmon resonances to lower photon energy with increasing nanodot size. The spectral linewidths of plasmon peaks gradually become narrow with increasing nanodot size. This is related to a reduction in plasmon damping with respect to the electronic band structure of VO2. This specific band structure of VO2 affects the optical dynamics of plasmon resonances at the sub-picosecond scale. The optical excitations of VO2 comprise intraband and interband transitions. The existence of plasmon bands induces long-lived lifetimes on decay processes. Intraband transitions in the conduction band (C.B.) play an important role in producing long lifetimes, attributing to free carriers in the C.B. By contrast, interband transitions related to bound electrons contribute to plasmon damping. The dynamic optical responses are closely related to the electronic band structures of VO2.",book:{id:"9202",slug:"novel-imaging-and-spectroscopy",title:"Novel Imaging and Spectroscopy",fullTitle:"Novel Imaging and Spectroscopy"},signatures:"Hiroaki Matsui",authors:[{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui"}]},{id:"69532",title:"Dielectric Analysis Model for Measurement of Soil Moisture Water Content Using Electrical Capacitance Volume Tomography",slug:"dielectric-analysis-model-for-measurement-of-soil-moisture-water-content-using-electrical-capacitanc",totalDownloads:789,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Electromagnetic methods have been widely used in the measurement of the water content of the soil. These methods utilize the permittivity as electrical properties of the soil, to determine the moisture content of the soil. Since the measurements are carried out indirectly, a calibration between permittivity and the water content of the soil is needed. Generally, the calibration method is generated by using an empirical and mixing model. This study presents a proposed model of calibration by using a normalization approach to calibrate the value of the permittivity of the water content of the soil. Then the model was applied using electrical capacitance volume tomography (ECVT) to image soil water content during infiltration of water in a soil column. Granular and silty sand were used as soil material in the experiments. The result showed that the model for measuring moisture water content can be seen in each layer during soil water infiltration in the soil column.",book:{id:"8434",slug:"modern-applications-of-electrostatics-and-dielectrics",title:"Modern Applications of Electrostatics and Dielectrics",fullTitle:"Modern Applications of Electrostatics and Dielectrics"},signatures:"Mukhlisin Muhammad and Saputra Almushfi",authors:[{id:"306980",title:"Prof.",name:"Muhammad",middleName:null,surname:"Mukhlisin",slug:"muhammad-mukhlisin",fullName:"Muhammad Mukhlisin"},{id:"306981",title:"MSc.",name:"Almushfi",middleName:null,surname:"Saputra",slug:"almushfi-saputra",fullName:"Almushfi Saputra"}]},{id:"71074",title:"Electrostatic Friction Displays to Enhance Touchscreen Experience",slug:"electrostatic-friction-displays-to-enhance-touchscreen-experience",totalDownloads:649,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Touchscreens are versatile devices that can display visual content and receive touch input, but they lack the ability to provide programmable tactile feedback. This limitation has been addressed by a few approaches generally called surface haptics technology. This technology modulates the friction between a user’s fingertip and a touchscreen surface to create different tactile sensations when the finger explores the touchscreen. This functionality enables the user to see and feel digital content simultaneously, leading to improved usability and user experiences. One major approach in surface haptics relies on the electrostatic force induced between the finger and an insulating surface on the touchscreen by supplying high AC voltage. The use of AC also induces a vibrational sensation called electrovibration to the user. Electrostatic friction displays require only electrical components and provide uniform friction over the screen. This tactile feedback technology not only allows easy and lightweight integration into touchscreen devices but also provides dynamic, rich, and satisfactory user interfaces. In this chapter, we review the fundamental operation of the electrovibration technology as well as applications have been built upon.",book:{id:"8434",slug:"modern-applications-of-electrostatics-and-dielectrics",title:"Modern Applications of Electrostatics and Dielectrics",fullTitle:"Modern Applications of Electrostatics and Dielectrics"},signatures:"Reza Haghighi Osgouei",authors:[{id:"286114",title:"Dr.",name:"Reza",middleName:null,surname:"Haghighi Osgouei",slug:"reza-haghighi-osgouei",fullName:"Reza Haghighi Osgouei"}]},{id:"69493",title:"Diffraction by a Rectangular Hole in a Thick Conducting Screen",slug:"diffraction-by-a-rectangular-hole-in-a-thick-conducting-screen",totalDownloads:766,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"The phenomenon of diffraction by a rectangular hole in a thick conducting screen is investigated for various structural parameters (aperture sizes, aspect ratios, and screen thicknesses) and some incident angles by making use of the exact solution based on the Kobayashi potential (KP) when an electromagnetic (EM) plane wave with any polarization is impinged on the aperture. Since the KP method yields an eigenfunction expansion of the present geometry, the solution satisfies the proper edge condition as well as all the boundary conditions, and therefore we can obtain highly accurate and fast-convergent results. Many numerical results, which are useful for scientists and engineers, are provided for various physical quantities, such as the far-field diffracted pattern, transmission coefficients (normalized transmitted power), and aperture electric field distributions, and by using these numerical results, we examine the convergent property of the KP solution and discuss the effect of the hole size and shape, screen thickness, and incident polarization on the transmission property of the rectangular hole.",book:{id:"9202",slug:"novel-imaging-and-spectroscopy",title:"Novel Imaging and Spectroscopy",fullTitle:"Novel Imaging and Spectroscopy"},signatures:"Hirohide Serizawa",authors:[{id:"301504",title:"Prof.",name:"Hirohide",middleName:null,surname:"Serizawa",slug:"hirohide-serizawa",fullName:"Hirohide Serizawa"}]}],onlineFirstChaptersFilter:{topicId:"1394",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. While a daunting task, learning is facilitated by identifying common and effective signaling pathways mediated by a variety of factors employed by nature to preserve and sustain homeostatic life. \r\nAs a leading example, the cellular interaction between intracellular concentration of Ca+2 increases, and changes in plasma membrane potential is integral for coordinating blood flow, governing the exocytosis of neurotransmitters, and modulating gene expression and cell effector secretory functions. Furthermore, in this manner, understanding the systemic interaction between the cardiovascular and nervous systems has become more important than ever as human populations' life prolongation, aging and mechanisms of cellular oxidative signaling are utilised for sustaining life. \r\nAltogether, physiological research enables our identification of distinct and precise points of transition from health to the development of multimorbidity throughout the inevitable aging disorders (e.g., diabetes, hypertension, chronic kidney disease, heart failure, peptic ulcer, inflammatory bowel disease, age-related macular degeneration, cancer). With consideration of all organ systems (e.g., brain, heart, lung, gut, skeletal and smooth muscle, liver, pancreas, kidney, eye) and the interactions thereof, this Physiology Series will address the goals of resolving (1) Aging physiology and chronic disease progression (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling, and (3) how changes in plasma membrane produced by lipid peroxidation products can affect aging physiology, covering new research in the area of cell, human, plant and animal physiology.",coverUrl:"https://cdn.intechopen.com/series/covers/10.jpg",latestPublicationDate:"May 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr. Thomas Brzozowski works as a professor of Human Physiology and is currently Chairman at the Department of Physiology and is V-Dean of the Medical Faculty at Jagiellonian University Medical College, Cracow, Poland. His primary area of interest is physiology and pathophysiology of the gastrointestinal (GI) tract, with the major focus on the mechanism of GI mucosal defense, protection, and ulcer healing. He was a postdoctoral NIH fellow at the University of California and the Gastroenterology VA Medical Center, Irvine, Long Beach, CA, USA, and at the Gastroenterology Clinics Erlangen-Nuremberg and Munster in Germany. He has published 290 original articles in some of the most prestigious scientific journals and seven book chapters on the pathophysiology of the GI tract, gastroprotection, ulcer healing, drug therapy of peptic ulcers, hormonal regulation of the gut, and inflammatory bowel disease.",institutionString:null,institution:{name:"Jagiellonian University",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:49,paginationItems:[{id:"80495",title:"Iron in Cell Metabolism and Disease",doi:"10.5772/intechopen.101908",signatures:"Eeka Prabhakar",slug:"iron-in-cell-metabolism-and-disease",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Iron Metabolism - Iron a Double‐Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81799",title:"Cross Talk of Purinergic and Immune Signaling: Implication in Inflammatory and Pathogenic Diseases",doi:"10.5772/intechopen.104978",signatures:"Richa Rai",slug:"cross-talk-of-purinergic-and-immune-signaling-implication-in-inflammatory-and-pathogenic-diseases",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81764",title:"Involvement of the Purinergic System in Cell Death in Models of Retinopathies",doi:"10.5772/intechopen.103935",signatures:"Douglas Penaforte Cruz, Marinna Garcia Repossi and Lucianne Fragel Madeira",slug:"involvement-of-the-purinergic-system-in-cell-death-in-models-of-retinopathies",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81756",title:"Alteration of Cytokines Level and Oxidative Stress Parameters in COVID-19",doi:"10.5772/intechopen.104950",signatures:"Marija Petrusevska, Emilija Atanasovska, Dragica Zendelovska, Aleksandar Eftimov and Katerina Spasovska",slug:"alteration-of-cytokines-level-and-oxidative-stress-parameters-in-covid-19",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}}]},overviewPagePublishedBooks:{paginationCount:27,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. 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His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 255 peer-reviewed papers, 32 book chapters, and 2 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. His Works are realted to the Green chemistry field, biolubricants, biodiesel, transesterification reactions for biodiesel production and the manipulation of oils for therapeutic purposes.",institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",country:{name:"Argentina"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",biography:"Francisco Javier Martín-Romero (Javier) is a Professor of Biochemistry and Molecular Biology at the University of Extremadura, Spain. He is also a group leader at the Biomarkers Institute of Molecular Pathology. Javier received his Ph.D. in 1998 in Biochemistry and Biophysics. At the National Cancer Institute (National Institute of Health, Bethesda, MD) he worked as a research associate on the molecular biology of selenium and its role in health and disease. After postdoctoral collaborations with Carlos Gutierrez-Merino (University of Extremadura, Spain) and Dario Alessi (University of Dundee, UK), he established his own laboratory in 2008. 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