Absolute contraindications for donor heart eligibility.
\r\n\tThis book will address the various modern, technical, and practical aspects of smart technology for capturing solar radiation and converting it into different forms of energy, as well as enabling it for renewables integration in energy generation and transformation, built environment, transportation, buildings, and agriculture.
\r\n\r\n\tThe book will cover the most recent developments, innovations and applications concerning the following topics:
\r\n\t• Solar radiation – Smart and enabling technologies for measurement, modelling, and forecasting
\r\n\tHigh-resolution measurement sensor and instrument technology (Pyranometers, Albedometers, Pyrheliometers, UV Radiometers, Sun Trackers, Spectroradiometer, Pyrgeometers, etc.), Artificial intelligence techniques for modelling and forecasting of solar radiation, Solar Irradiance forecast with satellite data, Solar potential analysis, Short-term forecasting of photovoltaic power and solar irradiance prediction with sky imagers.
\r\n\t• Renewable energy integration – Smart solutions for integration of RE in distributed generation, energy storage, and demand-side management.
\r\n\tIntegrated Photovoltaics: Smart technology for vehicle-integrated PV, Building Integrated PV, Agrivoltaics, Road-Integrated PV, Floating PV, Product-integrated PV.
\r\n\tRenewable Energy Applications in Built Environment and mobility: Solar cars, solar-powered electric charging stations, passive solar systems, solar heating, and cooling systems, building-integrated vegetation, multifunctional solar systems, solar pumps, solar lighting, solar shading, Natural lighting, Solar dryer, Greenhouse.
The eye is an excellent structure, both an optical and a neuronal device. There are many diseases related to the eye. Each anatomical part of this organ may show a defect and cause an eye defect. Diabetic retinopathy is one of the most common complications of type I and type II diabetes. One of the main causes of blindness worldwide is diabetic retinopathy. Although glucose controls are helpful for other diabetic complications, they cannot prevent the development of retinopathy. While many studies have been done on the physiology of the retina, there are many unknown dark spots. Studies suggest that radicals derived from reactive oxygen play an important role in the development of diabetic retinopathy. Due to high oxygen consumption, the brain and retina are very sensitive to oxidative stress. Oxidative stress has been found to cause brain and retinal damage in both diabetic humans and experimentally diabetic rats. Although various hypoglycemic drugs have been developed for the treatment of diabetes mellitus (DM), complications associated with diabetes remain major medical problems. Therefore, the development of new treatments is of great interest. The mechanisms in the development and progression of diabetic retinopathy are not yet fully understood as they are multifactorial and complex. Stem cell therapies for retinal diseases have been around for a long time. Few clinical trials are currently showing improvement [1].
The eye is the site of many acute or chronic physiopathological disorders, reversible or not, that can lead to partial or total vision loss or major changes in the quality of patients’ life. The search for innovative therapeutic strategies to correct these disorders is an important current issue. Gene and cell therapies are powerful therapeutic tools, but controlling the properties and spread of the injected material is a parameter that limits its application in humans. Anatomical isolation of the eye and ease of access, on the other hand, enable the use of such treatments, which have been previously developed in tissues and whose clinical application is complex [2].
Hillard Lazarus used mesenchymal stem cell (MSC) for the first time in 1995. Today, there are more than 400 applications in a wide variety of clinical fields such as inflammatory pathologies or immunological, fibrotic, or neurological disorders [3].
The use of MSC, which has a great potential, is promising for the treatment of many degenerative disorders, including the eye. In retinal degenerative diseases, MSC ameliorated retinal neurons and retinal pigmented epithelial cells in both
The development of modern life has brought with it an inactive life [5]. The human population is constantly increasing, and diseases are also increasing. In addition, the expectation of prolonging life, lifestyle, and dietary habits that support obesity creates possible conditions for the development of diabetes. Diabetes is shown as the third cause of death in industrialized countries after cardiovascular diseases and cancer. It is stated that about 110 million people on a global scale suffer from diabetes mellitus. This type of diabetes is also called diabetes mellitus. The main symptom of this disease is the presence of sugar in the urine. A diabetic patient occurs every 8 minutes according to the research of a health institution. DM is the inability of sugar to enter the cell and perform its function as a result of the insufficiency of pancreatic insulin secretion or the ineffectiveness of insulin or the inability of insulin to function due to structural defects in the insulin molecule. Insulin produced in the pancreas is responsible for the transition of blood glucose into cells. When insulin is deficient, the level of glucose in the blood increases and it increases the permeability of the vessel by causing defects in the inner surface and outer wall of the vessel in the vascular tissue. Diabetes damages the retina the most in the eye tissue. It is predicted that diabetes mellitus will rise sharply in the next decade. Patients with diabetes suffer from life-limiting and threatening complications and suffer from diseases such as stroke, peripheral arterial diseases, and retinopathy. [6]. Diabetic retinopathy is the most common microvascular complication of DM, resulting in blindness worldwide. Diabetic retinopathy (DR) is a global problem, affecting approximately 100 million people worldwide. Blindness is 25 times more common in diabetic patients than in non-diabetic patients. DR is the most common cause of blindness in patients aged 20–64 years in developed countries. The prevalence of the disease is related to the age of the cases and the duration of the disease. Biochemical changes detected in diabetic retinopathy increased oxidative stress, nonenzymatic glycosylation, protein kinase-C activation, polyol pathway, and increased nitric oxide [7].
Retinal neurons provide normal visual function. Vision loss in diabetes should be explained as a disorder in the function of neurons. To date, most research has generally focused on retinal vascular changes rather than the effect of diabetes on the neural retina. As a result of many studies, it has been determined that changes in neuronal function and vitality are effective in the pathological mechanism of diabetic retinopathy that starts in the early stage of diabetes. Neurophysiological changes have been observed immediately after the onset of diabetes in both humans and experimental animals [8].
The most common cause of retinopathy is diabetes. Retinopathy is responsible for about a third of vision loss and blindness in children. Microaneurysms, non-perfusion capillaries, hemorrhages and/or lipoprotein exudates, which are the onset of DR, indicate that DR is primarily a microvascular disease [9]. There is ample evidence of early retinal neurodegenerations in diabetes. Neuronal degenerations and early retinal disorders were observed in some animal models and studies in humans before the onset of diabetic vasculopathy [10]. Neurodegeneration, which causes thinning of the retina layer in animal studies, is not only limited to cell death and tissue loss but also causes functional disorders in neurotransmitters [11]. The most prominent feature of neurodegenerative diseases is increased neuronal loss with apoptosis. Increasing neuron frequency is accepted as an important component of pathology in diabetic retinopathy. Early studies characterized vascular lesions in postmortem specimens of human retinas [12, 13, 14].
Indeed, neurophysiological changes have been observed immediately after the onset of diabetes in both humans and experimental animals. It has been reported that vascular changes such as permeability changes during diabetes occur 8 days after the onset of diabetes in rats. Capillary dilation and increased blood flow are the earliest signs of diabetes in both humans and animals. Capillaries begin to close within a few years in dogs whereas in about 1 year of diabetes in rats. Typical retinopathy begins to develop in humans at 5–10 years, with microaneurysm, hemorrhage, macular edema, and neovascularization. The neural retina is transparent and invisible, so it is not visible on clinical examination. Vascular changes provide information about the course of the disease and the possibility of blindness. Apart from insulin therapy, the only proven treatment is laser photocoagulation, which destroys retinal regions with overt vascular disorders. This manipulation reduces macular edema and can improve visual acuity, but it cannot restore normal vision and prevent neuronal loss. If neurodegeneration begins shortly after the onset of diabetes, irreversible neuron damage occurs during laser therapy. Early neurophysiological and neurodegenerative changes should be considered as targets for current DR treatments. Psychophysical measurements also showed changes in vision in the early stage of diabetes onset. Contrast sensitivity decreases especially at mid and low spatial frequencies [1, 15].
Obesity is a major health problem in the world that is responsible for type II diabetes mellitus (DM) and its serious complications, such as retinopathy, cardiovascular disease, and nephropathy. In diabetic eyes, neovascularization results in blindness through a vitreous hemorrhage, retinal detachment, or glaucoma. Retinal hypoxia is the crucial factor for these complications [16]. Diabetic retinopathy is one of the most common complications of type I and type II diabetes. One of the main causes of blindness worldwide is diabetic retinopathy. Although glucose controls are helpful for other diabetic complications, they cannot prevent the development of retinopathy. The pathology of retinopathy is due to the deterioration of the vessels of the eye, which occurs due to various metabolic disorders in diabetic patients. These metabolic disturbances range from the level of vascular endothelial growth factor (VEGF) to the accumulation of end products of its glycosylation. The primarily tissue-damaging effects of chronic hyperglycemia cause a complex interplay of multiple mechanisms, which cause abnormal permeability within the retinal vessels, and occlusion with ischemia and subsequent neovascularization. Current treatments include laser photocoagulation and vitreotomy, but these treatments are not curative and do not target the pathological mechanism of the disease. Various studies have been conducted in diabetic rats and human models. Immunohistochemical studies were able to show that intravitreally injected stem cells were localized to the inner retina and it has been stated that this increases visual function. Human clinical trials are ongoing to evaluate the safety, success, and utility of hematopoietic stem cell (HSC) injection in treating retinal vascular diseases. Two patients with diabetic retinopathy injected with HCC showed improvement in visual acuity and ophthalmic measurements even 12 weeks after treatment. The mechanism of the behavior of HSC is unclear, but is thought to be dependent on paracrine signaling. In animal models, intravitreal HSC has been shown to improve retinal damage caused by light, ischemia, and diabetes. Apart from HSC, other stem cells such as mesenchymal stem cell (MSC), endothelial progenitor cell (EPC), and adipose stromal cell are also being investigated for their use in the treatment of diabetic retinopathy. Diabetes mellitus causes both functional and structural deficiencies by affecting both the peripheral and central nervous systems. Peripheral disorders develop within a few weeks after the onset of diabetes, while central disorders take months to develop [17]. Diabetic retinopathy is a major complication of diabetes. However, the effect of a prediabetic condition on the retina has not been clarified. Prediabetes refers to a metabolic disorder defined by glycemic variables lower than diabetes but higher than normoglycemia and considered a high-risk condition for the development of diabetes. It has been stated that the majority of prediabetic patients will eventually develop diabetes [18, 19]. Current treatments for DR as laser photocoagulation, intravitreal anti-VEGF agents, intravitreal corticosteroids, and vitreoretinal surgery are applicable only at advanced stages of the DR and are associated with significant adverse effects [20]. Therefore, new treatments for the early stages of the DR are needed. Retinal diseases are the leading cause of vision loss in the world. Because of the ability of stem cells to self-renewal and differentiation to various types of cells, stem cells are becoming an attractive source of cell therapy in repairing damaged cells as retina pigment epithelium or photoreceptors. Consequently, retinal stem cell therapy is one of the promising therapeutic alternatives to recover vision [21].
The organism begins to form from a cell and then develops into a complete organism with more than 200 cell types. This phylogenetic trend, the tendency to switch from pluripotent cells to mature cells is an integral part of human development. This process, in which cells differentiate and turn into cells without plasticity, is necessary to form all special tissues of the human and to minimize the risk of tumor proliferation. Basically, for a cell to be accepted as a stem cell, this cell should first be able to renew itself without losing its plasticity, and then lose its plasticity and differentiate into different sub-cell types [22]. A stem cell is an undifferentiated cell with the capacity to self-renewal and differentiate. These cells have also the capacity to differentiate into special cells that make up tissues and organs. Self-renewal is the capacity for a cell to reproduce indefinitely by maintaining its undifferentiated state. Differentiation potential is the capacity for a cell to differentiate into one or more types of mature cells.
In addition, stem cells are also characterized by maintaining a certain calm-stagnant state, apart from their capacity for self-renewal and differentiation. This quiescent phase is the G0 phase of the cell cycle, in which cells enter in the absence of mitotic factors. With this calm phase, stem cells can protect themselves against possible “attacks” and maintain their vitality. However, none of these features are sufficient to define the ‘root’ character of the cell. In fact, it should have the potential to rebuild the tissue’s excellent function in the long run. This means a large number of cellular divisions and differentiation
The two largest types of stem cells in mammals are embryonic stem cells isolated from the inner cell mass of the blastocyst and adult stem cells found in most adult tissues.
They are the first discovered and studied stem cells. They are cells that can renew themselves and have the capacity to differentiate into all cell types that can form a whole organism.
With the development of the embryo, embryonic pluripotent stem cells are replaced by stem cells with a more limited capacity, which will provide organ and tissue formation. Cells of different tissues are now specialized. Organs need a mechanism to regenerate cells by replacing cells lost by apoptosis or lesion, thus maintaining their homeostasis. An adult loses about 20 billion cells in a day. This requires a permanent restructuring system [26]. Some organs such as the brain, heart, and kidney are less regenerated [27]. On the other hand, tissues such as bone marrow, skin, and intestines are constantly renewed. To ensure the regeneration prosess, organs have a cell reservoir; adult stem cells which serve throughout life. Their stocks are provided by the balance between self-renewal and differentiation capacities. Adult stem cells are also known as somatic stem cells. It is assumed that all organs of the body have mature stem cells, and in most organs, they are active throughout life. They constantly form new cells to ensure tissue regeneration (skin, cornea, bone marrow, intestine) [28, 29, 30]. In some organs, these cells become active after birth and then go into dormancy. We see them in organs with slow or almost no cellular regeneration; it is seen only in organs such as the brain and liver, where stem cells divide only during serious injuries or rarely [31, 32]. Hematopoietic stem cells, stromal stem cells, and stem cells in organs are adult stem cells.
Bone marrow contains two types of cells: hematopoietic stem cells (HSC) and stromal mesenchymal stem cells (MSC). HSC can form all mature hematopoietic cells such as myeloid and lymphoid. MSC plays a supportive role in hematopoiesis. Bone marrow also contains other types of cells. Progenitor endothelial cells (PEC) are found in the marrow as well as adult multipotent progenitor cells [33]. When necessary, PEH enters the circulation and plays a role in angiogenesis. In addition, some studies refer to bone marrow stem cells (F-MSCs), which represent a heterogeneous stem cell population. These cells can differentiate into many different types of cells, such as hepatocytes, endothelial cells, epithelial cells, cardiac or skeletal muscle cells, neuronal cells, or astrocytes. This indicates that bone marrow cells have the potential to differentiate into cells of another tissue [34]. Stem cells are ubiquitous. Some niches are yet to be discovered. Although bone marrow-derived stem cells have been cited as a potential resource for regenerative therapy, their potential and usefulness are still open to debate [35, 36].
Deterioration in tissues or organ functions for any reason constitutes a very important problem in terms of seriously affecting an individual’s quality of life. For this reason, regenerative medicine is concerned with repairing the damage and restoring normal body functions through stem cell therapies. Advances in stem cell research have shown cell-based therapy as a useful option to treat medically incurable diseases [36]. Stem cells can migrate to damaged tissue. The effect and cellular mechanisms of stem cells vary according to their environment. They have excellent plasticity that allows these cells to adapt to their environment and act appropriately [33].
“Plasticity” is the ability of a stem cell to acquire different differentiation programs under certain microenvironmental conditions. Endogenous MSC or exogenously administered MSC can migrate to the injured tissue and participate in its healing. The therapeutic effects of MSC can be attributed to its ability to secrete a wide variety of paracrine factors. These mechanisms are likely independent, but they can also act together. In many cases, a combination of these protective mechanisms can work together to heal the damage [37]. However, the mechanism of the therapeutic effect of stem cell is still open to debate. There are two basic explanations; these are cell differentiation and the paracrine effect of stem cells. The combination of these two mechanisms seems to be a third theory [38].
Retinal degenerations are pathologies that affect the light-sensitive cells of the retina, photoreceptors, cones, and rods. Cell therapy is accepted as an interesting alternative for retinal degenerations. A mouse model of retinal degeneration has been shown to improve visual function after transplantation of photoreceptors [39]. Other cells, including MSC, also show great potential by altering photoreceptors or protecting against degenerations due to their paracrine effects [40]. Some researchers also emphasize that MSC can differentiate into retinal cells, especially photoreceptor-like cells. This plasticity feature of MSC has been observed
In general, cellular therapy works in two ways: to replace dead cells in the tissue to restore tissue function or to prevent/attenuate/slow tissue degeneration by reducing inflammatory infiltration or reduce apoptosis and cell death phenomena.
The eye is a small organ, and the number of stem cells required therapeutically is theoretically less than in larger organs. Compared to other internal organs, the retinal environment is easily accessible with small-gauge vitrectomy needles, greatly increasing the potential for stem cell-based therapy for the treatment of retinal degenerative diseases. The retina is layered and thin. It depends on the preservation of cells, nerve anatomy, and synaptic networks to maintain vision. Retinal neuron connectivity is an important therapeutic goal to alleviate blindness in millions of people worldwide for the preservation or restoration of the original neural structure of the retina and photoreceptor [43]. The emergence of studies shows the possibility of cell regeneration in the adult central nervous system, which makes it possible to envision the implantation of stem cells or progenitor cells as an approach to cell therapy. The restorative approach offers strong hope, given that key questions about the biology of development need to be explored. The transplantation of differentiated or undifferentiated retinal tissue (embryonic, newborn) in the subretinal position of the graft poses the problem of its structural and functional organization.
It is seen that different types of stem cells are used considering transplantation studies. When we look at transplantation studies, in studies using different types of stem cells (retina progenitor cell, neural stem cell, bone marrow-derived stem cell, and embryonic stem cell), although they settle in the retina, they are not able to express retinal-specific markers and cannot establish synaptic connections are encountered [44].
The discovery of stem cells has caused great excitement in the hopes of using such treatments to restore vision. Already, stem cells in the anterior segment of the eye have a remarkable clinical effect. Stem cell therapy provides re-epithelialization of the cornea and improves vision. The trabecular meshwork, located on the inner side of the junction of the sclera and the cornea, can also be regenerated with stem cells [38]. However, the most interesting studies have been done in the posterior segment of the eye. Most retinal degenerations begin with the loss of a neuron or damage to a neuron. Therefore, these cells should be replaced with a cell layer that is differentiated and functional in the appropriate medium. Sometimes pathology develops and destroys many cells. In this case, a graft consisting of several layers is required. To perform a transplant treatment for blindness, progenitor neuronal cells are isolated and transferred to different cells of the retina.
Studies on neuronal cell cultures that can differentiate are done. Today, very few of these differentiation mechanisms have been fully elucidated. Therefore, the use of cell transplantation in the retina seems distant [45].
Considering that stem cell therapy is promising in retinal diseases, studies were started with embryonic stem cells, and induced pluripotent stem cells were obtained. Many retinal cells such as retinal pigment epithelium, photoreceptors, and ganglion cells were obtained from induced pluripotent stem cells [46].
It is stated that the neuroretina, which is attached to the pigment epithelium (RPE), has a complex structure. Therefore, it has been stated that there are three different cells that can be considered in cell therapy: neuroretina (photoreceptors, bipolar cells, ganglion cells, and glial cells), RPEs, and vascular endothelial cells. Depending on retinal diseases, strategies to place different cells need to be developed [47].
Diabetic retinopathy (DR) is one of the largest causes of vision loss worldwide. The use of autologous stem cells for organ reconstruction offers a potential solution for the replacement of tissue or whole organs mechanisms in the development and progression of DR are not fully understood yet. Although many studies have been done about retinal physiology, many unknown dark spots are available about it. Stem cell therapy appears to be a possible option both to prevent neurovascular damage and to repair the damaged retina. Mesenchymal stem cell attracts great attention in retinal degenerations due to their ability to differentiate into neurons. However, the way and amount of stem cell administration will create different effects, it is important to know the effect of cell therapy on body after administration in relation to its use in the clinical practice.
To date, no treatment has been developed for the regeneration of retinal vasculature damage resulting from prolonged hyperglycemia. Cell therapy seems to be a possible option both to prevent neurovascular damage and to repair damaged retina [48]. Although clinical evaluations and retinal autopsies of diabetic patients provide information about the progression and features of diabetic retinopathy, its pathophysiological mechanism is not yet understood. Studies on animal models continue in order to better understand the development of diabetic retinopathy at the molecular and cellular level [49]. Retina, in the nervous system, provides a suitable environment to study the functions and distribution of stem cells. It is stated that intravenously administered mesenchymal stem cell transplantation can inhibit retinal apoptotic cells, reduce inflammatory responses, and limit the spread of damage [50].
In a study in which intravitreal mesenchymal stem cell application was performed, some physiological parameters were examined and it was seen that although there were decreases in body weight in diabetics, there was no change in body weight in the group administered intravitreal stem cells. These findings were interesting for us. While it was reported that body weight increased significantly in the mouse model in which the human adipose tissue-derived mesenchymal stem cell was transplanted
As a result, more clinical trials should evaluate the application methods, the timing of the practice, using cell count and repetition dose of stem cell and their results. In the near future, the regenerative stem cell therapy may be a standard treatment in many degenerative eye disorders.
Heart transplantation (HTx) has been established as the definitive therapeutic strategy in end-stage organ failure patients and results in satisfying long-term results. However, this surgical therapy is extremely limited by severe donor organ shortages worldwide, especially in Japan [1]. Therefore, adequate, and optimal assessment and management for deceased organ donors are mandatory to increase heart graft availability [2].
As the revised Japanese Transplant Act was issued on 17th July 2010 and organs can be donated after brain death (BD) with their family’s consent if he or she does not deny organ donation since this revision [1], BD organ donation increased from 13 cases in 2009 to 97 cases in 2019. However, the number of HTx was still extremely smaller than in other developed countries. The extraordinarily severe organ shortage and long waiting time for HTx had made Japanese transplant programs consider using extended criteria donor (ECD) hearts.
The most troublesome issue facing HTx is primary allograft dysfunction (PGD) [3, 4]. This complication is the leading cause of early post-HTx death in the world. The use of ECD hearts may increase the PGF rate. Therefore, it is essential to establish a special donor evaluation and management system to maximize donor heart utilization. Maximizing donor heart availability is also the last wish of donors and donor families. However, if a transplant recipient dies soon after HTx due to PGD, the donor family feels the loss of their lover again. Therefore, donor management strategies to improve heart graft function and reduce early post-HTx mortality are very important for the donor family as well as for recipients [2, 3, 4].
Disease-transmitted disease (DTD) is also an inherent risk of heart transplantation as well as other solid organ transplantation [5]. The Ad Hoc Disease Transmission Advisory Committee (DTAC) reported that unanticipated DTD occurred only in 0.18% of recipients, with 0.23% of proven or probable DTD to at least one recipient. DTD was related to significant morbidity and mortality with about 33% of graft loss or recipient death. The recipient death in malignancy occurred significantly higher than that in infection. Therefore, the procurement transplant coordinator (PTC) should carefully listen to the clinical course, data, and history of medical staff and family to rule out these absolute contraindications prior to obtaining informed consent for organ donation from the relatives.
Full-scale donor management begins after the potential donor is sentenced brain dead and his or her family\'s consent to organ donation is obtained [2, 3, 4]. Basic therapeutic strategies for donor management consist of interventions for impaired heart and lung function to optimize the patient’s hemodynamics, increase oxygen delivery to peripheral tissue, and finally improve the function of other organs, such as the liver and kidney. The hemodynamic targets are arterial blood pressure greater than 90 mmHg, central venous pressure (CVP) between 6 and 10 mmHg, urine output around 100 ml/h (0.3 to 3 ml/kg/h), and heart rate between 80 and 120/minutes. As there are only about 15 to 20 hours between the start of full-scale interventions for donor assessment and management and the start of organ retrieval surgery in Japan, we need to establish specific therapeutic strategies to optimize patient’s hemodynamics and restore the function of damaged organs as many as possible in such short period [2], which are extremely different from those in standard intensive that usually take several days to accomplish. Moreover, the donor management physicians need to understand the pathological and physiological mechanisms and characteristics of brain death from the initiation to the completion period.
Many investigators [3, 4] have reported that a short-lived catecholamine (CA) storm derived from acute intracranial hypertension caused systemic hypertension, acute left ventricular (LV) failure, and acute transient mitral valve regurgitation, leading to a rise in left atrial pressure in animal experiments. These events led to ischemic myocardial damage of LV associated with pulmonary edema. Histological examination of myocardial tissue exposed to CA storm shows widespread ischemic damage and necrosis in animal experiments. However, in the human clinical situation, a broad spectrum of adverse hemodynamic instability is observed and may depend on the speed of development of BD.
Soon after the initial surge of the CA storm, CA levels decreased to levels below the baseline and pituitary failure developed [6, 7]. In addition, the lung is also impaired by an acute systemic inflammatory response, neurogenic pulmonary edema, aspiration, hemopneumothorax, atelectasis, and later pneumonia.
The anti-diuretic hormone (ADH) is principally produced by neurosecretory cells that have their cell bodies in the supra-optic and paraventricular nuclei of the hypothalamus, and the ADH storage vesicles are transported down the axon via the hypothalamic-hypophysial tract, released into a portal system in the posterior pituitary and finally enter the body’s systemic circulation (Figure 1).
Hypothalamo-hypophyseal portal system.
ADH is the primary hormone to maintain tonicity homeostasis by promoting water reabsorption in the kidneys and causing vasoconstriction. Briefly, ADH binds to the V receptor on the renal principal cells within the late distal tubule and collecting ducts and promotes reabsorption of water guided by the osmotic gradient established by sodium chloride and urea in the kidney. This action makes concentrated, or hyperosmotic, urine, and keeps our body to conserve water in times of dehydration or blood volume loss [8]. ADH also binds to V receptors on vascular smooth muscle and activates the G protein signaling cascade, which leads to a contraction of vascular smooth muscle leading to increases in total peripheral resistance and thus maintaining sufficient arterial blood pressure and tissue perfusion [8].
BD causes profound supraventricular and paraventricular hypothalamic nuclei ischemia and secondary loss of ADH secretion into the posterior lobe of the pituitary gland, which results in diabetes insipidus. As ADH is also secreted from peripheral tissues, undetectable levels of ADH have been noted in 75% of BD. As water reabsorption action of ADH is decreased, the kidneys cannot concentrate urine and make large amounts of dilute urine, which leads to hyponatremia associated with high serum osmolality and hypovolemia. As the vasoconstrictive effect of ADH is decreased, the vascular tone of systemic arteries is decreased and leads to hypovolemia. Therefore, the absence or decreased secretion of ADH after BD causes hemodynamic instability and compromised transplanted organ function.
Administration of ADH [9, 10, 11], in addition to treating diabetes insipidus by volume supply, reduces inotropic requirements and has been associated with improved heart graft function. Pure vasopressors, such ADH, are less likely to cause reduced tissue perfusion, metabolic acidosis, or pulmonary hypertension and may be more appropriate medicine than noradrenaline for vasoplegic shock syndrome, especially after BD
After BD, the brain-heart connections are definitively interrupted and autonomic cardiovascular regulation mainly thorough baroreflex is gone. Therefore, the hemodynamics of BD persons become unstable [4]. For example, a decrease in the blood return to the heart due to blood loss, hypovolemia, and putting pressure on the upper abdomen or postural change may rapidly cause low blood pressure in BD persons. After 20 to 30 seconds of the hypotension phase, the somatically induced adrenal sympathetic reflex responses result in an increase in adrenaline secretions from the adrenal medulla, which induces subsequent high blood pressure usually higher than 150 mmHg and tachycardia. In BD patients who are poorly controlled, arterial blood pressure and heart rate may go up and down. This phenomenon is often observed in hypovolemic patients derived from reduced ADH secretion due to BD. The subsequent increase in serum adrenaline decreases the myocardial density of beta-adrenergic receptors (BAR), which leads to PDG early post-HTx.
Disrupted brain-heart connections, so-called denervation, are also observed in HTx recipients. The authors [12] previously described that the heart graft could not augment cardiac performance rapidly in response to an acute decrease in the preload due to the cessation of autonomic nerve regulation on the graft. In normal individuals, if a preload of the heart rapidly decreases, autonomic sympathetic nerves are activated through vagal reflexes increasing heart rate and left ventricular contractility. Therefore, LV Emax after releasing occlusion of vena cava inferior (VCIO) is significantly higher than LV Emax during VCIO (Figure 2A). However, as the heart graft cannot autonomically increase heart rate or LV contractility soon after a rapid decrease in LV preload, LV Emax after releasing VCIO is not different from LV Emax during VCIO (Figure 2B). The heart graft performance may be augmented only after elevated serum adrenaline levels by secretion of adrenaline from the adrenal gland. Thus, the denervated heart, such as the heart graft as well as the heart of a BD person, cannot rapidly enhance its performance in response to a rapid decrease in the LV preload, such as sudden blood loss or a sudden decrease in cardiac return. Therefore, denervation also causes hemodynamic instability in a BD person.
Changes in left ventricular Emax during and after releasing vena cava inferior (VCI): A. Healthy individuals, B. Brain dead persons or heart transplant recipients.
Although absolute contraindications for deceased donor eligibility depend on the organ procurement organization (OPO), most OPO provided a list of absolute contraindications for donor eligibility (Table 1).
Positive tests for |
Anti-HIV-1 or anti-HIV-2 |
Hepatitis B or C* virus |
Human T cell lymphotropic virus types I and II |
History or evidence of HIV high-risk behaviors, even if HIV antibody negative |
Prion-related disease |
Creutzfeldt-Jakob disease (CJD) |
family history of CJD |
recipient of human-derived pituitary hormone or dura mater |
Active systemic bacterial, viral, or fungal infections |
Leukemias, lymphomas, and active malignancies |
Absolute contraindications for donor heart eligibility.
Most organs from donors with a positive test for hepatitis C virus (HCV) can be transplanted to a recipient with a positive test for HCV.
HIV: human immunodeficiency virus.
As mentioned above, DTD is an inherent risk of heart transplantation [5]. Although DTAC reported that unanticipated DTD occurred only in 0.23% of proven or probable DTD to at least one recipient, DTD was related to significant graft loss or recipient death. It is important for PTC to carefully get information associated with DTD to rule out these absolute contraindications for heart transplantation.
Almost all OPOs determine that a positive test for human immunodeficiency virus infection and acquired immunodeficiency syndrome is an absolute contraindication, and most OPOs determined that hepatitis B virus (HBV) surface antigen (HBsAg), human T cell lymphotropic virus types I and II and determined or suspected prion-related disease are absolute contraindication.
Transplantation of donor hearts with anti-HBV core antibody (HBcAb) is associated with a small risk of virus transmission. In fact, Huprikar et al [13] reported that the risk of HBV transmission from HBcAb + HBsAg− donors are observed mainly in liver transplant recipients and that transmission is significantly lower in kidney transplant recipients and essentially negligible in thoracic transplant recipients. Even in liver transplantation, many investigators have reported that anti-hepatitis-B immunoglobulin (HBIg) or lamivudine can prevent HBV transmission by HBcAb + HBsAg− donors. In our institute, HBIg is routinely used in heart transplantation from anti-HBc + HBsAg− donors.
Most organs from donors with positive tests for hepatitis C virus (HCV) can be transplanted to a recipient with a positive test for HCV [5]. In the field of thoracic transplantation, transplantation of HCV + donor grafts to HCV + recipients is unacceptable, mainly because there are multiple strains of hepatitis C virus, and the presence of antiviral antibody in the recipient does not guarantee immediate immunity to HCV after heart transplantation.
Regards bacterial or yeast infection, sepsis or infectious vegetation in the heart are contraindications for heart transplantation. Although the donor organ contamination (DOC) rate is high, infections due to DOC are rare after heart transplantation if adequate perioperative antibiotic prophylaxis and aseptic organ procurement are strictly performed [14]. The heart from a donor with positive blood culture without any signs of systemic infection can be transplanted if the proven bacteria are Gram-positive cocci and sensitive to common antibiotics.
Of the 335 donors who transmitted proven or probable disease to at least one recipient being reported to UNOS from 2008 to 2017, 70 transmitted malignancies and kidney, lung, and liver cancers were the most common malignancies, with 18, 10, and 10 donors, respectively, transmitting to at least one recipient. Fifteen donors with potential donor disease transmission events involving breast cancer and 28 involving thyroid cancer were reported by either transplant centers or OPOs with no proven/probable transmissions.
Regards to central nervous system (CNS) tumors, Hynes et al. [15] analyzed a cohort of 58,314 adult thoracic organ recipients from the UNOS database and reported none of 337 recipients who received organs from the donor documented CNS tumor, developed CNS tumors at a median follow-up of 72 months and that Kaplan-Meier curves indicate no significant difference in the time to death between patients with and without receiving from the donor with CNS tumor.
Donors with past histories of certain types of cancers may be considered as donors, including certain types of primary CNS tumors. Desai et al. [16] reported that the use of organs from selected donors with a history of cancer had a potential overall benefit in survival. But a small, yet real, risk of cancer transmission is present, of which the recipient should be informed. Although the transmitted risk can be reduced by sophisticated evaluation, it cannot be no risk.
The real goal of donor heart assessment is not to evaluate the donor heart function just prior to the heart procurement but rather to predict the transplanted heart graft performance after weaning from the cardiopulmonary bypass in the operating room and through the postoperative period. One also should consider the preexisting myocardial damage as well as myocardial damage due to BD-related stress.
To accomplish optimal donor management, we need to obtain clinical information, such as the cause of BD, pathophysiological mechanism and findings of BD, past and family history, underlying disease, therapeutic interventions, especially inotrope dosage, ADH, thyroid hormone, and antibiotics, water and blood valance, and parameters of preload and afterload on the heart, such as systemic and pulmonary arterial pressure, CVP and pulmonary capillary wedge pressure, cardiac output, and/or mixed-venous oxygen saturation [2, 4].
Multicenter analysis (1719 consecutive primary HTx) reported that donor hearts requiring inotropic support of up to 6 mcg/kg/min of dopamine or dobutamine had satisfactory results [17]. Even if the donor experiences cardiopulmonary resuscitation (CPR) > 5 minutes, the donor heart might be acceptable to transplant, if optimal donor management stabilizes the donor’s hemodynamics, improve left ventricular wall motion, and restore ischemic myocardial changes in ECG [2].
As in usual clinical settings. cardiomegaly, chest trauma, or pleural effusions are checked by chest X-ray.
As most BD donors have some degree of myocardial damage caused by combined pre-underlying heart disease and BD events, ECG usually shows some degree of abnormality in ST segments and QRS waves. Sustained abnormalities in ST segments and QRS and multifocal ventricular ectopic beats under optimal donor management are considered high risks.
Even in an elderly donor with a history of cardiac arrest, the heart was acceptable for transplantation if hemodynamics becomes stable with a minimum dosage of inotrope administration and ischemic ECG changes disappear after optimal donor treatment.
Echocardiography is the most reliable assessment tool to determine donor heart suitability. Echocardiography can evaluate cardiac valve function and myocardial hypertrophy as well as the existence of congenital malformations. Even if global and even regional ventricular dysfunction may be induced by the BD event, these wall motion abnormalities can be reversible within hours. Therefore, serial echocardiography should be done before a heart graft is abandoned to use due to myocardial dysfunction
In the presence of LV underfilling, LV seems to be hypertrophic or to have suitable LV systolic function. Therefore, circulatory blood volume should be estimated by central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), or the size and respiratory movement of inferior vena cava (IVC), as well as the required dosage of inotropes prior to undergoing echocardiography to assess heart function.
As asymptomatic coronary atherosclerosis is found even in children and young people, coronary angiography, at least in donors >45 years or according to the donor risk factors, is routinely performed in western countries. However, it has not been elucidated which type or level of donor coronary atherosclerosis really impairs the post-transplant outcome, which suggested that angiography in donors <60 years might not be necessary. Of course, recent myocardial infarction especially during the completion of BD and diffuse coronary sclerosis are absolute contraindications for heart transplantation, but single stenosis with good myocardial performance in the responsible region is acceptable, especially if it can be treated by percutaneous cardiac intervention or concomitant bypass surgery during transplantation [18, 19].
For several social reasons in Japan, we do not routinely perform coronary angiogram before procurement. Therefore, we often check for coronary artery calcification (CAC) on conventional chest computed tomography (CT) to estimate the risk of pre-existing coronary artery disease in the donor heart. But we previously reported that the pre-existing CAC in a donor heart is significantly associated with the maximum intimal thickness of the coronary artery greater than 0.5 mm after transplantation, but that it was not a significant predictor for cardiac events in the future, probably due to the higher use of everolimus in the CAC group post-transplant [20].
In the future, contrast CT scan, especially cardiac CT scan, might be useful to rule out coronary arterial disease in the donor heart.
To expand the cardiac donor pool, ECD hearts should be used. In this section, extended donor criteria are shown and how to select and deal with ECD hearts are discussed (Table 2).
|
Extended criteria donor (ECD) for heart transplantation.
The donor myocardium is damaged to a greater or less extent, for many reasons, such as massive CA secretion at the BD completion, heart arrest, chest trauma, and the CPR maneuver.
As the brain-damaged patients are often maintained on the dry side to reduce brain edema, the heart appears to move with vigor due to reduced preload on the heart. To evaluate the precise cardiac systolic function, central venous pressure at the time of evaluation should be 8–10 mmHg. It is also important to adjust hemoglobin concentration, electrolyte balance, and acid-base equilibrium at that time. As Swan-Gatz catheterization or coronary angiography are not routinely able to perform in the procurement hospital in Japan for several social reasons, myocardial damage and underlying heart diseases are determined by hemodynamics, requirement doses of inotropes and ADH administration, the LV wall motion and morphology by echocardiogram, and electrocardiogram (ECG) findings.
It is very important to evaluate donor cardiac function after treating diabetes insipidus, adjusting the tone of peripheral vessels, and recovering the affinity of the β-adrenergic receptor for adrenaline in the myocardium by administrating ADH via the central venous line and optimizing circulating blood volume [2].
The heart with a history of cardiac arrest with cardiopulmonary resuscitation can be transplanted if the cardiac function is recovered and the heart has no significant underlying disease or ischemic ECG changes [2, 21]. Recently, the ISHLT registry report 2020 also reported that recipients of donors who died from anoxia or head trauma had the highest 1-year survival (89.9%), whereas the lowest 1-year survival (84.1%) was seen in recipients of donors who died from cerebrovascular accident/stroke [22].
Even hemodynamics or cardiac systolic function are well maintained, the myocardium is considered damaged if a high dose of inotrope administration is required to stabilize hemodynamics. Therefore, an assessment of LV function should be done after reducing dosages of inotropes as less as possible.
As high serum adrenaline concentration, as well as a high dose of intravenous adrenaline administration, has a significant relationship with a decrease in the myocardial density of β-adrenergic receptors [23, 24], the use of adrenaline should be used as less as possible. Less than 0.05 mcg/kg/min of adrenaline is acceptable. Regards to the dose of dopamine and others, the donor heart requiring greater than 15 mcg/kg/min of dopamine is considered ECD heart, especially with abnormal ECG and echocardiographic findings. Mostly, less than 15 mcg/kg/min of dopamine is acceptable.
The hearts with the most valvular and congenital cardiac abnormalities are not eligible for transplantation. Therefore, pre-existing heart diseases should be carefully assessed by the echocardiogram and the chest CT scan before procurement surgery.
In donors with acceptable heart function, however, a simultaneous repair can be done on a donor heart with simple congenital heart disease (e.g., atrial septal defect, ventricular septal defect, or patent ductus arteriosus), mild or moderate valvular regurgitation in the mitral and/or tricuspid valve or normally functioning bicuspid aortic valve.
As the hypertrophic myocardium is susceptible to ischemia-reperfusion injury, the hypertrophic heart with left ventricular wall thickness greater than 13 mm should be decided carefully to use. The hypertrophic heart with ECG criteria for LVH and total ischemic time (TIT) longer than 4 hours is inadvisable to transplant.
It has been reported that prolonged total ischemic time (TIT) was a significant correlation with the early post-transplant death after HTx. The acceptable safe preservation time limit for HTx might be less than 4 hours. In fact, the report of the International Society for Heart and Lung Transplantation (ISHLT) showed that the relative risk of 1-year mortality was affected by TIT for longer than 6 hours [23]. However, pediatric hearts with TIT longer than 8 hours were reported to be safely transplanted [21].
To prolong the safe limit of preservation period in immerse heart preservation method, many studies were carried out. The author of the chapter reported that the modification of preservation solution and the application of terminal leukocyte-depleted blood cardioplegia preserved good function of orthotopically transplanted cardiac grafts after 24-hour immersed preservation in the canines and goats [25].
As aging increases the risk to have the myocardial damage due to coronary arterial disease, left ventricular hypertrophy, and valvular disease, donors older than 50 years of age were generally considered to be ECD. In fact, older donor age is associated with decreased survival after heart transplantation, especially within the first month after transplantation [23]. Moreover, the relative risk of developing cardiac allograft vasculopathy within 8 years is also affected by donor age. Therefore, meticulous evaluation of coronary arteries with coronary angiography as well as left ventricular wall motion with echocardiography are essential to assess the heart of elderly persons.
Although coronary arterial interventions are applicable in the recipient after heart transplantation, several cases of simultaneous coronary arterial grafting have been reported to use the donor hearts with significant coronary artery disease [18, 19]. Overall graft patency at 2 years was reported to be 82%.
One may consider completion of BD as a certain kind of stress test on the myocardium such that if subsequent ECG or echocardiography is favorable, the chance of an elderly donor having significant CAD is probably low. This screening strategy without the use of coronary angiography is thought to make an efficient selection of elderly donor hearts for transplantation with a good outcome. But if the donor has left ventricular hypertrophy and/or significant ECG changes, the heart is not eligible for transplantation [2].
Although a small donor size relative to the recipient may increase a survival risk post-transplantation, a normal-sized adult male is suitable for most recipients. Russo et al. [26] demonstrated that transplanting a female donor heart into a male recipient is associated with a significantly higher risk of PGD. On the other hand, the risk of CAV universally increased with increasing donor age [22]. However, recipients of male allografts had an increased risk of CAV development, regardless of the recipient’s gender [22].
To manage a donor optimally, hemodynamics, cardiac and respiratory function, infection, and other organ functions of the donor should be assessed precisely. As there are no specialized therapeutic strategies for liver or renal dysfunction during a short period of donor management usually less than 20 hours, cardiopulmonary management to improve organ perfusion and blood gas supply, and metabolic management are the main therapeutic strategies for ECD management.
The repeated assessment and optimal management of donor left ventricular (LV) dysfunction offer a tremendous potential to increase cardiac donor utilization as a significant proportion of hearts are declined for reasons of “poor ventricular function.” However, it has been reported that in younger donors, left ventricular dysfunction can completely recover to normal overtime prior to procurement in a donor and after transplantation in a recipient. Although echocardiography is a very effective tool to assess heart anatomy, especially valvular anomalies, the use of a single echo assessment of ventricular function is not recommended to decide the functional suitability of a donor heart graft.
The goals of hemodynamic management are to achieve normovolemia, minimize vasoconstrictors and vasodilators to keep a normal cardiac afterload and optimize cardiac output with minimal doses of inotropes, which increase myocardial oxygen demands, deplete high-energy phosphates and the density of BAR in the myocardium. The targets of hemodynamic parameters are systemic blood pressure > 90 mmHg, central venous pressure (CVP) 6 to 10 mmHg, urine output 100 ml/h (0.5 to 3 ml/kg/h), and heart rate 80 to 120/minutes with a minimum dosage of inotrope administration.
The use of low-tidal-volume ventilation is recommended because a mechanical ventilator with high tidal volumes is potentially harmful and may exacerbate donor lung injury already damaged during the completion of BD. Recruitment maneuvers are an important component of donor optimization, especially when the oxygenation is subnormal and pulmonary abnormalities are visible on the chest x-ray. Repeated bronchoscopy (6 to 8 hours interval) is also important to improve donor lungs.
Administration of low-dose arginine vasopressin in conjunction with correction of hypovolemia due to diabetes insipidus reduces inotropic requirements and improves kidney, liver, and heart graft function, as shown previously [2]. As ADH increases both vascular tone and the affinity of BAR, ADH is effective even in patients with reduced urine output. ADH may stabilize hemodynamics, increase renal blood flow, and finally increase urine output.
Although desmopressin is mostly beneficial for the primary treatment of diabetes insipidus, it does not usually reduce inotrope requirements in organ donors [2]. Furthermore, desmopressin is reported to increase the incidence of thrombotic events.
ADH should be continuously given through a central venous line with a dose of 10–2o microU/Kg/h or 0.5–1 U/h. In case of hypotension, a loading bolus dose of ADH 0.5 to 1U is effective. If hemodynamics is stabilized by ADH administration, noradrenaline, and then adrenaline can be discontinued. If serum adrenaline level comes within a normal range, the heart rate is converged to an intrinsic heart rate between individuals of the same age, usually into a range of 90 to 120/minutes which is higher than the resting heart rate, because the autonomic regulation on the heart is gone in a BD patient. To optimize hemodynamics throughout procurement surgery, ADH should be continuously infused until the insertion of perfusion cannulas for all procured organs become ready and heparin is given [2].
Reduced ADH secretion due to BD may increase urine output, serum sodium, and osmolality, as well as reduce serum potassium, which decreases circulatory blood volume and intracellular fluid and cause hepatic or renal dysfunction and arrhythmia. Therefore, ADH administration can restore these consequences and is considered a key medication for donor management. Adjusting serum sodium and potassium with 135–150 and 3.8–4.5 mEq/l, respectively, hematocrit greater than 30%, blood sugar with 120–180 mg/dl, and body temperature with 35.5–36.5°C, are also important for optimal donor management.
Since BD organ transplantation was started on 28th February 1999 in Japan, every organ procurement team has taken its own staff physicians to the procurement hospital. They evaluated the donor heart function by performing echocardiography by themselves in ICU prior to procurement operation.
Since November 2002, special transplant management doctors (a medical consultant; MC), who used to be cardiac transplant surgeons and are currently cardiac transplant cardiologists, have been sent to the procurement hospital. They estimate donor heart function and determine whether the heart is useful for transplantation. They also intensively manage the donor by giving ADH as shown above, minimizing the dose of intravenous inotropes, and improving the donor organ function until the procurement heart team arrives at the procurement hospital.
Management strategy of lungs has been modified after the 50th organ procurement from a BD donor in December 2006. After then, in addition to routine bronchial toileting and posture change, repeated broncho fiberscope and frequent bronchial toileting were performed, if there were symptoms and/or signs of atelectasis or pneumonia in the chest x-ray and CT chest scan, After changing the lung management strategy, not only lung availability but also patient survival rate after lung transplantation significantly increased [27]. Then, since 2011, lung transplant surgeons played a role in evaluating and managing lungs as lung MC [28].
PTC of Japan Organ Tx Network (JOT) is sent to a hospital if there is a potential BD organ donor. They evaluate the patient clinical course and check clinical records to rule out the absolute contraindications, shown above. They obtain informed consent for BD organ donation from his or her relatives. After then, two times of legal examination for BD is carried out.
After completion of 1st legal examination for BD determination, MCs come to the hospital. They and JOT PTC obtain the donor’s clinical data such as past history, family history, clinical course during the completion of BD and after BD, such as the history of cardiopulmonary resuscitation and pulmonary aspiration, medication given, such as inotropes, ADH and antibiotics, transfusion, blood examination, blood gas examination, hemodynamic parameters, ECG findings, and data of image examination such as the chest x-ray and the abdominal and chest CT scan. MCs also perform ultrasound examinations for heart and abdominal organs and broncho fiberscope. Rule out malignancies by findings of the CT scan and ultrasound examination and support of making donor evaluation sheets by JOT PTCs are is also an important job of MC.
After 2nd legal examination for BD determination, the patient has declared dead and donor evaluation sheets and images of sequential ECGs, chest x-rays, echocardiography, and chest CT scans are sent to the heart transplant centers of potential recipients using a mobile system, called a donor data delivery system (DDDS) established by JOT. Then transplant center decides whether the recipient undergo heart transplantation from this BD donor and the procurement team is sent to the hospital
According to their assessment of donor hemodynamics and respiration, MCs proposed individualized donor management strategies to physicians taking care of the donor in the procurement hospital.
After arriving at the donor hospital, the procurement team also evaluates the donor heart function with echocardiography by themselves in ICU and determines whether the heart can be transplanted to their recipient. They send this information to their transplant team.
Before starting the procurement operation, all procurement surgeons, anesthesiologists, and operating room nurses gathered in the meeting room. They negotiated on the types of organs procured, the organ transportation method, the method of each organ procurement (e.g., organ dissection/perfusion technique, incision lines, blood drainage technique, etc), what kinds of samples (e.g., blood, lymph nodes, and spleen) were needed, and how to manage the donor during operation. A heart procurement surgeon also supports anesthesiologists to stabilize the patient’s hemodynamics throughout the procurement operation.
Skillful staff surgeons, not resident surgeons, harvests the donor heart. As it was reported that increased intraoperative colloid infusion was significantly associated with poor allograft function post-lung transplantation, maintenance of circulating blood volume and blood osmolality by infusing packed red blood cells and albumin during procurement operation are very important to improve lung graft function posttransplant. To achieve good organ perfusion with preservation solution, the dosage of inotropes should be kept to the minimum to dilate the procured organ vessels and ADH is continuously given until heparin sulfate (400 U/Kg) is given.
After opening the chest, the procurement team will evaluate the heart by inspection and palpation to decide to use the heart. They also look out for unexpected malignancies in the pleural and abdominal cavities.
For many years, heart transplantation has been an established treatment strategy for end-stage heart failure patients using the so-called “Standard Criteria” donor heart. However, over the past three decades, the number of annually listed patients for heart transplantation greatly increased worldwide, and the strict use of the “Standard Criteria” hearts has enhanced severe donor heart shortage, significantly prolonged waiting times and increased the death rate of listed patients prior to heart transplantation. Therefore, the use of ECD hearts has increased worldwide. However, even in 2020, only 3,658 hearts of 9,364 BD donors (39.1%) were transplanted in the USA. As only 760 BD donors have been available in Japan for more than 20 years until the end of 2020 because of the very strict Japanese Organ Transplant Act, only 297 donor hearts would have been transplanted if the rate of heart utilization from the BD donors in Japan is same as in the USA. These extraordinary pressures of donor heart shortage had made Japanese heart transplant programs use a much greater number of ECD donor hearts than in developed countries. Therefore, an original and sophisticated donor evaluation and management system have been established in Japan, such as MC and pre-procurement meetings and so on.
To elucidate the role of this Japanese donor evaluation and management system, consecutive 775 BD donors since the Act was issued until the end of August 2021 in Japan, were reviewed. A total of 611 hearts (78.8%) were transplanted, and organ transplanted per donor was 5.1 (3,985 organs from 775 donors). The number of heart donor ≥ 60 years of age was 63 (10.3%). In the heart donors who had information about the cause of death, the cause of BD was subarachnoid hemorrhage in 160, hypoxic brain damage in 126, other cerebrovascular disorders in 120, head trauma in 100, post-cardiopulmonary resuscitation in 29, and asphyxias in 23. Overall survival rates of cardiac recipients at 1 year, 5, 10, and 20 years were 93.3, 88.3, 79.1, and 75.3%, respectively. Patient survival at 10 years with donor aged 10–19 years, 20–29 years, 30–39 years, 40–49 years, 50–59 years, and 60–69 years were 100, 61.6, 95.5, 88.4, 92.7, 85.9, and 89.3%, respectively (Figure 3). Patient survival at 10 years from a donor with subarachnoid hemorrhage, hypoxic brain damage, other cerebrovascular disorders, head trauma, post-cardiopulmonary resuscitation, and asphyxias were 87.7, 93,2 (at 8.6 years), 82.9, 88.3, 96.6, and 85.2%, respectively (Figure 4). These values were not significantly different.
Cumulative patient survival rate of heart transplant recipients by donor age group (up to August 31, 2021). yrs: years.
Cumulative patient survival rate of heart transplant recipients by donor cause of death group (up to August 31, 2021). SAH: subarachnoid hemorrhage, Post-CPR: post-cardiopulmonary resuscitation.
As deceased organ donation has not increased compared to an increase in listed candidates for heart transplantation worldwide, extended criteria donor hearts have been used in many countries. However, in most countries, only 20–30% of donor hearts from BD donors have been used. Therefore, in Japan where donor shortage has been extremely sever than in other developed countries, special strategies for maximizing heart availability should be established. By establishing the MC system in Japan, the availability of hearts has been very high (79%) and the patient survival rate at high (89% at 10 years). MC doctors may play a great role in increasing donor heart availability as well as in improving outcomes of cardiac recipients even from elderly donors or donors who died of post-resuscitation and anoxia in Japan. These strategies may be useful for maximizing heart transplant opportunities and improving post-transplant outcomes.
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Poggi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8524",title:"Lactation in Farm Animals",subtitle:"Biology, Physiological Basis, Nutritional Requirements, and Modelization",isOpenForSubmission:!1,hash:"2aa2a9a0ec13040bbf0455e34625504e",slug:"lactation-in-farm-animals-biology-physiological-basis-nutritional-requirements-and-modelization",bookSignature:"Naceur M'Hamdi",coverURL:"https://cdn.intechopen.com/books/images_new/8524.jpg",editedByType:"Edited by",editors:[{id:"73376",title:"Dr.",name:"Naceur",middleName:null,surname:"M'Hamdi",slug:"naceur-m'hamdi",fullName:"Naceur M'Hamdi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:37,seriesByTopicCollection:[{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],seriesByTopicTotal:1,mostCitedChapters:[{id:"41563",doi:"10.5772/53504",title:"Fish Cytokines and Immune Response",slug:"fish-cytokines-and-immune-response",totalDownloads:5572,totalCrossrefCites:23,totalDimensionsCites:65,abstract:null,book:{id:"3193",slug:"new-advances-and-contributions-to-fish-biology",title:"New Advances and Contributions to Fish Biology",fullTitle:"New Advances and Contributions to Fish Biology"},signatures:"Sebastián Reyes-Cerpa, Kevin Maisey, Felipe Reyes-López, Daniela Toro-Ascuy, Ana María Sandino and Mónica Imarai",authors:[{id:"92841",title:"Dr.",name:"Mónica",middleName:null,surname:"Imarai",slug:"monica-imarai",fullName:"Mónica Imarai"},{id:"153780",title:"Dr.",name:"Sebastian",middleName:null,surname:"Reyes-Cerpa",slug:"sebastian-reyes-cerpa",fullName:"Sebastian 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Animals"},signatures:"Frédérique Chaucheyras-Durand, Eric Chevaux, Cécile Martin and Evelyne Forano",authors:[{id:"151065",title:"Dr.",name:"Frederique",middleName:null,surname:"Chaucheyras-Durand",slug:"frederique-chaucheyras-durand",fullName:"Frederique Chaucheyras-Durand"},{id:"151068",title:"Mr.",name:"Eric",middleName:null,surname:"Chevaux",slug:"eric-chevaux",fullName:"Eric Chevaux"},{id:"151069",title:"Dr.",name:"Evelyne",middleName:null,surname:"Forano",slug:"evelyne-forano",fullName:"Evelyne Forano"},{id:"160177",title:"Dr.",name:"Cécile",middleName:null,surname:"Martin",slug:"cecile-martin",fullName:"Cécile Martin"}]},{id:"28679",doi:"10.5772/32100",title:"Values of Blood Variables in Calves",slug:"values-of-blood-variables-in-calves",totalDownloads:9614,totalCrossrefCites:16,totalDimensionsCites:36,abstract:null,book:{id:"1667",slug:"a-bird-s-eye-view-of-veterinary-medicine",title:"A Bird's-Eye View of Veterinary Medicine",fullTitle:"A Bird's-Eye View of Veterinary Medicine"},signatures:"Martina Klinkon and Jožica Ježek",authors:[{id:"90171",title:"Prof.",name:"Martina",middleName:null,surname:"Klinkon",slug:"martina-klinkon",fullName:"Martina Klinkon"}]},{id:"16107",doi:"10.5772/16563",title:"Effect of Cryopreservation on Sperm Quality and Fertility",slug:"effect-of-cryopreservation-on-sperm-quality-and-fertility",totalDownloads:15483,totalCrossrefCites:10,totalDimensionsCites:35,abstract:null,book:{id:"185",slug:"artificial-insemination-in-farm-animals",title:"Artificial Insemination in Farm Animals",fullTitle:"Artificial Insemination in Farm Animals"},signatures:"Alemayehu Lemma",authors:[{id:"25594",title:"Dr.",name:"Alemayehu",middleName:null,surname:"Lemma",slug:"alemayehu-lemma",fullName:"Alemayehu Lemma"}]},{id:"57645",doi:"10.5772/intechopen.71780",title:"Antibiotics in Chilean Aquaculture: A Review",slug:"antibiotics-in-chilean-aquaculture-a-review",totalDownloads:1945,totalCrossrefCites:17,totalDimensionsCites:29,abstract:"Aquaculture in Chile has been practiced since the 1920s; however, it was not until the 1990s that aquaculture became an important sector here. Important species in Chilean aquaculture include salmonids, algae, mollusks, and turbot. Salmonids are the dominant species in Chilean aquaculture for both harvest volume and export value, their production reaching greater than 800-thousand tons in 2015. However, this growth has been accompanied by an increase in disease presence, requiring greater drug use to control. This increase in drug use is an environmental and public health concern for the authorities, the salmon industry itself, and the destination markets. In this chapter, we review the literature on drug use, antibiotic resistance, regulatory framework, and alternatives, with focus on Chile.",book:{id:"6179",slug:"antibiotic-use-in-animals",title:"Antibiotic Use in Animals",fullTitle:"Antibiotic Use in Animals"},signatures:"Ivonne Lozano, Nelson F. Díaz, Susana Muñoz and Carlos Riquelme",authors:[{id:"208847",title:"Dr.",name:"Ivonne",middleName:null,surname:"Lozano",slug:"ivonne-lozano",fullName:"Ivonne Lozano"},{id:"208895",title:"Dr.",name:"Nelson F.",middleName:null,surname:"Díaz",slug:"nelson-f.-diaz",fullName:"Nelson F. Díaz"},{id:"208897",title:"Dr.",name:"Carlos",middleName:null,surname:"Riquelme",slug:"carlos-riquelme",fullName:"Carlos Riquelme"},{id:"208898",title:"MSc.",name:"Susana",middleName:null,surname:"Muñoz",slug:"susana-munoz",fullName:"Susana Muñoz"}]}],mostDownloadedChaptersLast30Days:[{id:"56612",title:"Reproduction in Goats",slug:"reproduction-in-goats",totalDownloads:2917,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Reproductive activity of the goat begins when the females reach puberty, which happens at 5 months of age. The ovarian or estrous cycle is the period between two consecutive estrus. It is also the time that lasts the development of the follicle in the ovary, until rupture occurs and ovulation takes place, which coincides with the appearance of estrus. This chapter will describe the physiological and endocrinological bases of estrus in the goat. Likewise, factors affecting the presence of estrus and ovulation will be described. At another point, synchronization of estrus and ovulation, factors affecting the presence of estrus and external symptoms of estrus, will be described. To achieve synchronization of estrus or induction of ovulation within or outside the breeding season, it may be necessary to manage light hours, male effect, and/or use of hormones. The importance of artificial insemination is described, as well as the current situation of this technique worldwide. Currently, the techniques of artificial insemination in goats have been limited worldwide, due to the lack of resources of producers and trained technicians. The techniques of artificial insemination with estrous synchronization programs and ovulation with current research results will be described.",book:{id:"5987",slug:"goat-science",title:"Goat Science",fullTitle:"Goat Science"},signatures:"Fernando Sánchez Dávila, Alejandro Sergio del Bosque González\nand Hugo Bernal Barragán",authors:[{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila"},{id:"206127",title:"Dr.",name:"Alejandro Sergio",middleName:null,surname:"Del Bosque-Gonzalez",slug:"alejandro-sergio-del-bosque-gonzalez",fullName:"Alejandro Sergio Del Bosque-Gonzalez"},{id:"206128",title:"Dr.",name:"Hugo",middleName:null,surname:"Bernal-Barragán",slug:"hugo-bernal-barragan",fullName:"Hugo Bernal-Barragán"}]},{id:"58095",title:"The Innovative Techniques in Animal Husbandry",slug:"the-innovative-techniques-in-animal-husbandry",totalDownloads:3811,totalCrossrefCites:4,totalDimensionsCites:8,abstract:"Technology is developing rapidly. In this development, the transfer of computer systems and software to the application has made an important contribution. Technologic instruments made farmers can work more comfortable and increased animal production efficiency and profitability. Therefore, technologic developments are the main research area for animal productivity and sustainability. Many technologic equipment and tools made animal husbandry easier and comfortable. Especially management decisions and applications are effected highly ratio with this rapid development. In animal husbandry management decisions that need to be done daily are configured according to the correctness of the decisions to be made. At this point, smart systems give many opportunities to farmers. Milking, feeding, environmental control, reproductive performance constitute everyday jobs most affected by correct management decisions. Human errors in this works and decisions made big effect on last product quality and profitability are not able to be risked. This chapter deal with valuable information on the latest challenges and key innovations affecting the animal husbandry. Also, innovative approaches and applications for animal husbandry are tried to be summarized with detail latest research results.",book:{id:"6384",slug:"animal-husbandry-and-nutrition",title:"Animal Husbandry and Nutrition",fullTitle:"Animal Husbandry and Nutrition"},signatures:"Serap Göncü and Cahit Güngör",authors:[{id:"215579",title:"Prof.",name:"Serap",middleName:null,surname:"Goncu",slug:"serap-goncu",fullName:"Serap Goncu"},{id:"218971",title:"Dr.",name:"Cahit",middleName:null,surname:"Güngör",slug:"cahit-gungor",fullName:"Cahit Güngör"}]},{id:"58486",title:"Quality of Chicken Meat",slug:"quality-of-chicken-meat",totalDownloads:3344,totalCrossrefCites:19,totalDimensionsCites:28,abstract:"Chicken meat is considered as an easily available source of high-quality protein and other nutrients that are necessary for proper body functioning. In order to meet the consumers’ growing demands for high-quality protein, the poultry industry focused on selection of fast-growing broilers, which reach a body mass of about 2.5 kg within 6-week-intensive fattening. Relatively low sales prices of chicken meat, in comparison to other types of meat, speak in favor of the increased chicken meat consumption. In addition, chicken meat is known by its nutritional quality, as it contains significant amount of high-quality and easily digestible protein and a low portion of saturated fat. Therefore, chicken meat is recommended for consumption by all age groups. The technological parameters of chicken meat quality are related to various factors (keeping conditions, feeding treatment, feed composition, transport, stress before slaughter, etc.). Composition of chicken meat can be influenced through modification of chicken feed composition (addition of different types of oils, vitamins, microelements and amino acids), to produce meat enriched with functional ingredients (n-3 PUFA, carnosine, selenium and vitamin E). By this way, chicken meat becomes a foodstuff with added value, which, in addition to high-quality nutritional composition, also contains ingredients that are beneficial to human health.",book:{id:"6384",slug:"animal-husbandry-and-nutrition",title:"Animal Husbandry and Nutrition",fullTitle:"Animal Husbandry and Nutrition"},signatures:"Gordana Kralik, Zlata Kralik, Manuela Grčević and Danica Hanžek",authors:[{id:"207236",title:"Dr.",name:"Gordana",middleName:null,surname:"Kralik",slug:"gordana-kralik",fullName:"Gordana Kralik"},{id:"227281",title:"Prof.",name:"Zlata",middleName:null,surname:"Kralik",slug:"zlata-kralik",fullName:"Zlata Kralik"},{id:"227283",title:"Dr.",name:"Manuela",middleName:null,surname:"Grčević",slug:"manuela-grcevic",fullName:"Manuela Grčević"},{id:"227284",title:"BSc.",name:"Danica",middleName:null,surname:"Hanžek",slug:"danica-hanzek",fullName:"Danica Hanžek"}]},{id:"56453",title:"Goat System Productions: Advantages and Disadvantages to the Animal, Environment and Farmer",slug:"goat-system-productions-advantages-and-disadvantages-to-the-animal-environment-and-farmer",totalDownloads:4368,totalCrossrefCites:5,totalDimensionsCites:20,abstract:"Goats have always been considered very useful animals. Goats success is related to its excellent adaptability to the difficult mountain conditions, extreme weather and low value feed acceptance, versatile habits and high production considering their size. These are some reasons because goats are among the first animals to be domesticated. In terms of evolution, goats could be separated by their dispersion area in three large groups: the European, the Asian, and the African. Global goat populations, mainly in Africa and in Asia, have increased for centuries but very strongly in the past decades, well above the world population growth. They are also used for forest grazing, an integrated and alternative production system, very useful to control weed growth reducing fire risk. Despite some exceptions, no large‐scale effort to professionalize this industry has been made so far. There are consumers for goat dairy products and there is enough global production, but misses a professional network between both. Regarding goat meat, the world leadership also stays in Africa and Asia, namely in China, and there is a new phenomenon, the spreading of goat meat tradition through Europe due to migrants from Africa and other places with strong goat meat consumption.",book:{id:"5987",slug:"goat-science",title:"Goat Science",fullTitle:"Goat Science"},signatures:"António Monteiro, José Manuel Costa and Maria João Lima",authors:[{id:"190314",title:"Prof.",name:"António",middleName:"Cardoso",surname:"Monteiro",slug:"antonio-monteiro",fullName:"António Monteiro"},{id:"203680",title:"Prof.",name:"Maria João",middleName:null,surname:"Lima",slug:"maria-joao-lima",fullName:"Maria João Lima"},{id:"203683",title:"MSc.",name:"José Manuel",middleName:null,surname:"Costa",slug:"jose-manuel-costa",fullName:"José Manuel Costa"}]},{id:"70760",title:"Induction and Synchronization of Estrus",slug:"induction-and-synchronization-of-estrus",totalDownloads:1745,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Estrus cycle is a rhythmic change that occur in the reproductive system of females starting from one estrus phase to another. The normal duration of estrus cycle is 21 days in cow, sow, and mare, 17 days in ewe, and 20 days in doe. The species which exhibit a single estrus cycle are known as monstrous and species which come into estrus twice or more are termed polyestrous animals. Among them some species have estrus cycles in a particular season and defined as seasonal polyestrous. It includes goats, sheep, and horses. On the other hand, cattle undergo estrus throughout the year. The estrus inducers can grossly be divided into two parts, that is, non-hormonal and hormonal. Non-hormonal treatments include plant-derived heat inducers, mineral supplementation, uterine and ovarian massage, and use of Lugol’s iodine. The hormones that are used in estrus induction are estrogen, progesterone, GnRH, prostaglandin, insulin, and anti-prolactin-based treatment. Synchronization can shorten the breeding period to less than 5 days, instead of females being bred over a 21-day period, depending on the treatment regimen. The combination of GnRH with the prostaglandin F2α (PGF2α)- and progesterone-based synchronization program has shown a novel direction in the estrus synchronization of cattle with the follicular development manipulation.",book:{id:"8545",slug:"animal-reproduction-in-veterinary-medicine",title:"Animal Reproduction in Veterinary Medicine",fullTitle:"Animal Reproduction in Veterinary Medicine"},signatures:"Prasanna Pal and Mohammad Rayees Dar",authors:[{id:"299126",title:"Dr.",name:"Mohammad Rayees",middleName:null,surname:"Dar",slug:"mohammad-rayees-dar",fullName:"Mohammad Rayees Dar"},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal"}]}],onlineFirstChaptersFilter:{topicId:"25",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82991",title:"Diseases of the Canine Prostate Gland",slug:"diseases-of-the-canine-prostate-gland",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.105835",abstract:"In dogs, the most frequent diseases of the prostate gland are benign prostate gland hyperplasia (BPH), acute and chronic prostatitis, squamous metaplasia, and prostate tumors. New diagnostic tools comprise diagnostic markers in the blood and urine, as well as advanced imaging methods. The therapy can be initialized with the 5α-reductase-inhibitor finasteride or an anti-androgenic compound, and prolonged with a long-acting gonadotropin-releasing-hormone (GnRH)-agonist such as deslorelin. In case of prostatitis, effective antibiotics must be applied for weeks. Antibiotics must be able to penetrate into the prostate tissue; fluoroquinolones, clindamycin, and erythromycin are good choices and are in addition effective against mycoplasms. The chronical prostatitis cannot be differentiated from a neoplasia by sonography; a biopsy, histological, and bacteriological examination are required. Tumors of the prostate gland are seldom and mostly occur in castrated but in intact dogs. For the final diagnosis, a biopsy must be taken. Partial and total resection of the prostate gland by use of laser technique is possible but coincedes with many side effects and the prognosis is still futile. Immunotherapy combined with NSAIDs, targeted noninvasive thermotherapy, BRAF gene inhibitors, or prostate artery chemoembolization are promising methods.",book:{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg"},signatures:"Sabine Schäfer-Somi"},{id:"82956",title:"Potential Substitutes of Antibiotics for Swine and Poultry Production",slug:"potential-substitutes-of-antibiotics-for-swine-and-poultry-production",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.106081",abstract:"Early of the last century, it was detected that antibiotics added to the animal feeds at low doses and for a long time can improve technical performances such as average daily gain and gain-to-feed ratio. Since then, the antibiotics have been used worldwide as feed additives for many decades. At the end of the twentieth century, the consequences of the uses of antibiotics in animal feeds as growth promoters were informed. Since then, many research studies have been done to find other solutions to replace partly or fully to antibiotic as growth promoters (AGPs). Many achievements in finding alternatives to AGPs in which probiotics and direct-fed microorganism, prebiotics, organic acids and their salts, feed enzymes, bacteriophages, herbs, spices, and other plant extractives (phytogenics), mineral and essential oils are included.",book:{id:"11578",title:"Antibiotics and Probiotics in Animal Food - Impact and Regulation",coverURL:"https://cdn.intechopen.com/books/images_new/11578.jpg"},signatures:"Ho Trung Thong, Le Nu Anh Thu and Ho Viet Duc"},{id:"82905",title:"A Review of Application Strategies and Efficacy of Probiotics in Pet Food",slug:"a-review-of-application-strategies-and-efficacy-of-probiotics-in-pet-food",totalDownloads:13,totalDimensionsCites:0,doi:"10.5772/intechopen.105829",abstract:"In companion animal nutrition, probiotics (direct-fed microbials) are marketed as functional ingredients that add value to pet foods due to the impact they have on gastrointestinal and immune health of dogs and cats. The nature of the beneficial effect each probiotic strain exerts depends on its metabolic properties and perhaps most importantly, the arrival of a sufficient number of viable cells to the large bowel of the host. Pet food manufacturing processes are designed to improve food safety and prolong shelf-life, which is counterproductive to the survival of direct-fed microbials. Therefore, a prerequisite for the effective formulation of pet foods with probiotics is an understanding of the conditions each beneficial bacterial strain needs to survive. The aims of this chapter are: (1) To summarize the inherent characteristics of probiotic strains used in commercial pet foods, and (2) To review recently published literature on the applications of probiotics to pet foods and their associated challenges to viability.",book:{id:"11578",title:"Antibiotics and Probiotics in Animal Food - Impact and Regulation",coverURL:"https://cdn.intechopen.com/books/images_new/11578.jpg"},signatures:"Heather Acuff and Charles G. Aldrich"},{id:"82773",title:"Canine Transmissible Venereal Tumor: An Infectious Neoplasia in Dogs",slug:"canine-transmissible-venereal-tumor-an-infectious-neoplasia-in-dogs",totalDownloads:14,totalDimensionsCites:0,doi:"10.5772/intechopen.106150",abstract:"Canine transmissible venereal tumor is the oldest cancer in dogs and is transplanted via viable cancer cells. This cancer has a specific host, easy transmission, noticeable gross lesions, a predictable growth pattern, an immunologic relative host response, unique molecular characteristics, and is responsive to chemotherapeutic treatment. These points make researchers and practitioners interested in this cancer. Genital cases are noticeable and therefore easier to diagnose and treat than extragenital cases. By contrasting the anatomical features of the two types of cases, we highlight the uniqueness of canine transmissible venereal tumors and discuss the diagnosis, treatment, and prevention of this ancient cancer.",book:{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg"},signatures:"Chanokchon Setthawongsin, Somporn Techangamsuwan and Anudep Rungsipipat"},{id:"82797",title:"Anatomical Guide to the Paranasal Sinuses of Domestic Animals",slug:"anatomical-guide-to-the-paranasal-sinuses-of-domestic-animals",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.106157",abstract:"Paranasal sinuses are paired cavities within the skull, which develop by evagination into the spongy bone between the external and internal plates of the cranial and facial bones. Thus, each sinus is lined by respiratory epithelium and has direct or indirect communication to the nasal cavity. The purpose of this chapter is to present an anatomical reference guide of the paranasal sinuses in domestic animals, including large and small ruminants (cattle, buffalo, sheep, and goats), camels, canines (dog) and equines (horse and donkey), appropriate for use by anatomists, radiologists, clinicians, and veterinary students. Topographic descriptions and the relationships between the various air cavities and paranasal sinuses have been visualized using computed tomography and cadaver sections images. The anatomical features (including head bones, muscles, and soft tissues) have been compared using both dissected heads and skulls and computed tomography images. This chapter will therefore be useful as a normal reference guide for clinical applications.",book:{id:"10665",title:"Updates on Veterinary Anatomy and Physiology",coverURL:"https://cdn.intechopen.com/books/images_new/10665.jpg"},signatures:"Mohamed A.M. Alsafy, Samir A.A. 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In this chapter, we review the studies on reproduction of marine mammals using δ13C and δ15N values analyzed in several tissues and describe the typical changes reported to date in those values and Hg concentrations in offspring and milk during lactation. Next, we present data on ontogenetic changes in δ15N and δ13C profiles and Hg concentration, especially focusing on the lactation period, in muscle samples of hunted bowhead whale, and stranded common minke whale (mysticetes), Dall’s porpoise (odontocete), and the harbor seal (phocid). 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He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. 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He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. 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I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. 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Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. 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He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). 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Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. 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His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. 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To tackle global challenges of development and environment, the United Nations General Assembly in 2015 adopted the 17 Sustainable Development Goals. SDGs emphasize that environmental sustainability should be strongly linked to socio-economic development, which should be decoupled from escalating resource use and environmental degradation for the purpose of reducing environmental stress, enhancing human welfare, and improving regional equity. Moreover, sustainable development seeks a balance between human development and decrease in ecological/environmental marginal benefits. Under the increasing stress of climate change, many environmental problems have emerged causing severe impacts at both global and local scales, driving ecosystem service reduction and biodiversity loss. Humanity’s relationship with resource exploitation and environment protection is a major global concern, as new threats to human and environmental security emerge in the Anthropocene. 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