**4. Biology of mutant genes**

**2. Genetic contribution to glaucoma: Classification and pathophysiology**

Glaucoma is a group of complex, genetically and clinically heterogeneous condition and af‐ fects all age groups throughout the world [10]. Approximately 70 million people worldwide are affected and it is one of the leading causes of bilateral blindness in humans [11]. The glaucomas are classified into primary and secondary glaucomas and within these two groups the disorder is divided into primary open-angle (POAG; the trabecular mesh work seems to be open and unobstructed by the iris), primary closed angle (PCAG; partial or com‐ plete anterior chamber angle closure) and primary congenital glaucoma (PCG; which mainly affects children). The disorder is characterized by the progressive degeneration of the retinal ganglion cells (RGCs) and is frequently associated with elevated intraocular pressure (IOP) [12]. A host of genetic and environmental factors contribute to the glaucoma phenotypes. For instance in certain population, older age, history of thyroid diseases, higher IOP and high myopia have been reported to be significant risk factors for POAG [13-16]. Similarly, drinking coffee, antioxidant intake and post menopausal hormone use may influence the de‐ velopment of POAG. These environmental risk factors exert their effects on IOP (by decreas‐ ing or increasing) and/or the rate of retinal ganglion cell apoptosis. In advanced glaucoma, the cone photoreceptors were also affected suggesting that photoreceptors may also be se‐

Epidemiological studies suggest that POAG is the most common type of glaucoma in most populations and is consistently associated with elevated IOP [18-19]. However, patients with POAG can also have IOP within the normal range and they are classified as having normal tension glaucoma (NTG) – most likely an independent entity [20]. In NTG, the optic nerve head is just susceptible to normal IOP. This may be due to the difference in the ultra structure of the optic nerve head or due to micro-level of biochemical agents. It is only a lim‐ ited subset of patients with elevated IOP will develop POAG. This is consistent with the finding that, a significant number of glaucoma patients although respond well to therapies to lower the eye pressure, continue to lose vision [21-22]. Many individuals have IOP eleva‐ tion without optic nerve damage (they are considered as having ocular hypertension) and some individuals develop optic nerve degeneration without elevated IOP [10]. Therefore, it has been proposed that elevation in IOP is neither necessary nor sufficient for the onset of the progression of the disorder or optic nerve damage [10, 23-24]. Recent research suggests that transforming growth factor - beta (TGF - beta) and tumor necrosis factor - alpha (TNF alpha) signaling pathways may contribute to the optic nerve disease in glaucoma [10].

The genetic basis of glaucoma is not fully understood. However, familial aggregation, occur‐ rence of bilateral PCG in monozygotic twins and environmental factors such as advanced age, race, vascular risk factors, diabetes and hypertension suggest a multifactorial contribu‐ tion to the etiology of the disease [12, 25-26]. Although details about the inheritance of the

quentially damaged in the disorder [17].

58 Glaucoma - Basic and Clinical Aspects

**3. Primary open-angle glaucoma (POAG)**

Although the exact role of MYOC and OPTN genes in the pathogenesis of glaucoma is un‐ known, it was suggested that myocilin might be involved in the trabecular meshwork (TM) homeostasis. Interestingly, MYOC mutations Y437H and I477N were shown to sensitize cells to oxidative stress induced apoptosis. Similarly, invitro transfection experiments sug‐ gested that mutations in MYOC might also cause mitochondrial defects that may lead to TM cell death. Additionally, biological and cell biological studies demonstrated that mutant MYOC was misfolded and accumulated in the endoplasmic reticulum (ER). This leads to ER stress and activates the unfolded protein response that may cause cellular toxicity and death. However, MYOC gene overexpression is not a cause or effect of elevated IOP. Simi‐ larly, OPTN may have a role in reducing the susceptibility of RGCs to hydrogen peroxideinduced cell death. Mutations in OPTN gene may also cause oxytosis and apoptosis. For instance, OPTN gene regulates endocytic trafficking of transferin receptor that is important for maintaining homeostasis. The E50K mutation of OPTN was shown to impair with traf‐ ficking and this may have implications for the pathogenesis. The TM is the target tissue in the anterior chamber. The development and progression of glaucoma was reported to cause the oxidative damage to the tissue. These changes can be minimized by the use of anti-oxi‐ dants and IOP lowering substances. Therefore, it is possible to reduce the progression of POAG by preventing the oxidative stress exposure to the TM tissue. The WDR gene on the other hand, encodes a member of the WD (tryptophan and aspartic acid) repeat protein fam‐ ily and the members of this family are involved in a variety of cellular processes such as apoptosis and signal transduction. Mutations in the gene may interfere in its normal func‐ tions. Despite strong genetic influence in POAG pathogenesis, only a small part of the dis‐ ease can be explained in terms of genetic mutations.

mapped. More than 60 different mutations in CYP1B1 (or GLC3A) – a member of the cyto‐ chrome P450 superfamily enzyme-encoding gene - have been reported in several PCG fami‐ lies [33-38]. Mutations in CYP1B1 were associated with wide range of phenotypes and the alterations of this gene could impair the morphogenesis of the outflow angle because it has been suggested that CYP1B1 gene participates in iridocorneal angle development [39]. In short, the current concept of glaucoma pathogenesis (Fig. 1) suggests that it is a group of het‐ erogeneous optic neuropathies caused by genetic, epigenetic and environmental factor [40].

Emerging Concept of Genetic and Epigenetic Contribution to the Manifestation of Glaucoma

http://dx.doi.org/10.5772/52279

61

**Figure 1.** A complex glaucoma pathogenesis may include interplay among several factors such as genetic, epigenetic

Inherited glaucoma also occurs in several breeds of dogs including beagles. Primary glauco‐ ma in beagles is inherited as an autosomal recessive trait and appears when the animals are 9 to 18 months old. The pathogenesis, clinical signs and pharmacological responses of glau‐ coma in beagles have been investigated and reported previously [41-43]. Glaucoma in bea‐ gles however, does not involve mutations in MYOC and CYP1B1 genes [44-45]. Similarly, mutations in MYOC gene are unlikely to play a role in the pathogenesis of PCAG in Shiba Inu dogs [46]. Recently, a candidate gene for the beagle model has been isolated [47] and the mutant protein is suggested to be altering the processing of the extracellular matrix that may affect the aqueous humor outflow thereby contributing to the elevated IOP. However, the mechanism underlying RGCs death is not well understood. Interestingly, it was reported that impaired neurotrophin signaling or compromised trophic support as well as p53 medi‐ ated apoptosis may not be the underlying mechanism of RGCs death in a beagle model of glaucoma [48]. Recently, there has been some success in stem cell therapy in animal models [49]. Transplantation of induced pluripotent stem (iPS) cells restored retinal structure and function in degenerative animals. Therefore, these animal models are very useful in further

understanding of the pathogenesis as well as drug development in glaucoma.

and environmental factors.

**7. Inherited glaucoma in animals**

ANP = Atrial natriuretic peptide; MTHFR = methylenetetrahydrofolate reductase; IL-1beta = interleukin 1-beta; NCK = adapter protein 2; OPA1 = optic atrophy-1; PARL = presenilin associated rhomboid-like; EDNRA = endothelin receptor type A; CDKN1A = cyclin dependent kinase inhibitor 1A; HSPA1A = heat-shock 70 kD protein 1A; TNF = Tumor necrosis factor; NOS-3 = nitric oxide synthetase –3; PON1 = paraoxonase –1; TLR4 = toll-like receptor 4; IGF2 = insulin-like growth factor 2;CDH-1 = E-cadherin; TP53 = tumor protein p53; APOE = apolipoprotein E; NTF-4 = neurotrophin 4; AGTR2 = angiotensin II receptor type 2; GSTM1 = glutathione S-transferase mu 1; Asterisk (\*) = detailed references can be found in ref. # 18.

**Table 1.** A partial list of genes that are reported to be associated with POAG and NTG \*


**7. Conclusion**

Tree nuts are healthy foods with significant economic values. Postharvest processing technologies are essential in preserving the quality and safety of tree nuts. In this chapter, the status, recent advances, and challenges of drying, disinfection, disinfestation, blanching, peeling, and roasting of almonds, walnuts, and pistachios in scientific research, as well as in industrial productions are summarized. Current processing practices can be improved by optimizing the operating parameters. Novel thermal and non-thermal drying technologies, such as IR, MW, RF, ultrasound, vacuum, etc. and combined technologies, have shown great potential to improve the drying efficiency and safety of nuts without compromising the nut quality. It was noted that the postharvest processing methods of different tree nuts share some similarities but are also different due to the differences in physical properties and chemical compositions. Each processing practice has significant impacts on the quality and safety of the final products, such as lipid oxidation, loss of nutrients and formation of acrylamide. Therefore, suitable processing technologies and operating conditions must be carefully selected. Additionally, processing wastes of tree nuts, such as hulls and shells, have potential to be utilized as high value bioresources for producing value-added products. Being important economic crops with large market size, improvements in the postharvest processing technologies of tree nuts could translate into significant global influence in reducing the energy consumption and environmental impacts for improved sustainability, economic values, and competitiveness of tree nut industry.

*Postharvest Technology - Recent Advances, New Perspectives and Applications*


**4. Clinical finding and diagnosis**

Although total plasma volume increases, as a result of collection of blood in the splanchnic area, effective blood capacity cannot be achieved, and central hypovolemia develops. After these changes, activation of the sympathetic nervous system and renin‐aldosterone system occurs; vasopressin release from the hypothalamus increases, which results in fluid and salt

The vasoconstrictor and vasodilator substances in the pathogenesis PHT become effective together. The most important vasoconstrictor substances are norepinephrine, angiotensin II, vasopressin, thromboxane (TX), and leukotrienes. The effects of these substances are related with activation of the sympathetic nervous system and renin‐angiotensin‐aldosterone system. Researches have shown that portal venous tension can be decreased using alpha‐adrenergic antagonists (prazosin), beta‐adrenergic antagonists (propranolol), angiotensin‐II antagonists, cyclooxygenase isoenzyme blockers, and TX antagonists. Results of these researches support

Endothelin (ET) can show vasoconstrictor or vasodilator effects according to the type. Endo‐ thelins are classified as ET‐1, ET‐2, and ET‐3 according to their region in the body. ET‐1 is mainly found in endothelial cells, the kidney, and the brain and ET‐2 in the small intestine and kidney, and ET‐3 is found in the blood. ET‐1 and ET‐2 create a vasoconstrictor effect, whereas ET‐3 has a vasodilator effect. These two opposite effects are associated with the induction of nitric oxide and prostacyclin release. The most potent vasoconstrictor substance in the body is ET‐1, and it is reported that this substance is very effective in the development of PHT complications [22,

Nitric oxide (NO) is another very potent substance in the pathogenesis of PHT. NO is synthe‐ sized from arginine by nitric oxide synthetase (NOS) and causes vasodilatation by increasing cyclic guanosine monophosphate. NO initially increases to compensate against the elevated vasoconstrictor agents in the early stage of PHT, but secondary systemic and splanchnic vasodilatation develops because of excessive NO production. This event is a result of stimu‐ lation of NOS by cytokines such as TNF‐alpha, which increases in cirrhosis [22, 30–36].

The other important vasodilator substances in the pathogenesis of PHT are carbon monoxide (CO), hydrogen sulfide (H2S), prostaglandins, glucagon, and endocannabinoids. CO formed through the heme‐oxygenase system is a weaker vasodilator agent than NO, but it is important for regulation of intrahepatic vascular tone. H2S is formed by intestinal microbiota and

Prostaglandins are endogen vasodilators produced in the endothelium and are important for hyperdynamic circulation. Prostacyclin is produced from the vascular endothelium. It leads to vasodilatation, which increases the level of intracellular cyclic adenosine monophosphate (c‐AMP) through the activation of adenylate cyclase. In recent studies, it was shown that indomethacin, a prostacyclin inhibitor, decreased the hyperdynamic circulation and balanced

Glucagon is a hormone released from the pancreas. Glucagon levels increase as a result of low hepatic clearance and stimulation of pancreatic alpha cells in patients with cirrhosis. Glucagon also has the effect of reducing endogenous vasoconstrictor activity in addition to having a

increases the effects of other vasodilator substances and PHT severity [22, 30–36].

retention [30–33].

262 Cardiomyopathies - Types and Treatments

29–34].

the pathogenesis [22, 29–34].

the vasoconstrictor effect [22, 30–36].

Cirrhotic cardiomyopathy (CCMP) represents a condition in which no real cardiac disease is present but a functional cardiac abnormality exists. With time, CCMP progresses to the chronic phase. In a resting state, there is no real disease, but with stress, the cardiac muscle does not contract appropriately and and/or electrophysiologic abnormalities appear [10–12]. There is no exact classification for CCMP and the criteria proposed by Moller et al. are still used (**Table 2**). These data are taken from an adult studies, pediatric data are very limited [41–45]. The most important points from these criteria are (1) at rest, normal, or increased left ventric‐ ular contractibility; (2) abnormal systolic contraction or diastolic relaxation with pharmaco‐ logic, physiologic, or surgical stress; and (3) cardiac electrical abnormalities [10, 11].

Diagnosis of CCMP in children with cirrhosis is difficult, because invasive methods are life‐ threatening and noninvasive tests are unreliable for them. In recent years, a new article was published in which CCMP criteria for children were reviewed [45]. According to this literature, a prolonged QT interval on electrocardiography (ECG) is an important finding after all non‐ liver causes are excluded, and shows latent cardiomyopathy due to cirrhotic changes. If there is the presence of echocardiographic abnormalities, this event is a manifest CCMP [45].

Cirrhotic cardiomyopathy is a latent disease in which there is no abnormality except under stress conditions. In such patients, there is no cardiac disease till end‐stage disease. At end stage, infrequent arrhythmias or cardiac insufficiency may be seen. If these findings exist in an early cirrhotic stage, other causes of cardiomyopathy such as infections, metabolic disor‐ ders, endocrinopathies, ischemic or toxic causes, and genetic and systemic diseases should be investigated [46].

Cirrhotic cardiomyopathy is more likely dilated cardiomyopathy where some stress factors cause cardiac dysfunction. With stress, the clinical status of the patient deteriorates and decompensation may exist. These stress factors are exercise, infection, positional changes, feeding, paracentesis with high volumes, changes in intravascular volume, the use of vaso‐ constrictor drugs, transjugular intrahepatic portosystemic shunts (TIPS), or surgical proce‐ dures such as minor operations or liver transplantation [10–12]. Exercise tolerance in patients with cirrhosis is abnormal due to cardiac function abnormalities, and this correlates with the patient's Child score [47].

BNP, brain natriuretic peptide; E/A ratio, the ratio between the early (E) and late atrial (A) phases of ventricular velocity

**Table 2.** Diagnostic criteria of cirrhotic cardiomyopathy.

There is a relationship between CCMP and hepatorenal syndrome (HRS), which has been reported in many articles published in recent years, so patients with HRS are at more risk [5, 25, 48].

Cardiac functions in patients with liver cirrhosis are determined by physical examination, ECG, and telecardiography besides of echocardiography. Cardiac functions such as systolic, diastolic, and electromechanical functions should be evaluated in suspected CCMP. ECG is sufficient for determining electrophysiologic function. Systolic and diastolic functions are checked using M‐Mod, two‐ and three‐dimensional echocardiocardiography, and spectral and tissue Doppler echocardiocardiography. Cardiac magnetic resonance imaging, radio nuclear angiography, and myocardial perfusion techniques are more advanced methods. Many times, for a diagnosis of CCMP, the findings on ECG and echocardiocardiography are enough.

Firstly, systolic function worsens in the late stage of CCMP. After then, the diastolic functions gradually decay. Diastolic dysfunction is best shown with echocardiographic measurement of the E/A ratio. Deceleration time (DT) and the isovolumetric relaxation time (IVRT) also are used. The E/A ratio results from blood velocity from the left atrium to the left ventricle, the velocity of which during early systole causes the E wave and the same flow causes the A wave during late diastole.

The measurement of E and A waves is expressed as cm/sec and best is done from mitral valve projection. A normal E/A ratio in healthy individuals until the age of 50 years is 1–2 cm/s, but in older people, it decreases below 1 cm/s. An E/A ratio in healthy individuals aged less than 50 years below 1 cm/s shows diastolic dysfunction. However, the restrictive pattern can be observed in advanced stages depending on the severity of the disorder in the patients with CCMP; the E/A ratio may reverse in these cases and may be determined >2 [10, 11, 49] (**Figure 2**).

**Figure 2. Diastolic dysfunction stages** [49]. MAP, mean atrial pressure; NYHA, New York Heart Association; Ddf stage, diastolic dysfunction stage.

DT, deceleration time; E/A, transmitral early diastolic flow (E)/transmitral late diastolic flow (atrial) (A) ratio; IVGT, isovolumetric relaxation time (msn).

**Table 3.** Echocardiographic stages of left ventricular diastolic dysfunction [49].

**Systolic dysfunction criteria Supporting criteria**

**•** Electrophysiologic abnormalities

**•** Abnormal chronotropic response

**•** Prolonged QT intervals

**•** Expended left atrium

**•** Increased myocardial mass

**•** Increased troponin I levels

BNP, brain natriuretic peptide; E/A ratio, the ratio between the early (E) and late atrial (A) phases of ventricular

There is a relationship between CCMP and hepatorenal syndrome (HRS), which has been reported in many articles published in recent years, so patients with HRS are at more risk [5,

Cardiac functions in patients with liver cirrhosis are determined by physical examination, ECG, and telecardiography besides of echocardiography. Cardiac functions such as systolic, diastolic, and electromechanical functions should be evaluated in suspected CCMP. ECG is sufficient for determining electrophysiologic function. Systolic and diastolic functions are checked using M‐Mod, two‐ and three‐dimensional echocardiocardiography, and spectral and tissue Doppler echocardiocardiography. Cardiac magnetic resonance imaging, radio nuclear angiography, and myocardial perfusion techniques are more advanced methods. Many times, for a diagnosis of CCMP, the findings on ECG and echocardiocardiography are enough.

Firstly, systolic function worsens in the late stage of CCMP. After then, the diastolic functions gradually decay. Diastolic dysfunction is best shown with echocardiographic measurement of the E/A ratio. Deceleration time (DT) and the isovolumetric relaxation time (IVRT) also are used. The E/A ratio results from blood velocity from the left atrium to the left ventricle, the velocity of which during early systole causes the E wave and the same flow causes the A wave

The measurement of E and A waves is expressed as cm/sec and best is done from mitral valve projection. A normal E/A ratio in healthy individuals until the age of 50 years is 1–2 cm/s, but in older people, it decreases below 1 cm/s. An E/A ratio in healthy individuals aged less than 50 years below 1 cm/s shows diastolic dysfunction. However, the restrictive pattern can be observed in advanced stages depending on the severity of the disorder in the patients with CCMP; the E/A ratio may reverse in these cases and may be determined >2 [10, 11, 49]

**•** Increased BNP and pro‐BNP levels

**•** Electromechanical uncoupling/dyssynchronism

**•** Inadequate cardiac flow to pharmacologic agents,

exercise, blood volume changes

264 Cardiomyopathies - Types and Treatments

**•** Resting ejection fraction under 55 %

**•** E/A ratio <1,0 (corrected according to age)

**•** Prolonged isovolumetric relaxation time

**Table 2.** Diagnostic criteria of cirrhotic cardiomyopathy.

**Diastolic dysfunction**

(>80 milliseconds)

during late diastole.

(**Figure 2**).

velocity

25, 48].

**•** Prolonged deceleration time (>200 milliseconds)

> There are different stages in CCMP. Clinical findings differ according to stage (**Table 3**). The E/A ratio worsens according to the severity of hepatic disease and it is worse in patients with ascites than in patients with non‐ascites and normal persons. The E/A ratio improves after paracentesis and this event supports that ascites is the negative effect on cardiac functions [50– 53]. There are no publications on these themes in children. There is no definitive normal value for the E/A ratio in children, but in some publications, it is proposed to be between 1.7 and 2.5 cm/s.

> Electrical conduction abnormalities and arrhythmias can be seen in the patients according to severity of cirrhosis [8, 9] [54–58]. There are three types of electrophysiologic abnormalities caused by cirrhosis: (1) prolonged QT on ECG, (2) inadequate response to chronotropic stress, and (3) electromagnetic dyssynchronism [10, 11, 14]. The prolonged QT on ECG means a corrected QT interval (QTc) is longer than 0.440 value [41, 54, 55]. Prolonged QT shows abnormal myocardial repolarization as a sign of CCMP [10–12, 56–58]. QT prolongation

proportionally increases with cirrhotic stage [56]. Prolonged QT on ECG is frequently seen in patients with CCMP. The rate of determination of prolonged QT is 30–60 % in adults with CCMP and in 18–45 % of pediatric patients [5, 41, 44, 56].

Actually, a prolonged QT interval may cause life‐threatening arrhythmias [55], but in many patients with CCMP, despite a prolonged QT interval, no significant clinical problem and arrhythmia are not observed. Cardiac arrhythmias in cirrhotic patients are frequently related to vasopressin use. There is no evidence that a prolonged QT interval in patients with CCMP causes life‐threatening arrhythmias. Probably, some compensatory mechanisms in cirrhotic patients prevent the disturbances and the disease occurs latent until end stage.

### **5. Treatment**

Treatment consists of preventing stress exposure in patients with CCMP; rest and oxygen supplementation are important [10, 59]. There is no need for pharmacotherapy when there is no cardiac insufficiency. Drugs have adverse effects and pharmacotherapy response is weak in patients with CCMP. In recent years, aldosterone antagonists, cannabinoid receptor antagonists, and spironolactone have been used, but only the effectiveness of beta‐blockers has been proved [10, 35, 59]. Beta‐blockers can decrease QT wave duration [10, 32, 33]. Diagnosis of CCMP at an early stage is important. Early diagnosis and proper treatment with cardioprotective agents are important for decreasing complications during and after liver transplantation. There are no exact data on prognosis for liver transplantation in patients with CCMP. Data from the past showed that CCMP worsens in the early period after liver trans‐ plantation, and later cardiac functions and cardiac electromechanical dysfunctions improve gradually by supplying hemodynamic stabilization of the patient [10, 59–64]. Liver transplan‐ tation can be a definitive treatment for CCMP. New pharmacologic agents are needed to help these patients because many patients do not have the chance to receive a transplant.

### **Author details**

Coskun Celtik1\*, Nelgin Gerenli1 , Halil Haldun Emiroglu2 and Nimet Cındık3

\*Address all correspondence to<EMAIL_ADDRESS>
1 Pediatric Gastroenterology, Health Sciences University, Istanbul Umraniye Training and Research Hospital, Istanbul, Turkey

2 Pediatric Gastroenterology, Selcuk University, Faculty of Medicine, Konya, Turkey

3 Pediatric Cardiology, Health Sciences University, Istanbul Umraniye Training and Re‐ search Hospital, Istanbul, Turkey

### **References**

proportionally increases with cirrhotic stage [56]. Prolonged QT on ECG is frequently seen in patients with CCMP. The rate of determination of prolonged QT is 30–60 % in adults with

Actually, a prolonged QT interval may cause life‐threatening arrhythmias [55], but in many patients with CCMP, despite a prolonged QT interval, no significant clinical problem and arrhythmia are not observed. Cardiac arrhythmias in cirrhotic patients are frequently related to vasopressin use. There is no evidence that a prolonged QT interval in patients with CCMP causes life‐threatening arrhythmias. Probably, some compensatory mechanisms in cirrhotic

Treatment consists of preventing stress exposure in patients with CCMP; rest and oxygen supplementation are important [10, 59]. There is no need for pharmacotherapy when there is no cardiac insufficiency. Drugs have adverse effects and pharmacotherapy response is weak in patients with CCMP. In recent years, aldosterone antagonists, cannabinoid receptor antagonists, and spironolactone have been used, but only the effectiveness of beta‐blockers has been proved [10, 35, 59]. Beta‐blockers can decrease QT wave duration [10, 32, 33]. Diagnosis of CCMP at an early stage is important. Early diagnosis and proper treatment with cardioprotective agents are important for decreasing complications during and after liver transplantation. There are no exact data on prognosis for liver transplantation in patients with CCMP. Data from the past showed that CCMP worsens in the early period after liver trans‐ plantation, and later cardiac functions and cardiac electromechanical dysfunctions improve gradually by supplying hemodynamic stabilization of the patient [10, 59–64]. Liver transplan‐ tation can be a definitive treatment for CCMP. New pharmacologic agents are needed to help

these patients because many patients do not have the chance to receive a transplant.

, Halil Haldun Emiroglu2

1 Pediatric Gastroenterology, Health Sciences University, Istanbul Umraniye Training and

3 Pediatric Cardiology, Health Sciences University, Istanbul Umraniye Training and Re‐

2 Pediatric Gastroenterology, Selcuk University, Faculty of Medicine, Konya, Turkey

and Nimet Cındık3

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CCMP and in 18–45 % of pediatric patients [5, 41, 44, 56].

**5. Treatment**

266 Cardiomyopathies - Types and Treatments

**Author details**

Coskun Celtik1\*, Nelgin Gerenli1

Research Hospital, Istanbul, Turkey

search Hospital, Istanbul, Turkey

\*Address all correspondence to<EMAIL_ADDRESS>

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270 Cardiomyopathies - Types and Treatments

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#### **Takotsubo Cardiomyopathy as a Neurocardiogenic Injury after Subarachnoid Hemorrhage: Hemodynamics and Fluid Management Takotsubo Cardiomyopathy as a Neurocardiogenic Injury after Subarachnoid Hemorrhage: Hemodynamics and Fluid Management**

Tatsushi Mutoh, Tomoko Mutoh, Yasuyuki Taki and Tatsuya Ishikawa Tatsushi Mutoh, Tomoko Mutoh, Yasuyuki Taki and Tatsuya Ishikawa

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/65011

#### **Abstract**

Takotsubo cardiomyopathy (TCM) is a life-threatening systemic disorder that may occur early after aneurysmal subarachnoid hemorrhage (SAH), but precise hemodynamics and fluid management remain unclear. Although TCM is often regarded as a reversible or self-limited phenomenon, it contributes significantly to morbidity and mortality of SAH patients, especially when it is complicated with other neurogenic injuries such as severe left ventricular dysfunction, pulmonary edema, and pneumonia. The purpose of this chapter is to introduce the current practice in intensive hemodynamic monitoring and goal-directed fluid management of post-SAH TCM using advanced hemodynamic devices based on our institutional protocol and the relevant literature and to evaluate their effects on clinical outcomes.

**Keywords:** Takotsubo cardiomyopathy, neurogenic stress cardiomyopathy, fluid therapy, pulmonary edema, subarachnoid hemorrhage

### **1. Introduction**

Postoperative management of aneurysmal subarachnoid hemorrhage (SAH) is sometimes complicated by systemic cardiopulmonary complications to affect a significant impact on the morbidity and mortality of the patients [1, 2]. The neuro-cardiac injury of SAH is of particular importance because of theirimpact on the ability to manage blood pressure and volume status, especially in the setting of cerebral vasospasm or delayed cerebral ischemia (DCI). The pattern

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

of injury produced is commonly referred to as neurogenic stress cardiomyopathy [3]. One distinct morphological variant of stress cardiomyopathy is Takotsubo cardiomyopathy (TCM), which was first described by the Japanese physician in the early 1990s to be a reversible cardiomyopathy, the shape of which named after an octopus trap used by the native fishermen [4]. Although TCM is typically associated with acute emotional stress in postmenopausal women [5], triggers may also include physical stressors such as head trauma, intracranial bleeding, ischemic stroke, medical, and surgical procedures and catecholaminergic drugs [6]. Previous reports suggest the demographics and clinical characteristics of TCM are similar irrespective of their etiologies. However, there are notable differences in post-SAH TCM from other non-neurologic stressors in that the patients tended to be younger and more frequent in females than what is typically reported and had high in-hospital mortality (25%) [7].

**Figure 1.** Subarachnoid hemorrhage-induced neurogenic injuries. Note that apical ballooning suggestive of Takotsubo cardiomyopathy (TCM) and left ventricular dysfunction detected by apical two-chamber view on initial echocardiogram. Acute pulmonary edema was also observed on chest X-ray. 123I-metaiodobenzylguanidine (MIBG) SPECT depicting apical defect in the two-chamber view and the analysis of two-dimensional polar maps (bull's eyes) show decreased myocardial perfusion in apex. In 4-h delayed images, washout is increased, suggesting the presynaptic sympathetic dysfunction caused by TCM.

TCM is originally characterized by transient hypokinesis which results from apical wall motion abnormalities with sparing of the base. Although most of the TCM patients (>65%) can present such typical patterns on echocardiography (**Figure 1**), there are several different variants of regional wall motion abnormalities (RWMA) that spares the cardiac apex, as well as one that affects the right ventricle. The right ventricle involvement is noted in 26% of the patients with TCM and bilateral pleural effusions are commonly seen in these patients [8].

The diagnosis of TCM is made based on a modified version of the Mayo Clinic Criteria [9] as described in **Table 1**.

1. Transient hypokinesis, akinesis or dyskinesis of the LV mid-segments with or without apical involvement; the

RWMA extend beyond a single epicardial vascular distribution; a stressful trigger is often, but not always, present.

2. Absence of obstructive coronary artery disease or angiographic evidence of acute plaque rupture.

3. New ECG abnormalities (either ST elevation and/or T wave inversion) or modest elevation in cardiac troponin.

4. Absence of other precipitants such as pheochromocytoma and myocarditis.

of injury produced is commonly referred to as neurogenic stress cardiomyopathy [3]. One distinct morphological variant of stress cardiomyopathy is Takotsubo cardiomyopathy (TCM), which was first described by the Japanese physician in the early 1990s to be a reversible cardiomyopathy, the shape of which named after an octopus trap used by the native fishermen [4]. Although TCM is typically associated with acute emotional stress in postmenopausal women [5], triggers may also include physical stressors such as head trauma, intracranial bleeding, ischemic stroke, medical, and surgical procedures and catecholaminergic drugs [6]. Previous reports suggest the demographics and clinical characteristics of TCM are similar irrespective of their etiologies. However, there are notable differences in post-SAH TCM from other non-neurologic stressors in that the patients tended to be younger and more frequent in

females than what is typically reported and had high in-hospital mortality (25%) [7].

**Figure 1.** Subarachnoid hemorrhage-induced neurogenic injuries. Note that apical ballooning suggestive of Takotsubo cardiomyopathy (TCM) and left ventricular dysfunction detected by apical two-chamber view on initial echocardiogram. Acute pulmonary edema was also observed on chest X-ray. 123I-metaiodobenzylguanidine (MIBG) SPECT depicting apical defect in the two-chamber view and the analysis of two-dimensional polar maps (bull's eyes) show decreased myocardial perfusion in apex. In 4-h delayed images, washout is increased, suggesting the presynaptic sym-

TCM is originally characterized by transient hypokinesis which results from apical wall motion abnormalities with sparing of the base. Although most of the TCM patients (>65%) can present such typical patterns on echocardiography (**Figure 1**), there are several different variants of regional wall motion abnormalities (RWMA) that spares the cardiac apex, as well as one that

pathetic dysfunction caused by TCM.

274 Cardiomyopathies - Types and Treatments

LV: left ventricular; RWMA: regional wall motion abnormalities; ECG: electrocardiogram.

**Table 1.** The Mayo Clinic published diagnostic criteria for TCM after SAH.

Patients with akinesis or hypokinesis of left ventricular (LV) apical segments with preserved contractility of the basal segments are considered to have the apical variant of TCM (apical ballooning), while those with akinesis of the basal segments with preserved contractility of the apex and mid-ventricular segments are classified as having reverse TCM (non-apical ballooning).

A massive release of catecholamines into the systemic circulation after aneurysmal rupture has been considered responsible for SAH-induced TCM. In view of the literature reviews (**Table 1**), the incidence of TCM in SAH patients ranges from 0.8 to 17% [1, 2, 7, 10–12], which makes it a relatively common postoperative complication. However, the management of TCM becomes cumbersome in the setting of volumetric and hemodynamic therapy for DCI. In this chapter, we will review the current practice in intensive hemodynamic monitoring and goaldirected fluid management of post-SAH TCM using advanced hemodynamic devices based on our institutional protocol and the relevant literature and to evaluate their effects on clinical outcomes (**Table 2** ).

**Table 2.** Incidence and characteristics of TCM in patients after subarachnoid hemorrhage.


3.5.1. Energy Efficiency

While EVs are extremely efficient in energy consumption, reports have shown that as much as 57% of the energy used by the car is for overcoming frictional losses [29]. The main components considered to make up the large frictional loss include motor, tires, steering system, wheel bearings, joints, suspensions, and a few others [29]. Friction losses observed in electrical motors (EMs) are attributed to the heat produced by rotors, vibration, wear, and going against wind resistance. In rolling bearings, the main sources of friction loss are from churning, sliding, which is the source of the greatest friction loss of bearings, rolling, and seal sliding friction [30]. For these, a good lubricant or grease is expected to properly offset the frictions. To improve the energy efficiency of grease in these bearing applications, synthetics, primarily polyalphaolefins (PAOs), are used. Given the mix of sliding and rolling contact in the load zone of point contact bearings (ball and spherical roller bearings), PAO-formulated greases have improved traction properties compared to mineral oil-formulated greases. Greases are mainly used in bearings and gears due to them being more of a solid than oil lubricants, as they will not leak out of components and cause damage. Since the usage of greases is much easier with bearings and gears, about 85% of all bearings are lubricated with grease. As increasing energy efficiency is a big focus in the EV industry, all opportunities to reduce friction will help achieve the goal of reaching a range of up to 400 miles [31].

Energy efficiency can be correlated to lubricating film thickness. Thinner lubricants reduce viscous friction, allowing more energy to be conserved. However, greases will reduce lubricating film thickness at high temperatures and bring their own challenges on wear protection of sliding surfaces. A thinner lubricating film will be closer to the mixed and boundary lubrication regimes where wear is a concern. Striking a balance between the capability to remain in a full film lubrication regime and the wear protection towards thinner lubricating films is a crucial turning point that enhances energy efficiency using low-viscosity lubricant or grease. Several papers have emphasized that a new approach using either surface coatings or lower-roughness surfaces will ensure a thin lubricating film to separate surfaces and mitigate wear.

One of the most significant challenges for EVs is to extend the driving range besides energy efficiency. This challenge also imposes the infrastructure of wide-spread recharging stations. Without recharging infrastructure, all passengers must be prepared to give up the 300- to 400-mile ranges they are accustomed to in a conventional vehicle. Automotive engineers are looking for innovation approaches to improve energy efficiency by making vehicles lighter and by reducing torque in all components.

## 3.5.2. Electrification Components

The projected growth of EVs and HVs in the automotive industries has made evolutional changes in propulsion system electrification components. Powertrain and driveline components will be enhanced by electric motors and E-drive configuration. Electrification components including electric motors or regenerative brake components will be integrated in this advanced configuration with thermal management systems for cooling applications. Electric motors and power electronics will be in contact with the cooling fluids. Coolants are required to cool motors and power electronics by removing heat for thermal management. In addition, automotive lubricants for electrified propulsion systems must function as effective coolants and reduce the corrosion of copper windings, on top of needing composites and rare earth magnetic materials while upholding wear and oxidation protection and energy efficiency.

Dr. Kuldeep K. Mistry [28] at The Timken Co. in Ohio also indicated that the development of electric vehicles will influence the selection and development of gear oils, coolants, and greases, because the lubricating oils or greases will be in contact with electric modules, sensors, and circuits. It will be affected by electrical current and electromagnetic fields. Soon, the number of electrical connections is expected to quadruple. In this context, one of the key life-limiting considerations will be corrosion.

Although grease oils will prevent moisture from reaching the surfaces, thus preventing rust, the presence of electromagnetic fields will create another challenge. Electromagnetic fields can propagate without the need for a solid medium. The amount of energy transferred is dependent on the intensity of the field, the frequency of its oscillation, and the dielectric properties of the material. The more energy the object absorbs, the more quickly the object will be heated. The object will gain heat as the frequency of the electromagnetic field increases. However, if the temperature diffusion rate is slower than the rate at which the electromagnetic field releases its energy, the temperature will increase rapidly [31]. As electric motors produce electromagnetic fields, there is a chance for the premature degradation of greases. The electrical discharge and free radicals will react with the oxygen in greases, creating hydrogen peroxide and continuing the chain of free radical reactions. This leads to the oxidation of base oils and thickeners, which causes a loss in lubricity. In addition, components within the grease will start to separate and the thermal effects from the electrical discharge will cause certain parts to evaporate and eventually cause grease failure [18,31]. To this degree, experiments have shown that a conductive lubricant will help with its corrosion prevention. This is because non-conductive greases will trap the energy from electrical currents and electromagnetic fields, leading to a sudden release and causing great damage [18,31]. However, if the material is conductive, then while the electrical currents will pass through, it will be in a much smaller amount and cause less damage.


**3. Spectral Data Preprocessing Method**

Before the qualitative and quantitative analysis, proper pretreatment of spectrum reduces or even eliminates the impact of various non-target factors on the spectrum, and cleans the spectral information. Spectral preprocessing is very important method to establish a good and robust predictive model, and sometimes even plays a decisive role. Common spectral preprocessing methods include removing interference bands, smoothing algorithms, mathematical transformations, and differential algorithms.


2. Mathematical solution for representing the viscoelasticity

An increase in strain over time under constant stress is a viscoelastic phenomenon. Mathematically, viscoelasticity can be represented by a time-dependent function associated with rheological models capable of describing the phenomenon [6]. The slow deformation for concrete parts is a phenomenon that is related to loads and deformations but is partially reversible [7]. It is a phenomenon that is directly related to the movement of moisture inside concrete. When a sample of concrete is loaded for 90 days and then unloaded, the immediate or elastic recovery is approximately the same magnitude as the elastic deformation when the first load is applied [8].

It is conceptually convenient to consider classic viscoelastic models in which only two types of parameters, relating to elasticity and viscosity, appear [9]. Classic viscoelastic models are obtained by arranging springs and dampers, or dashpots, in different configurations. Springs are characterized by elastic moduli and dashpots by viscosity coefficients. The best known of these mechanical models are the Maxwell model, containing a spring in series with a dashpot, and the Kelvin-Voigt model, containing a spring and dashpot in parallel. One model used to represent the viscoelasticity of solids is the three-parameter model, in which the elastic parameter E0 is connected to the viscoelastic Kelvin-Voigt model with parameters E1 and η1, which is a simplification of the Group I Burgers model, as shown in Figure 1.

The three-parameter model sufficiently describes the viscoelastic nature of many solids and is often used to study the phenomenon in various scientific fields. The total deformations of the

Figure 1. Viscoelastic model of three parameters.

Kelvin-Voigt model are given by ε = εe + εv , where εe is the deformation of the elastic model, and εv is the deformation of the Kelvin-Voigt model. When differentiated with respect to time, the total deformation is obtained as

$$
\varepsilon = \dot{\varepsilon}^e + \dot{\varepsilon}^v \tag{1}
$$

The previous solution for consideration of the viscoelastic behavior of materials was used by [10] to evaluate the stability of a slender wooden column, for example. However, it is of interest, at this moment, to make clear that the present work is a numerical approximation, which takes into account the viscoelastic behavior of the concrete by assuming a viscoelastic

Analytical and Mathematical Analysis of the Vibration of Structural Systems Considering Geometric Stiffness…

http://dx.doi.org/10.5772/intechopen.75615

353

It is important to note that the viscoelastic behavior of the considered material is completely represented by the temporal modulus of elasticity. Therefore, the solid such behavior is wished to study should be according that adopted model. Any material can be represented by it, being, however, its usage conditioned by performing of experimental studies in order to confirm if it is correct or not. Keeping this in mind, the concrete viscoelastic behavior is assumed to be represented by the solid standard model, as an approximation of the reality. However, criteria from regulatory codes can be used in substituting of that model or even any

A piece can be considered as prestressed reinforced concrete when it is subjected to the action of the so-called prestressing forces and of permanent and variable loads, so that the concrete is not subjected to tension or it occurs below the limit of its resistance. As an example, take the normal stresses beam diagrams of the prestressed beam of Figure 2, where P is the prestressing force, MP the bending moment due to eccentricity of the load P, Mp is the bending moment due to uniformly distributed load p and R is the resultant, each one of these with their corresponding normal stresses. Under the conditions presented, the lower fibers of the beam, under positive bending moment, will have the tension stresses overturned by the superposi-

Prestressed concrete was developed scientifically from the beginning of the last century. Prestressing can be defined as the artifice of introducing, in a structure or a part, a previous state of stresses, in order to improve its resistance or its behavior in service, under the action of

tion of those produced by the normal stress of the applied stress eccentrically.

rheological model of three parameters or as also is known of the solid standard.

other rheological models can be adopted.

3. Beam as a basis of supporting

Figure 2. Normal stresses in a prestressed beam.

3.1. Basic considerations prestressing in reinforced concrete

which is the constitutive equation of the elastic and Kelvin-Voigt models, respectively. Considering E1 = E0 as the modulus of elasticity for both parts of the rheological model,

$$
\sigma = E\_0 \varepsilon^{\varepsilon} \text{ and } \dot{\sigma} + \frac{E\_0 + E\_0}{\eta\_1} \sigma = E\_0 \dot{\varepsilon} + \frac{E\_0 E\_0}{\eta\_1} \varepsilon \tag{2}
$$

are found. From the previous equations, one derives the following differential equation:

$$
\sigma = E\_0 \varepsilon^v + \eta\_1 \dot{\varepsilon}^v \tag{3}
$$

where σ = 0 for t < 0 and σ = σ0 for t > 0, with t representing the time and t = 0 the instant of loading application. As the stress remains constant, the stress derivate with respect to time is zero. Applying the previous stress condition, the following ordinary differential equation is found:

$$E\_0 \dot{\varepsilon} + \frac{E\_0 E\_0}{\eta\_1} \varepsilon = \sigma\_0 \tag{4}$$

for which the general solution for t > 0, taking the initial condition ε(0) = σ0/E0, is

$$\varepsilon(t) = \sigma\_0 \left[ \frac{1}{E\_0} + \frac{1}{E\_0} \left( 1 - e^{-\frac{E\_0}{\eta\_1}t} \right) \right] \tag{5}$$

Obviously, if the stress level remains constant, the modulus of elasticity should decrease concurrently with increasing strain:

$$E(t) = \frac{1}{\frac{1}{\frac{1}{E\_0} + \frac{1}{E\_0}} \left(1 - e^{-\frac{E\_0}{\eta\_1}t} \right)}\tag{6}$$

The previous solution for consideration of the viscoelastic behavior of materials was used by [10] to evaluate the stability of a slender wooden column, for example. However, it is of interest, at this moment, to make clear that the present work is a numerical approximation, which takes into account the viscoelastic behavior of the concrete by assuming a viscoelastic rheological model of three parameters or as also is known of the solid standard.

It is important to note that the viscoelastic behavior of the considered material is completely represented by the temporal modulus of elasticity. Therefore, the solid such behavior is wished to study should be according that adopted model. Any material can be represented by it, being, however, its usage conditioned by performing of experimental studies in order to confirm if it is correct or not. Keeping this in mind, the concrete viscoelastic behavior is assumed to be represented by the solid standard model, as an approximation of the reality. However, criteria from regulatory codes can be used in substituting of that model or even any other rheological models can be adopted.


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134 New Research on Knowledge Management Technology

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**6. Conclusion**

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 *Latvia*

**Agent Based Personal Knowledge**

**Management System Supported by**

Kaspars Osis1 and Janis Grundspenkis2

**Mobile Technology Cross-Platform Solution**

A historic transition from the industrial age to the information age has happened during several previous decades. The industrial age can be characterized by following: standardized information routines, usage of fixed procedures, and creation of material goods and consumption of them. In opposite the information age is focusing on creation and consumption of information, usage of ad-hoc approaches and non-standardized information for decision making. During this time of transition the Web has developed very rapidly along with information explosion. That has led to a notion of information overload. In organizations workspace environment and equipment is turning to be more sophisticated. Also learning environment is becoming more information and technology dense. As a result work is becoming increasingly complex (Wiig, 2004) requiring additional knowledge and skills to handle it. In turn that leads to recognition that knowledge has become a very important asset both for individuals and for organizations. Thus knowledge more increasingly has been seen as an active area of research. Notions of knowledge work and accordingly of knowledge worker have strengthen their positions out of transition from

Much of attention is focused towards researching different knowledge related areas. Knowledge management (KM) is one of such areas. It was first defined by Wiig in 1986 (Wiig, 1997). As per (Tiwana, 2002) KM has three basic processes: knowledge acquisition, sharing, and utilization. Knowledge is divided in two broad categories: tacit (i.e. tacit knowing) and explicit (i.e. explicit knowing) (Polanyi, 1966). There are also several other ways of classifying knowledge based on particular perspective of research (Maier, 2004). Majority of research is connected with knowledge that we do know and with knowledge we know that we do not know. However per (Frappaolo, 2004) there still remains knowledge which we do not know that we know and knowledge which we do not know that we do not know. Thus we propose a new concept of knowledge substance to encompass all knowledge

New technological solutions such as mobile technology and accordingly different types of mobile devices have appeared in addition of transition to the information age and development of the Web and the Internet. These devices have greatly influenced

**1. Introduction**

information to knowledge.

elements (KE) as a basis for further research.

*1Faculty of Engineering, Vidzeme University of Applied Sciences, Valmiera 2Institute of Applied Computer Systems, Riga Technical University, Riga*

Zach, M.; McKeen, J. & Singh, S. (2009). Knowledge management and organizational performance: an exploratory analysis. *Journal of Knowledge Management*, Vol. 13, No. 6, pp. 392-409, ISSN 1367-3270


**2. Cyanobacterial secondary metabolites by chemical structure and biosynthesis**

### **2.1. Nonribosomal peptides and polyketides**

Commonly occurring as secondary metabolites in cyanobacteria are nonribosomal peptides NRPs. These are produced using specialised nonribosomal peptide synthases (NRPS). NRPS contains modules, which are responsible for integrating specific amino acids into peptide chains. These modules consist of an adenylation domain, peptidyl carrier domain and a condensation domain, which incorporates proteinogenic and nonproteinogenic amino acids. Other domains can also be present for further modifications such as N-methylation, epimerization and cyclisation of the amino acid backbone, which gives rise to the intricate chemical structures produced [9]. Lyngbyatoxins, such as lyngbyatoxin-a (**Figure 1 (1)**), are biosynthesised *via* NRPS pathway in *Lyngbya majuscule* and comprise of an indolactam ring composed of L-valine, L-tryptophan and methionine [10]. Lyngbyatoxin-a is a dermatoxin with potent tumour promoting activity by activation of protein kinase C (PKC) [11].

Another large class of secondary metabolites found in cyanobacteria are the polyketides, which are biosynthesised from acetyl-CoA using polyketide synthases (PKS). Similarly to NRPS, PKS modules consist of a acyltransferase domain, acyl carrier protein domain and ketosynthase domain as well as additional domains for further modification [12]. The neurotoxin anatoxin-a (**Figure 1 (2)**) from *Anabaena* sp. Binds irreversibly to nicotinic acetylcholine receptors and is biosynthesised from L-proline using three PKS modules [9].

Hybrid metabolites are primarily derived from the attachment of polyketide or fatty acids using PKS to nonribosomal peptides in a natural combinatorial biosynthetic pathway to produce an array of chemical structures with specific roles and bioactivity. Microcystin-LR (**Figure 1 (3)**) is biosynthesised using multi-enzymes of NRPS and PKS modules and has potential as a lead compound for the treatment of cancer due to its cytotoxicity [13].

#### **2.2. Ribosomal peptides**

Ribosomal peptides (RPs) are synthesised on the ribosome and only use proteinogenic amino acid. They are similar to NRPs due to their posttranslational modifications. A prevalent group of ribosomal peptides found in cyanobacteria are the cyanobactin. These are cyclic and less commonly linear peptides formed through the post-ribosomal peptide synthesis (PRPS) pathway, which then undergoes post modifications to form their final complex structures [14], formally known as ribosomally synthesised and posttranslationally modified peptides (RiPP). Examples include the cyclic peptides patellamides, such as patellamide A (**Figure 1 (4)**) and the linear peptide aeruginosamide (**Figure 1 (5)**) [9].


**8. Conclusion**

A recent retrospective single center analysis in 38 PD and 268 HD patients describes a higher incidence of DGF and primary allograft failure for HD patients, but was no difference in acute

A case control study the incidence of DGF, defined as necessity to perform dialysis after transplantation, was analyzed in 117 PD and HD patients with a follow-up of 6 months. When matching the patients for age, sex, HLA compatibility PD-patients developed less DGF (23.1%) than HD patients (50.4%). In addition the decline of creatinine levels after transplantation was faster in PD patients. However, PD patients developed more acute rejection episodes, than HD patients, but creatinine levels after 6 weeks and 6 months were not different between the

Besides a bundle of published single center experiences with renal transplantation in PD patients we do have at least two registry studies reporting on the effect of pre-transplant

Data from the United Network of Organ Sharing on all cadaveric graft recipients who were dialysis-dependent at the time of transplantation were analyzed with respect to different outcomes in the immediate post-transplant period for HD or PD patients. In total more than 9000 patients were evaluated, showing that PD patients were on dialysis for a shorter period of time, were more likely to be white, had a better HLA match, and had a lower PRA. After adjusting for comorbidities, the odds of oliguria were 1.60 times higher in black HD patients compared with PD patients and 1.29 times higher in white HD patients. Also, the odds of requiring dialysis in the first week were 1.56 times higher in black HD patients versus PD patients and 1.40 times higher in white HD patients. The rate of acute rejection was similar during the first hospitalization. Therefore, the authors suggest that there may be an association between hemodialysis and delayed graft function assuming that differences in biocompati‐

A large retrospective analysis compared transplantation rates in PD and HD and outcomes after transplantation in more than 22000 patients from the years 1995 to 1998 in a US cohort. PD patients were more likely to be transplanted and their death censored graft failure was higher. However, mortality and overall graft failure were not different. Interestingly, the risk

Because of the in part contradictory data published in the literature we analyzed our own population of renal transplant recipients with the means of a retrospective case control study. Therefore, we chose 50 consecutive peritoneal dialysis patients transplanted since 1999. For match-pair-analysis, and as control group we selected the next hemodialysis patient subse‐ quently transplanted after each PD patient. Follow-up data were available with a maximum

Kruskal-Wallis Test and Chi-Square-Test were calculated, with assuming a p<0.05 as signifi‐

for early graft failure was higher for PD patients despite DGF was less common [39].

bility between the two modalities could potentially be responsible [38].

**7. Own experience with PD and renal transplantation**

of ten years after transplantation.

cant, for statistical purposes.

rejection episodes, long-term survivals, or renal function [36].

dialysis modality on renal transplant results.

198 Current Issues and Future Direction in Kidney Transplantation

groups [37].

Peritoneal dialysis (PD) is an established method of renal replacement therapy. PD and hemodialysis (HD) seem to be equivalent for long-term survival of the patients. Nevertheless, there is a beneficial effect of PD on patient survival after initiation of dialysis therapy. Probably, better preservation of residual renal function in PD patients compared to HD patients may be responsible for this effect.

Renal transplantation is the best treatment option for patients with endstage renal disease. The potential risk of infectious complications in PD patients after renal transplantation is attributed to the remaining PD catheter. However, this risk seems to be low and without effect on graft survival. For patients on HD a higher percentage of delayed graft function after renal trans‐ plantation is constantly reported in the literature. Nevertheless, long time patient and graft survival are not different between both treatment modalities.

Our own long-time clinical experience is congruent with the published literature and proves that peritoneal dialysis is a valuable treatment option for patients with end stage renal disease waiting for renal transplantation.


**1. Introduction**

[77] Vermorken AJ, Zhu J, Van de Ven WJ. Is curcumin for monoclonal gammopathy of undetermined significance without risk?-letter. Clin Cancer Res. 2010;16(7):2225. [78] Rajkumar SV. Preventive strategies in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Am J Hematol. 2012;87(5):453-54.

132 Multiple Myeloma - A Quick Reflection on the Fast Progress

Today, multiple myeloma (MM) can be defined as a heterogenous disease composed of different clinical conditions. The differences are a result of patient related factors (age, sex, comorbidity), disease related complications (renal failure, bone disease, neuropathy, throm‐ bosis) and biological characteristics (cytogenetics, lactate dehydrogenase level, plasma cell labelling index, beta2-microglobulin, gene expression profiles). The widely used international scoring system is a powerful tool for determining survival. However, it cannot be used for treatment planning. The biological determinants of disease determined by flourescein in situ hybridization (FISH) and/or conventional cytogenetics are better tools to stratify myeloma subgroups with different survival profiles. Thus these are better tools for designing therapeutic approaches. A risk stratification of newly diagnosed MM according to FISH/Karyotyping has been recently reviewed by Rajkumar (Rajkumar, 2012).

High dose melphalan supported by autologous stem cell transplantation (ASCT) can increase response rates and prolong progression free and overal survival compared to conventional chemotherapies (Attal et al., 1996; Child et al., 2003; Fermand et al., 2005; Koreth et al., 2007). The initial induction regimen is chosen according to whether the patient is eligible or ineligible for a subsequent HDT-ASCT as well as the risk stratification of the patient. Advanced age or significant comorbidity are important limitations for ASCT. High dose therapy has been generally considered for patients ≤ 65 years. However, in medically fit patients, this can be extended up to age 70-75 years. Achievement of high quality responses (VGPR, CR/nCR) at the time of transplantation has been demostrated to be an early predictor of improved outcomes after ASCT (Harousseau et al., 2009; Chanan-Khan&Giralt, 2010). Elderly patients or patients ineligible for transplantation may also benefit from chemotherapy by achieving high quality responses preferably CR in terms of progression free survival (PFS) and overall survival (OS). As such, the choice of induction therapy is crucial for survival for most patients with MM. The emergence of novel agents (thalidomide, lenalidomide and bortezomib) and

© 2013 Bakanay and Beksac; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

incorporation of these agents in to the current induction protocols has increased the rate of CR and at least VGPR before ASCT and significantly improved the OS in MM (Kumar et al., 2008; Kastritis et al., 2009). This opened a new area of debate 'upfront' versus 'delayed' transplantation. However, current recommendations from experts is that high dose therapy supported by autologous stem cell transplantation (HDT-ASCT) should be the standard of care for eligible patients (Ludwig et al., 2011).

( ≥PR; 76% vs 52%, respectively, p<0.001) (Cavo et al., 2005). Based on the subsequent phase III studies which confirmed the superior response rates achieved with thalidomide containing regimens compared with the conventional induction therapies, TD regimen received an accelerated approval in patients with newly diagnosed MM (Rajkumar et al.,2006; Rajkumar et al., 2008). The summary of the phase II-III studies involving thalidomide-based induction

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 135

Rajkumar et al. in a randomized double blind placebo-controlled study, provided the first data on significant prolongation of time to progression (TTP) and progression free survival (PFS) with TD compared with dexamethasone alone in patients with newly diagnosed MM ( 14.9 vs. 6.5 months; p<0.001). However, this study was not powered enough to compare the differences in OS (Rajkumar et al., 2008). Barlogie et al. randomized their patients to receive two cycles of high dose melphalan based chemotherapy each supported with ASCT (Total therapy-2) with or without thalidomide added from outset until disease progression and reported that addition of thalidomide improved the rate of CR and EFS but failed to prolong OS (Barlogie et al., 2006). In a retrospective pair-matched analysis, thalidomide incorporated to induction regimen and continued until the second ASCT revealed significantly improved clinical outcomes and a trend towards extended OS at 5 years ( 69% vs. 53%; p=0.07) (Cavo et al., 2009). The HOVON-50 trial incorporated doxorubicin to TD (TAD) and compared this regimen with conventional VAD as frontline therapy showing a better response before and after HDT-ASCT (Lokhorst et al., 2008). After long term follow-up, the TAD arm folowed by thalidomide maintenance after ASCT was able to induce longer event free survival compared to the VAD arm folloowed by interferon ( 34 vs. 22 months; p<0.001) but this did not translate into an improved OS (73 vs. 60 months; p=0.77). Which can be explained by a decreased survival from relapse while on thalidomide maintenance (Lokhorst et al., 2010). A recent MRC Myeloma IX randomized trial compared oral combination therapy CTD (cyclophosphamide, thalidomide, dexamethasone) with oral cyclophosphamide incorporated into conventional VAD (CVAD). Significantly superior response rates were attained with CTD compared with CVAD both after induction and after ASCT. CTD could not significantly prolong PFS or OS but longer followup suggests a trend towards a late OS advantage(Morgan et al., 2012).

Thalidomide does not compromise successful harvest of stem cells. However, it is associated with an increased risk of venous thromboembolism (VTE) and sensory peripheral neuropathy (PNP). Without thromboprophylaxis, the thrombosis risk is 15-17%, which is more frequent during the first 3 months of treatment and warrants prophylactic anticoagulation. Peripheral neuropathy improves within 3-4 months after dose reduction or cessation of the drug in most patients. However, thalidomide induced PNP may be irreversible if appropriate action is not taken when an emerging neuropathy is encountered. Thalidomide at low dose may be effective in the management of patients with renal failure, but close monitorization for complications is required in patients with serious renal and hepatic failure. Major thalidomide toxicities and the summary of the supportive care guidelines regarding the approach to PNP is given in

It is clearly understood that thalidomide-based regimens have produced better post-induction response rates (≥PR; 63-82.5%) and PFS than conventional high dose dexamethasone based

tables 7 and 8, respectively (Beksac et al., 2008, Bird et al., 2011).

regimens is shown in table-1.


2.3.3. Inhibition of Albumin Denaturation (IAD)

The anti-inflammatory efficacy was evaluated using an inhibition of albumin denaturation (IAD) in vitro study. Sakat method [14] with a modest modification [15] was used to finish the analysis.

Human albumin was used in the experiment. In distilled water, an albumin (1%) solution was prepared (pH 7.4). The tested compounds/standard were first dissolved in 1.2 mL DMF and PBS up to 25 mL, resulting in a stock solution with a final concentration of 1000 μg/mL. Then, in PBS, a series of working solutions with varying concentrations (20–500 μg/mL) were prepared. The reaction mixture contained 2 mL of different concentrations of test sample/standard and 1 mL of albumin (1%). The mixture was incubated at 37 ◦C for 15 min before being heated in a water bath at 70 ◦C for 15 min. After cooling, the turbidity was measured with a spectrophotometer at 660 nm (Camspec M508, Leeds, UK). The experiment was carried out three times. The inhibition of albumin denaturation (IAD) was calculated as a percentage of the control. The control sample was albumin dissolved in distilled water at the same concentration.


**5. Discussion**

### *5.1. Reduction of Crime at a Moderate Level*

The Safe City Program is capable of reducing street crime at a moderate level and is less sensitive in predicting the outcome of all the good e fforts made by various agencies. Amongst the 27 initiatives in the Safe City Program, only "access control","full council meeting", and "city status website" could predict the outcome of reducing street crime significantly. However, the impacts of these three initiatives were not powerful enough in reducing street crime with β coe fficient values 0.109, −0.091, and 0.021, indicating low sensitivity. In detail, "access control" is an important concept emphasized in CPTED [18]. Controlling the accessibility of a road or an area contributes to a sense of territoriality, resulting in e ffective crime prevention [19]. This result is in line with [76], which tested the relative effects and found the strongest direct e ffect of territorial variables on crime prediction. Humans are used to establishing hierarchies or territories that range from private to semi-private to public space by marking their turf using fences, signs, and plain border definition. The most common are fencing and walling for separating physical space to create safety as well as a sense of safety [19].

For "full council meeting", the authors note that it is crucial to hold the meetings to sustain the Safe City Program because important decisions are usually made during council meetings. Out of the 27 initiatives, most of the respondents were unaware of the "fixed agenda on Safe City Program at full council meeting" at the local authority level as a platform for inter-agency discussions and collaboration planning. The Federal Government has defined the Safe City Program in Malaysia as city-based, involving cross-ministry and agency partnerships, being led by the mayor of each local authority with a fixed agenda for the monthly council meetings, and having the aim of reducing street crime through target hardening, physical initiatives, and public involvement [7]. For the "set up city status websites at local level", the result a ffirming its significant contribution to crime prevention suggests that this initiative should be included in future safe city programs, as this initiative was ignored in the second version of the Safe City Program 2009 in Malaysia. Besides, it can create online awareness by providing a long-term reference with favorable impacts.

### *5.2. Reduction of Fear of Crime at a Weak Level*

None of the elements in the Safe City Program was able to predict the outcome of reducing the fear of crime significantly in multiple regression modelling. Hence, the study concludes that the Safe City Program is acceptable at a weak level in increasing perceived pedestrian safety and reducing the fear of crime, particularly among city users in the Kuala Lumpur CBD area.

The purpose of the study was to identify e ffective general factors concerning fear and crime prevention within a Safe City Program. Thus, demographic variables like gender were not set as control variables in the regression analysis, even though female respondents revealed higher levels of fear and tended to be actual victims of street crime.

Based on the holistic safe city program thesis formed in Figure 2, the authors suggest that the Safe City strategies should be well integrated since separate implementations of each initiative will not be able to reduce crime or the community's perception of disorder.

### *5.3. O*ff*enders' Perspectives of Curbing Crimes and Fear of Crime*

Among the three significant factors, i.e., "access control", "full council meeting", and "city status website", all of these are from the e fforts of the guardians such as the local authorities, and police forces. In terms of e fforts from the potential victims from communities, none of the strategies is significantly found in this study. Thus, a question arises to what other contributing factors that will be able to fill in the gap of sustaining safe city program. Since the factors in reducing fear and crime may not be lying under the factors of "capable guardians" (authorities), and "suitable victims" (community), but possible strategies could be view/search from the factors of "likely o ffenders". This suggestion is derived from [2] who mentioned that guardians, victims, and o ffenders are three important actors in everyday crime prevention theories. Thus, from the o ffenders' perspective, it could be divided into two groups, namely those are potential, and those already an o ffender. Education to the former group is essential, such as cultivating ideas of living in a harmonious life, family, and society, and understanding of the punishment to o ffenders and wrong social impression on those criminals. If lesser people do not/potentially perform crimes, then it will not/be less likely to impose fear to the community, or deeply commit any crimes. As for the already-o ffenders, support and rebuild after-criminal life is essential such as counselling support in jail, social support, acceptance, and opportunity in having decent jobs for everyday expenses and living [13].

### *5.4. Victims*/*Communities Perspective Needed to Be Enhanced*

The authors posited that indicators for victims and communities might be under-explored in the limited literature covering CPSD [29–31,77]. The authors suggest that for those "already victims", society needs to study the social problems that lead to crime, build more robust psychological health, heal from fear, accept fear reality, positively face life after the crime, and help them back to a safe society. Since the deeper issue facing is although statistics showed that crime rate decrease, but fear is deepening. In other words, the real quantity of crimes happening might be low, but other none "real" crime or non-police reported cases such as harassment, threatening will "impact" on third parties. Meaning, a direct victim might be one single person, but the people around that victim, such as those family members, and the victims' communities, may face "fear in the heart", as though they will be mentally more cautious and preventing themselves from becoming a real victim. Thus, the topic of "fear of crime" should be highlighted more in a safe city program and solutions from responsible communities should be explored further than the existing superficial engagement of communities in sustaining a safe city environment.


**Author details**

António Gerson Bastos Francisco, Isaura da Conceição Almeida Lopes, Amílcar Bernardo Tomé da Silva and Henrique Cotchi Simbo Muela\* Department of Physiology of Faculty of Medicine, Agostinho Neto University, Luanda, Angola

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© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


**Author details**

Delfín Ortega-Sánchez\* and César Barba-Alonso University of Burgos, Burgos, Spain

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*What Predictors Explain Holocaust and Human Rights Education in Spain? A Study with… DOI: http://dx.doi.org/10.5772/intechopen.112553*