**3.2 GRKs in heart failure**

Myocardial GRK2 and GRK5 have been shown to be involved in the pathophysiology of heart failure [40]. Indeed, several evidences highlight GRK2 as well as GRK5 as the key regulators of β-adrenoceptor [59, 60]. Of importance, recently published paper describes that GRK2 and GRK5 are new therapeutic targets for pathological cardiac hypertrophy and may attenuate morbidity and mortality rates [61]. Dysregulation of β-adrenoceptor is a pathological characteristic of heart failure; in particular, the receptors are considerably downregulated and desensitized as a result of the upregulated levels of GRK2 and GRK5 [16]. Enhanced expression and activity of GRK2 are associated with the loss of β-adrenoceptor functions that induces deleterious effects in the heart functionality contribute to progression of heart failure [62]. Overstimulation of β-adrenoceptor as a subsequent of continuous sympathetic activation, resulting in GRK and β-arrestins induced desensitization and downregulation of β-adrenoceptor [63]. Initially, this process is adaptive response to overcome receptor

overactivation. However, prolonged excessive stimulation mediated receptor downregulation has been reported inducing harmful effect to the heart and consequently heart failure development [63, 64]. Notably, alterations in GRKs have been observed in heart failure [39, 65, 66]. Indeed, several evidences highlight GRK2 as well as GRK5 as the key regulators of β-adrenoceptor [59, 60]. Several reported evidence have shown that GRK2 expression and activity are significantly increased in the failing heart [39, 67, 68]. Enhanced GRK2 expression and altered functionality have been found in heart failure status [39, 65, 66, 69]. Moreover, up-regulation of GRK2 level was detected in end-stage dilated heart failure patient [65]. Even though the mechanism of β-adrenoceptor overstimulation mediated GRK2 upregulation is not clearly understood, published reports show that GRK2 dysfunction plays an essential function in the pathophysiology of heart failure [70] suggesting that alteration in GRK2 function participates in heart failure pathology. Altered GRK2 expression or activity appears to contribute to disease progression through various molecular mechanisms. Therefore, targeting GRK2 expression or inhibition of its activity has been suggested as a therapeutics strategy for treatment of heart failure patients [71, 72].

Reported evidence shows that overexpression of a peptide inhibitor of GRK2; carboxy terminal domain (βARKct) which lacks to membrane translocation function inhibits GRK2 activity and prevents desensitization of the receptors resulting in restoring of β-adrenoceptor function and enhanced cardiac contractility in experimental animals of heart failure [73–75]. Moreover, Gβγ-GRK2 inhibition reduces pathological effect of myofibroblast activation. Thus, Gβγ-GRK2 inhibition might be a potential therapeutic strategy to attenuate pathological myofibroblast activation, interstitial fibrosis, cardiac remodeling, and progression of heart failure [76].

It has been reported that cardiac dysfunction could be attenuated by inhibition of GRK2 activity [62]. Interestingly, it has been reported that paroxetine, selective serotonin re-uptake inhibitor (SSRI) approved by FDA for treatment of depression, significantly inhibited GRK2 kinase activity [49, 77, 78]. Published studies showed capability paroxetine as GRK2 inhibitor in reversing cardiac remodeling in experimental models of acute myocardial infarction [79, 80]. Therefore, paroxetine may perhaps be used as a therapeutic approach for targeting GRK2 catalytic activity and potentially provide a protective role against cardiac hypertrophy development via its function as GRK2 inhibitor.

GRK5 another GRK member that mediates phosphorylation and desensitization of β-adrenoceptor is well known to regulate heart functions [72]. Several studies suggest that GRK5 plays a crucial role in various cardiovascular diseases. For instance, previous studies show that GRK5 overexpressing mice developed cardiac hypertrophy, which rapidly progressed to heart failure [81]. Moreover, GRK5 knockout mice showed attenuated hypertrophic responses [82]. Furthermore, GRK5 overexpressing mice showed an alteration in myocardial performance including attenuation of contractility, cardiac output, stroke work, and stroke volume [83]. Of note, GRK5 levels were shown to be markedly elevated in heart failure patients and patients with left ventricular volume overload disorders and dilated cardiomyopathic hearts [84–86].

GRK5 overexpressed transgenic mice exhibited enhanced susceptibility to pressure overload-induced cardiac hypertrophy and cardiac dysfunction [87]. Furthermore, cardiac-specific GRK5 transgenic mice demonstrated reduced cardiac function and increased adverse cardiac remodeling in a myocardial infarctioninduced heart failure mice model [64]. On other hand, heart hypertrophic responses were attenuated in GRK5 knockout mice [88], these studies demonstrated the possible functions of GRK5 in pathological cardiac remodeling development. Interestingly,

#### *DOI: http://dx.doi.org/10.5772/intechopen.105403 G Protein-Coupled Receptor Regulation in Cardiovascular Disease: Role of G Protein-Coupled…*

several lines of evidence show that GRK5 can translocate to the nucleus, exerting its non-canonical functions. For instance, it was shown that GRK5 in the cardiomyocyte nuclei acts as a class II histone deacetylase (HDAC) kinase, phosphorylating HDAC5 and leading to de-repression of myocyte enhancer factor 2 (MEF2)-mediated hypertrophic gene transcription [81, 89]. In addition, it was demonstrated that GRK5 interacts with hypertrophic transcription factors like nuclear factor of activated T cell (NFAT) and nuclear factor κ-B (NF-κB) [81, 87, 90, 91]. These studies indicate that GRK5 has a major role in the pathogenesis of the cardiovascular disorders and GRK5 might be a therapeutic target for heart failure. Recently, it has been demonstrated that KR-39038, a novel small molecule inhibitor of GRK5, significantly inhibited cellular hypertrophy and HDAC5 phosphorylation in neonatal rat ventricular myocytes. This inhibitor was able to minimize the left ventricular weight, improve cardiac function and ameliorate myocardial remodeling in animal model of heart failure [92]. Another important agent proposed as a GRK5 inhibitor is an anti-inflammatory and anti-allergic immunomodulator, named amlexanox [93]. This agent was able to inhibit GRK5 induced MEF2 activation in neonatal rat ventricular myocytes and inhibit GRK5 mediated HDAC5 phosphorylation in cellular model of cardiac hypertrophy [93, 94].

#### **3.3 GRKs in myocardial infarction**

It has been reported that GRK2 expressions upregulated in peripheral blood lymphocytes in patients with acute ST-segment elevation myocardial infarction. Enhanced lymphocyte GRK2 expressions are associated with worse cardiac functionality. These studies indicate that GRK2 could be predictive of myocardial remodeling after myocardial infarction [95, 96]. Enhanced GRK2 levels and activity are deleterious to post-ischemic myocardium in acute ischemia/reperfusion (I/R) injury animal model [97]. It has been reported that GRK2 peptide inhibitor; βARKct provides cardioprotective effect, which modulate GRK2-mediated PI3K-Akt-NOS signaling pathway in the ischemic heart which validates GRK2-related effect on survival and apoptotic signaling in the ischemic heart [97]. βARKct expression mediated GRK2 inhibition modulate Akt downstream pro-survival signaling such as reduced Caspase-3 activity, increased eNOS activation and NO production and then reduced apoptosis and cell death [97]. Furthermore, decreasing GRK2 expression in cardiomyocytes attenuate myocyte apoptosis possibly via Akt/Bcl-2 mediated mitochondrial protection and limits I/R- provoked injury and improves post-ischemia recovery in the heart [98]. Additionally, it has been reported that fibroblast specific GRK2 knockout has a protective effect after myocardial I/R injury in mice. GRK2 fibroblast knockout mice decreased the infarct size, increased ejection fraction, preserved cardiac function, and also reduced tumor necrosis factor-α expression, fibrotic gene expression, and fibrosis development [99].

## **4. Conclusions**

Cardiovascular diseases are a leading cause of death worldwide. The pathophysiological mechanisms are regulated by a GPCR mediated complex network of transduction pathways. The functions of GRKs, negative regulators of GPCR, are not limited to receptors desensitization. It is expanded further to activations of many transductions in non-classical manner. As the expression and kinase activity of GRK2 and GRK5 are altered in cardiovascular diseases, Therefore, better knowledge of the

transduction events which mediated by up-regulated GRK2 and/or GRK5 in terms of the expression, activity, and localization would help to develop a novel strategy for targeting their expressions or inhibiting activity. This will participate in building a knowledge-based platform identifying a new therapeutic target to prevent the progression of cardiovascular diseases. Many different approaches could be applied, including small molecule inhibitors, gene therapy, and the use of advanced drug delivery systems to potentially prevent the progression of cardiovascular disease. Overall, GRKs play an important role in cardiovascular diseases progression. Pharmacological intervention of GRK5 as well as GRK2 would provide a novel possible future target for cardiovascular disease progression prevention.


*Review* **Development of Macozinone for TB treatment: An Update**

**Vadim Makarov 1,\* and Katarína Mikušová 2**

**\*** Correspondence<EMAIL_ADDRESS>
Received: 5 March 2020; Accepted: 25 March 2020; Published: 26 March 2020

**Abstract:** Macozinone, a piperazine-benzothiazinone PBTZ169, is currently undergoing Phase 1/2 clinical studies for the treatment of tuberculosis (TB). In this review we summarize the key findings that led to the development of this compound and to identification of its target, decaprenylphospohoryl ribose oxidase DprE1, which is involved in the synthesis of the essential arabinan polymers of the cell wall in a TB pathogen, *Mycobacterium tuberculosis*. We present the results of the pilot clinical studies, which raise optimism regarding its further development towards more efficient TB drug regimens.

**Keywords:** macozinone; DprE1 inhibitor; clinical studies


Preface

**Section 2 Diabetes and Oxidative Stress 91**

Chapter 7 **Savior of Diabetes: Antioxidants 107** Zar Chi Thent and Azian Abd Latiff

and Cristina Campoy

Chapter 10 **Exercise and Diabetes Mellitus 167** Asmare Yitayeh Gelaw

**Mellitus 145**

Valdebenito

**Diabetes 93**

**VI** Contents

Chapter 6 **Trace Elements Modulates Oxidative Stress in Type 2**

**Section 3 Updates and Novel Approaches of Combating Diabetes 119**

Estefanía Diéguez Castillo, Ana Nieto-Ruíz, Mireia Escudero-Marín

Chapter 8 **Influence of Glycaemic Control on Cognitive Function in Diabetic Children and Adolescents 121**

Chapter 9 **Medical Nutrition Therapy for Special Groups with Diabetes**

Chapter 11 **New Insights into Alleviating Diabetes Mellitus: Role of Gut Microbiota and a Nutrigenomic Approach 183**

> Lissé Angarita Dávila, Valmore Bermúdez Pirela, Nadia Reyna Villasmil, Silvana Cisternas León, Waldo Díaz-Vásquez, Ma Cristina Escobar, Paula Carrasco, Samuel Durán, Kristian Buhring, Rodrigo Buhring, Constanza Bugman, Virginia Céspedes, Marcell Gatica, Diana Rojas-Gómez, Marion Guerrero Wyss and Francisco

Muhammed Kizilgul, Meltem Mermer and Bekir Ucan

Ines Gouaref and Elhadj-Ahmed Koceir

Diabetes is a disease that has caused immense economic burden across both the developed and developing countries as a whole. There is no permanent cure in sight, and the preva‐ lence of the disease appears to be increasing beyond control. Novel means of control have been recommended from time to time, but the measures seem to fail with new forms and figures of the disease surfacing just as frequently. Dietary control appears to be the more effective means nevertheless, although a multitude of other factors have been highlighted through research as being the causes.

This book primarily focuses on three aspects: (1) dietary interventions for diabetes, (2) dia‐ betes and oxidative stress, and (3) updates and novel approaches of combating diabetes. There have been many publications that have appeared recently on diabetes and dietary in‐ terventions. However, it is hoped that this book serves as an update in highlighting gaps and voids as well as providing insights into novel developments of the disease.

I would like to extend my most sincere gratitude to the authors who have kindly contribut‐ ed chapters to this book, without whom this project would not have been a success. Also, my heartfelt thanks go to IntechOpen Publishing with whom I have been working for quite a number of book projects of similar nature. Last but not least, my appreciation goes to Ms. Kristina Kardum, the Publishing Process Manager assigned to this book, who has rendered her utmost support in putting the material together.

In conclusion, it is hoped that this book will be of value to both scientific and nonscientific communities in making informed choices about diabetes and possible dietary interventions in preventing its occurrence.

> **Dr. Viduranga Waisundara** Department of Food Technology Faculty of Technology Rajarata University of Sri Lanka Mihintale, Sri Lanka

**Section 1**

**Dietary Interventions for Diabetes**

**Dietary Interventions for Diabetes**

**Chapter 1**

**Provisional chapter**

**Introductory Chapter: The Need for Dietary**

regimental level, such as diet, exercise, and even environmental changes.

along with the improvements in aerobic fitness and dietary intake.

**Introductory Chapter: The Need for Dietary**

DOI: 10.5772/intechopen.72897

Noncommunicable diseases pose a significant challenge to most of the high-income and lowincome countries, with growing numbers of people experiencing the health and economic burden of one or more chronic disease conditions. As such, the incidence of diabetes has been on the rise worldwide. The disease may be associated with the poor quality of life and the risk of developing long-term comorbidities and a higher standard rate of mortality. Healthcare professionals are burdened with the task of motivating patients to follow appropriate dietary and exercise guidelines as well as to take insulin injections to improve the regulation of diabetes, and thereby prevent the occurrence of diabetic micro- and macrovascular complications. At present, various interventions are being discussed on an authoritative and

The more frequently discussed intervention of all is dietary change. Food habits have been shown to be related to the development and management of diabetes—both types 1 and 2, especially through means of influencing glycemic control and insulin resistance. Dietary patterns, rather than individual nutrients, such as the Mediterranean diet, Western diets, and traditional diets, have recently received a great deal of attention in assessing the association between diet and health. In general, to improve glycemic control, a diet rich in fiber and low in saturated fat, sugar, and salt is recommended. Based on considerable medical literature and clinical practice, it has actually been shown that the prognosis of individuals with type 2 diabetes, in particular, is improved with better diet and resulting weight loss. For instance, according to the systematic review by Aguiar et al. [1], it was found that interventions of multicomponent lifestyle involving diet, aerobic exercise, and resistant training were sufficient in inducing modest weight losses and imparting minor improvements in glycemic control,

> © 2016 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,

© 2018 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.

and reproduction in any medium, provided the original work is properly cited.

**Interventions for Diabetes**

**Interventions for Diabetes**

Viduranga Yashasvi Waisundara

Viduranga Yashasvi Waisundara

http://dx.doi.org/10.5772/intechopen.72897

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter


**Review of the Impact on Water Quality and Treatment Options of Cyanide Used in Gold Ore Processing Review of the Impact on Water Quality and Treatment Options of Cyanide Used in Gold Ore Processing**

Benias C. Nyamunda Benias C. Nyamunda

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

http://dx.doi.org/10.5772/65706

### **Abstract**

Cyanide has been widely used in several industrial applications such as electroplating photography, metal processing, agriculture, food and the production of organic chemicals, plastics, paints and insecticides. The strong affinity of cyanide for metals such as gold and silver makes it suitable for selective leaching of these metals from ores. Cyanide is highly toxic; hence, there is a need to regulate and limit the amount of cyanide that may be discharged into the environment. Technologies focusing on the use of physical, chemical and biological methods have been developed to reduce the concentration of cyanide and cyanide compounds in wastewaters to permissible limits. This chapter reviews the current and emerging technologies for treatment of cyanide from wastewaters generated in gold mining processes.

**Keywords:** cyanide, gold, leaching, oxidation, wastewater


**INSIGHTS FROM ANIMAL REPRODUCTION**

Edited by **Rita Payan Carreira**

#### **Insights from Animal Reproduction**

http://dx.doi.org/10.5772/60829 Edited by Rita Payan Carreira

#### **Contributors**

Alexandre Rodrigues Silva, Alexsandra Fernandes Pereira, Gabriela Liberalino Lima, Ana Liza Paz Souza, Gislayne Christianne Xavier Peixoto, María-José Carrascosa Argente, Marek Switonski, Izabela Szczerbal, Malgorzata Duda, Malgorzata Grzesiak, Malgorzata Knet-Seweryn, Zbigniew Tabarowski, Sandhya Dungdung, Arpita Bhoumik, Sudipta Saha, Prasanta Ghosh, Kaushik Das, Sandipan Mukherjee, Debjani Nath, Jitamanyu Chakrabarty, Chanakyanath Kundu, Bijay Shankar Jaiswal, Mahitosh Mandal, Arunima Maiti, Saswati Banerjee, Madhumita Roychowdhury, Debleena Ray, Debdas Bhattacharyya, Gopal Chandra Majumder, Vicente Freitas, Luciana Melo, Dárcio Teixeira, Maajid Bhat, Irina Aleksandrovna SEROVA, Lyudmila Evgenievna ANDREEVA, Oleg Leonidovich SEROV, Francisco Pelegri, Yoon-Won Kim, Sungman Park, Sang-Kon Lee, Ricardo Romão, Carla Marques, Elisa Bettencourt, Rosa Pereira, Maria Dos Anjos Pires, Hugo Vilhena, Sónia Miranda, Miguel Tavares Pereira, Fernanda Seixas, Ana Laura Saraiva

#### **© The Editor(s) and the Author(s) 2016**

The moral rights of the and the author(s) have been asserted.

All rights to the book as a whole are reserved by INTECH. The book as a whole (compilation) cannot be reproduced, distributed or used for commercial or non-commercial purposes without INTECH's written permission. Enquiries concerning the use of the book should be directed to INTECH rights and permissions department (permissions@intechopen.com).

Violations are liable to prosecution under the governing Copyright Law.

Individual chapters of this publication are distributed under the terms of the Creative Commons Attribution 3.0 Unported License which permits commercial use, distribution and reproduction of the individual chapters, provided the original author(s) and source publication are appropriately acknowledged. If so indicated, certain images may not be included under the Creative Commons license. In such cases users will need to obtain permission from the license holder to reproduce the material. More details and guidelines concerning content reuse and adaptation can be foundat http://www.intechopen.com/copyright-policy.html.

#### **Notice**

Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book.

First published in Croatia, 2016 by INTECH d.o.o. eBook (PDF) Published by IN TECH d.o.o. Place and year of publication of eBook (PDF): Rijeka, 2019. IntechOpen is the global imprint of IN TECH d.o.o. Printed in Croatia

Legal deposit, Croatia: National and University Library in Zagreb

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Insights from Animal Reproduction Edited by Rita Payan Carreira p. cm. ISBN 978-953-51-2268-5 eBook (PDF) ISBN 978-953-51-7279-6


**3.5 Other clinical features**

*Neurodevelopment and Neurodevelopmental Disorder*

DDR controlled pathway and vascularization [121, 122].

**3.3 Immunodeficiency and inflammation**

**3.4 Radiosensitivity and increased cancer risk**

**3.2 Telangiectasia**

[117]. Paused RNA polymerase sites activate ATM, which then elicit a response that includes interactions with spliceosome components that may mediate R-loop resolution [118]. In the cerebellum, the combination of high levels of oxidative stress with high demands of transcription may produce an abnormally high amount of paused transcription sites due to DNA damage. In the absence of ATM, R-loops may not be adequately resolved, eventually creating a scenario incompatible with cell life.

The localized abnormal vascular formations that A-T patients show in several parts of their bodies—particularly in the eyes—is one of the most obvious and yet least investigated phenotypes of the disease [119]. Telangiectasia is highly prevalent in A-T, only missing in patients bearing mild ATM mutations that maintain some residual protein function [120]. Very little is known about the molecular mechanism that prompts telangiectasia when ATM is absent or dysfunctional. The current model proposes that oxidative stress caused by a lack of functional ATM may upregulate HIF1A levels, a hypoxia-activated transcription factor that can induce vascularization by increasing the levels of angiogenesis factor VEGF [120]. Intriguingly, SAPS also induces secretion of VEGF, suggesting a link between this

A-T patients can show low levels of at least one type of immunoglobulin, inadequate antibody responses to infections and abnormal T and B lymphocyte counts [123, 124]. These phenotypes can be attributed to the roles that ATM has in regulating NHEJ during V(D)J recombination and class-switch recombination (CSR), two recombination processes required to produce antibody diversity during adaptive immunity. Both V(D)J and CSR involve induction of programmed DSBs followed by ATM-aided NHEJ repair [125]. For instance, during V(D)J ATM localizes to break sites and regulate NHEJ components, while p53BP1 phosphorylation by ATM is a crucial event during CSR. The regulatory roles that ATM exerts on these two processes are likely to be extensive and involve other DDR pathways. In A-T patients with immunodeficiencies, programmed DSBs remain unrepaired, and their persis-

There is growing evidence that the innate immune response may be tightly linked to several clinical manifestations observed in A-T patients. Lack of ATM creates high levels of ROS and oxidative damage, which is known to induce pro-inflammatory cytokines [111, 129, 130]. ATM-deficient cells cannot trigger pexophagy and other forms of autophagy to counteract the negatives effect of oxidative damage, further compounding the problem [91]. Persistent genotoxic stress can, therefore, create chronic inflammation in A-T patients, a condition linked to several A-T symptoms: increased levels of cardiovascular and autoimmune diseases, insulin resistance, and aging. Tellingly, the immune response contributes to neurodegeneration during Alzheimer's disease, possibly suggesting that in A-T patients, chronic inflammation may also contribute to neurodegeneration in cerebellar tissues suffering high levels of genotoxic stress [131].

Several DDR pathways contribute to the increased cancer risk seen in A-T patients. The inability of A-T cells to coordinate DNA repair with other DDR pathways can leave unrepaired genomic injuries and elevate the number of mutations in cells—including perilous DSBs—rendering cells highly sensitive to ionizing

tence can cause severe T and B-cell developmental problems [126–128].

**76**

Both male and female A-T patients show infertility due to abnormal meiosis progression. During meiosis, ATM controls the number of DSBs created by SPO11 and ensures their even distribution in the genome [134]. This is achieved by recruiting ATM to SPO11-generated DSBs, which inhibits the formation of further cuts in the vicinity of break sites. Mice models have shown a meiotic arrest in prophase I, faulty synapsis, and chromosome fragmentation leading to massive germ cell loss [107, 135], suggesting that the loss of ATM's roles during meiosis is the underlying cause of infertility in A-T patients.

A-T patients can suffer from insulin resistance and thus, have a higher risk of developing diabetes, a clinical feature that they share with carriers of the disease. The cause for this phenotype is likely to be multifactorial, but it is well-defined that ATM phosphorylates several targets—e.g., translation regulation 4E-BP1—in response to insulin [25]. Furthermore, a lack of fully functional ATM correlates with an inhibition of IRS1 (insulin receptor substrate 1) and low levels of IGF1-R (insulin-like growth factor1 receptor), suggesting possible mechanisms causing this clinical feature [94, 136, 137].


*3.2.5 Negative attitudes of traumatic health care providers towards a traumatic abdominal patient*

Saving lives and avoidance of the occurrence of complications for traumatic abdominal patients would be achieved if all trauma care providers approach to them with good attitude. Negative attitude of trauma care providers towards a traumatic abdominal patient can be marked by various factors. For instance, neglecting the patient, failure to follow standards of trauma care, abusive language etc. as per observation of an author working in one of developing countries, negative attitudes of health workers towards patients is real fact. As such many innocent traumatic patients (including those with abdominal trauma) continue to die and some survival patients develop numerous complications.


**3. Energy profile and transitions**

SDG 7 obligates member states to ensure access to affordable, reliable, sustainable, and modern energy for all. The Government of Uganda recognizes that energy is catalytic to economic and social development and that there is a direct relationship between per capita consumption of electricity to GDP and overall prosperity [16]. Recognizing, the link between energy and development, the Uganda Vision 2040 and NDP III (2020/21–2014/15) recognizes the critical role of electricity in the attainment of their key development priorities of economic growth, job creation and inclusive development. However, although Uganda is rich in energy resources, access to affordable, reliable electricity remains a major constraint to the country's socio-economic transformation and achievement of sustainable development. The energy resources potentials include renewables such as hydropower, biomass, solar, wind and geothermal, but also fossil fuels such as peat, and oil and gas, and these resources and are fairly distributed throughout the country.

Uganda has one of Sub-Saharan Africa's largest hydroelectric potential estimated to be well over 4,500 MW [2, 17] with a big portion of this potential lying along the Nile River, which increases dependency on the Nile. Renewable energy resource potential, estimated to be well over 7,500 MW, includes hydro, geothermal (450 MW), biomass cogeneration (1,650 MW), wind and peat (300 MW), as well as 460 million tons of biomass standing stock with a sustainable annual yield of 50 million tons, and an average of 5.1 kWh/m2 of solar energy [2, 17, 18]. As at 2019, the country's energy mix was dominated by biomass energy (88%) consumed mainly through firewood and charcoal, electricity (2%) and oil or fossil fuels at 10% [19], and energy consumption has been on rise over the years (see **Figure 2**).

The dominance of biomass energy in the country's energy mix remains socioeconomic and environment challenge; hindering socio-economic transformation, a source of indoor air population with the associated health challenges, a driver to increased deforestation and forest degradation and a source of GHG emissions. However, limited availability of alternative affordable clean energy sources for cooking means that biomass will remain Uganda's most important source of cooking energy in the foreseeable future. Currently, Uganda depends on imported

*The Energy and Climate Change Nexus in Uganda: Policy Challenges and Opportunities… DOI: http://dx.doi.org/10.5772/intechopen.99353*

**Figure 2.**

*The trends of contribution main energy by type (data sourced from MEMD and ERA 2010–2019).*

oil/petroleum with the annual imports of petroleum products having increasing over the years e.g. from 1.4 billion liters in 2014 to 2.1 billion in 2018 [10]. Transport consumes 90% of the imported petroleum products, while 6% is consumed as kerosene in households consumes mainly for lighting [19].

Uganda depends on hydropower for its electricity accounting for more 80% of the country's electricity supply, the other sources being thermal (8%), cogeneration (8%) and solar (4%). The grid installed electricity generation capacity has been increasing over the years from 183 MW in 1997 to 1,246 MW in 2019, while the energy losses in the distribution segment have reduced from 34% in 2008 to 16.4 in 2019% [16, 20]. Construction of Uganda's largest power plant (the Karuma hydropower plant) with 600 MW installed capacity is ongoing and could be commissioned by the end of 2021 or early 2022, and together with other small hydroelectricity plants that are under construction will increase the country's grid electricity generation to approx. 2,000 MW by 2025. However, the country's sustainable energy transition is still being hindered by the government's emphasis on large-scale hydroelectricity over other renewables [11], even when it is known that hydro-electricity is highly climate sensitive. Some interest in decentralized renewables exists, including solar and bioenergy, but they have not attracted the required state attention, and of late government attention is rather shifting to tap into oil and gas development for domestic power generation in the near future.

Nearly all the electricity generated in Uganda is consumed domestically, with households consuming the largest amount (61%), followed by commercial (14%), transport (13%), industry (8%), and others including export consuming only 4%. But then even at household level, the use of electricity is limited to lighting due to the high tariffs and for most households, charcoal and firewood remain the most accessible and affordable sources of energy for cooking. While there has been general increase in energy consumption in all the main sectors of economy over the last decade (see **Figure 3**), consumption of electricity in the industrial and commercial sectors remains low due to the low levels of industrialization, urbanization and overall economic development in the country.

Energy poverty is as electricity access remain low in Uganda with connectivity at only 28%, [21], which far lower than Sub-Saharan Africa average of 45% in 2017 [22]. In addition, electricity consumption per capita is approx. 100kWh [19], which is one of the lowest in the world. Besides the high costs of electricity, coupled with unreliable supply contribute to overdependence on biomass energy for cooking and the high cost of doing business which reduces the country's competitiveness [23].

#### **Figure 3.**

*Trends in energy consumption by sector (data sourced from UBOS 2010–2019; and MEMD, 2015–2020).*

This makes it more than urgent for the country to increase access to modern energy in rural and urban so as to reduce deforestation, stimulate the growth of economies, and promote green and resilient development.

The government's target is to increase electricity connections to 60% by 2025 and 80% access to modern energy by 2040 [2]. An estimated US\$1.6bn capital investment will required to meet the present plan of 60% electrification [16]. With the Uganda Vision 2040 foreseeing a country developing at a high to achieving an upper MIC status by 2040, Uganda will need much more modern energy with the energy demand is likely to outstrip the supply by 2030. By 2040, energy demand (including energy to propel industrial and commercial sectors) could reach 41,738 MW and capita electricity consumption could increase from the current 100 KWh to 3,668 kWh, indicating that therefore there is still a lot to be done in the energy sector.

### **4. Climate vulnerabilities of energy systems and adaptation**

Uganda's climate is changing: temperatures are rising, rainfall is becoming more variable, and extreme weather events are increasing in frequency and severity. Between 1900 and 2010 temperatures in Uganda increased by 0.8°C - 1.5°C and are projected to increase by between 2-5O by 2100 and rainfall received in 2000–2010 was on average about 8% lower than rainfall received between 1920 and 1969rainfall was observed to be variable [24, 25]. Melting of the ice caps on Mt. Rwenzori, increased occurrence of droughts, rainstorms and flooding and landslides have been observed in the last three decades.

Drought and rising temperatures affect biomass availability, causing gradual drying up of biomass which will increasing hardship for the majority of Ugandan's who are dependent on wood fuel for their domestic energy needs. During extreme wet seasons, access to firewood is limited because of the reduction in the amount of available dry firewood, and the dangers associated with fetching firewood in such conditions. The scarcity and increasing prices of firewood greatly affects poor rural households that largely depend on biomass energy as they move long distances to collect firewood, a process that disproportionately affects women and girls exposing them to gender based sexual violence (GBSV), including sexual assault, rape and defilement. The projected change in climate means that droughts will occur which will increase scarcity of biomass. Even without climate change, the unmet demand for biomass energy will become extreme by 2050, estimated

#### *The Energy and Climate Change Nexus in Uganda: Policy Challenges and Opportunities… DOI: http://dx.doi.org/10.5772/intechopen.99353*

at 1,710 million tonnes over the period 2010–2050, and climate change will add a plausible loss of 5 to 10% of domestic wood between 2020 and 2050, which could increase the costs of inaction from US\$123.6 bn to between US\$130 bn and 136 bn [6]. Therefore, the current growth in demand for biomass is not sustainable and a sustainable solution is needed to address the predicted deficit [5]. Besides, the reliance on biomass energy is a major driver to widespread deforestation and land degradation across the country. Uganda's forest cover reduced from 24% percent in the 1990s to a mere to 12.4% currently, a two percent annual loss of forest cover, which is among the world's highest forest cover losses, driven by among others by increased demand for fire wood and charcoal, but also by expansion of farming and urban centres into forest land. But deforestation and forest degradation also results catchment degradation that indirectly affects hydro-electricity generation. i.e. it is a driver to soil erosion, run-off and flooding in the catchments which lead to siltation and sedimentation of lakes and rivers that in turn reduces water availability for hydro-power generation.

The impacts of climate change also significantly affect electricity supply. The Stern Report posits that that a 3-6°C increase in temperature in the next few years could result in a 30–50% water reduction [26] and this could disrupt hydro energy supply, alter energy demand patterns but also damage energy infrastructure [27]. With Uganda's temperature projected to increase by 2-5OC by 2100, the effect on energy will be significant, and indeed the functioning of electricity supply systems is already being adversely affected by the rising temperatures, increased rainfall variability, drought and flooding [28]. Hydro electricity generation, on which Uganda highly depends, is the most affected as droughts and higher temperatures often reduce water in lakes and rivers causing a reduction in electricity generation. For example, persistent droughts have in the past reduced water levels in Lake Victoria affecting hydropower generation at the Nalubale electric power generation dam in Jinja [29]. Electricity generation at hydro-power plant on Mpanga river in Western Uganda significantly declines during prolonged dry seasons or droughts [6]. A study conducted by MWE with support from the Climate and Development Knowledge Network (CDKN) predicts a reduction in rainfall that could reduce Uganda hydropower potential by about 26% by 2050 [5].

In **Figure 4**, the possible the impact of climate change on electricity generation is illustrated further. The loss in hydro electricity production is due to reduced runoff, a scenario where a drop in available capacity is between 0% in 2025 and 26% in 2050 [5]. The loss would be met by increasing generation through nuclear and renewables (geothermal and solar) where nuclear accounts for 95% of the difference of the reduced yield (35.4 TWh). However, global opposition to nuclear power generation is very high due to its environmental and political sensitivity, and besides nuclear power plants are very expensive to put up.

Besides, that is only part of the story as significant increase in rainfall amounts and intensity, and flooding as predicted could also seasonally increase water levels in lakes and rivers and also become barriers to energy generation. Between 2019 and 2020, the Lake Victoria basin received increased rainfall and run-off which increased the water level of Lake Vitoria to unprecedented levels, by 13.42 metres at Entebbe, which exceeded the 13.41 metres level recorded in 1964 [30]2 . This rise in water level created some challenges to electricity generation, with moving islands/ floating vegetation blocking water flow to the hydro power stations on the Nile in Jinja. According to Eskom, Uganda's major power generation company, on April 14, 2020 a floating island docked at the Nalubale power dam blocking water for power

2 https://storymaps.arcgis.com/stories/bd820937c06845faa86f7f8944d56f47

#### **Figure 4.**

*Impact of climate change on electricity generation in TWh/yr. under the scenario of reduced runoff assuming high electricity demand with low supply capacity (DHSLWBC) vs. no impact of climate change (source [5]).*

generation causing a nationwide power blackout.3 However, Uganda's National Environment Management Authority (NEMA) also attributes the floating islands on the lake to environmental degradation in the lake basin. The old Maziba hydroelectric power station, in south western Uganda, was closed due persistent siltation that affected electricity generation and all these point to need to "climate-proof" the country's energy infrastructure.

Another major source of energy vulnerability is that the impacts of climate change disrupt the energy supply chain. The increased intensity and frequency of extreme weather events such as heavy rainfall storms and floods affect energy infrastructure - power plants, transmission lines and power lines - that disrupt energy supply resulting in power cuts and higher energy prices [31, 32]. Moreover, the heavy rains and flooding make road and rail transportation inaccessible. The disruption of rail and road transport indirectly affects energy supply, as fuel is typically imported into the country by train from the coast and distributed by trucks [23].

Adaptation to climate change for energy sector should that focus significantly reducing dependence on traditional biomass. A biomass supply deficit is already being experienced, with prices of charcoal rising each passing day, and indeed supply will not meet demand in the future even without climate change. It is also important to ensure the efficiency gains in biomass use (e.g. efficient cook stoves) are increased, and diversifying energy sources and promoting renewable energy that transition into more households switch to LPG, biogas, and electricity. It is critical to increase electricity connectivity, affordability, and reliability and de-risking the use of LPGs through tax incentives and supply in rural areas. The adaptation cost for replacing lost biomass is estimated at between \$5 and \$11 bn over the period 2020–2050 at a 10 percent discount rate [5].

The best use of hydropower needs careful management of the water resources and thus catchment management is also important. Afforestation and reforestation measures to protect watersheds that supply major hydroelectricity generating sources should be a key part of such protection, and Uganda is promoting

3 Eskom Uganda Limited. Press Release. April 16, 2020.

*The Energy and Climate Change Nexus in Uganda: Policy Challenges and Opportunities… DOI: http://dx.doi.org/10.5772/intechopen.99353*

catchment-based water resource management, and the country is divided into 17 catchments, for which catchment management plans are prepared to address the issues affecting water and other related resources (forests, biodiversity, wetlands, soils etc.) that could among others ensure sustained water availability for electricity generation.

Above all, coping with extreme events requires strengthening the structures of small dams to withstand increase in rainfall intensity or reduced water levels.

But still, Uganda government's preference for large hydro-power projects in areas of rich ecosystems and biodiversity, and eco-tourism sites is an environmental controversy, given the dependence on hydropower on natural systems (climate and water availability). The ongoing construction of Karuma hydro-electricity dam/station and the proposal to construction another hydro-electricity dam on Murchison Falls (and adjacent Uhuru Falls), all projects in Murchison Falls National Park, a protected area with rich biodiversity and eco-tourism potential is are cases in point. These energy projects remain controversial given that Uganda is not lacking alternative renewable energy resources – solar and geothermal potential is very high and there are many other alternative sites for hydro-electricity development. The larger questions are the levels of Uganda government's assessment of the 'economic benefits' versus 'environmental costs' of its energy development model. Besides, the dams on the Nile remain insecure to current and future climate risk i.e. fluctuating water levels and extreme weather events. But also, the Nile is a transboundary resource and water governance and security concerns are hot topic of debate and a potential source conflict in the Nile basin countries, especially with downstream neighbors (Sudan and Egypt), putting Uganda's dams at future risk of reduced flow.


**9.1 Infectious**

*Current Cancer Treatment*

in small (<1 cm3

**8.1 Open biopsy**

accurate diagnosis.

combined.

**8.2 Stereotactic biopsy**

**8.3 Endoscopic biopsy**

**8. Histologic confirmation of diagnosis**

Histopathologic diagnosis of brain tumours is necessary for decision making regarding appropriate management. Stereotactic biopsy has emerged as a comparatively safe method of histological diagnosis and has significantly reduced the risks associated with brain biopsy [16]. Tissue sampling can be obtained either with

Greater than 90% diagnostic yield, while it may be significantly lower (60–70%)

It can be frame based and frameless. The frame-based method is focused on the fixation of the stereotactic frame on the patient's head, whereupon the localizer is attached to the frame with many N-shaped posts. Under stereotactic circumstances, neuroimaging (CT, MRI, positron emission tomography [PET], etc.) is carried out and radiological information is transmitted to the specialized computer platform. The localizer posts are used as space coordinate references. For optimizing the target location and defining the ideal trajectory for biopsy, multiple pictures are

The frameless biopsies are generally technically easier and require less prepara-

It is recommended for intra- and periventricular tumors and can be done with or

without frameless stereotactic guidance. The advantages of this technique are

4. cerebrospinal fluid (CSF) samples can be taken for tumor marker analysis

Exception may be produced in chosen patients such as patients with known active systemic cancer and numerous lesions radiographically associated with brain metastases, patients with classic clinical and MRI results of brain stem glioma or optic nerve meningioma, HIV-positive patients with CT or MRI results consistent with primary CNS lymphoma and positive Epstein-Barr virus polymerase chain

reaction in the CSF, or patients with secretory germ-cell tumors [19].

In case obstructive hydrocephalus, third ventriculostomy can be simultaneously

2.vascular structures can be seen during tissue sampling

3.more pathological specimens can be taken.

tory efforts in comparison to frame-based ones [18].

1.direct visualization of the lesion

It is performed as an open technique by intraoperative neuronavigation. Typically, it is asserted for surface brain lesion, where hemostasis is critically vital or a surgical resection depending on frozen section histopathology is arranged. Although morbidity and mortality of open biopsy is more as compared to stereotactic biopsy but neoplastic tissue yield is better and it influences the likelihood of an

stereotactic, open, or endoscopic procedures and, overall, provides.

) and/or heterogeneous lesions [17].

**154**

done [10].

Abscess-fever, acutely ill, ±systemic infection, ct findings show cyst cavity with smooth thin walls and restricted diffusion within cavity.

Cerebritis-fever, acutely ill, ±systemic infection, mri findings show diffuse T2 change, no mass meningitis-diffuse enhancement of meninges on T1-weighted imaging.