Iris Publishers-Open access Journal of Biology & Life Sciences | Role of Gene Therapy in Treating Heart Failure

 

Authored by Ammar Almehmi*,

Abstract

Heart failure (HF) is a global public health problem that affects 1-2% of the western countries. Further, it is associated with high morbidity, mortality and health expenditures. Despite the advancements in the pharmacological treatment of HF, only 50% of patients survive at 5 years.
Recent advances in the pathophysiologic mechanisms of HF have created a new opportunity in developing non-pharmacological approaches for treatment. Physiologic studies showed that cardiac sarco-endoplasmic reticulum Ca2+ATPase (SERCA2a) plays a major role in regulating the calcium levels in cardiomyocytes. Alteration in calcium handling within the cardiomyocytes is one of the main pathognomonic processes that occurs in the failing heart caused by the reduction in SERCA2a activity, which adversely affects both systolic and diastolic functions.
Gene transfer therapy is a novel approach that is used to target the calcium dysregulation seen in the failing cardiomyocytes. New vectors, namely adeno-associated viruses (AAVs), were re-engineered to become more cardiotropic resulting in sustained transgene expression within the affected cardiac tissue. The above advancements have been coupled with the development of new delivery methods that include endovascular, surgical, and direct myocardial approaches. As a promising target for treating HF, AAV1-SERCA2a is being used in several clinical trials with promising clinical outcomes.
Despite the significant progress of the cardiac gene therapy field, several challenges remain to be overcome including host neutralizing antibodies of AAV, improving AAV vector cardiac-transduction affinity, and optimizing the dose, route and method of delivery.

Keywords: Heart failure; Gene therapy; Ca2+ATPase; Vector; Cardiomyocytes

Introduction

Heart failure (HF) is a global public health problem with high prevalence in the world. HF is the common final clinical presentation of a variety of cardiovascular diseases. Further, with aging of world population, it is expected that the number of HF patients will continue to increase [1]. Over the last 50 years, many effective pharmacologic therapies have been developed. However, HF morbidity and mortality remain high with only 50% of patients survive at 5 years [1,2]. Several mechanisms have been implicated in the pathogenesis of HF including adrenergic signaling abnormalities, alterations in calcium handling, disturbances cardiomyocyte relaxation, and activation of apoptosis pathways [2]. It is within this context that new approaches, such as gene transfer therapy, have been developed for treating HF [3]. The main focus of the current work is the calcium handling dysregulation seen in HF, with special attention to the role of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) in the health and disease state of the cardiomyocytes [1-3]. Accordingly, the overarching objective of this paper is to review the role of SERCA2a gene transfer in treating HF and its clinical implications.

Materials and Methods

The information about HF and GT were collected by conducting literature search using PubMed search engine (the MEDLINE library), American Heart Association website and google search engine. The main words that were used in this search included heart failure, pathogenesis, cardiomyocytes, target of HF treatment and GT. The search was restricted to review articles, English language and time limit of 10 years. Basic physiologic background of the heart contractility was reviewed. Despite the multiple targets of GT, the main focus of this paper was the calcium regulation within the cardiomyocytes as the main target for gene therapy [4,5].

Outcomes

Heart failure is an epidemic of the developed world that is associated with increased morbidity and mortality. Despite the improved outcomes in HF population, the current pharmacological approaches are limited by the side effect profiles of medications requiring the search for new therapeutic approaches [1,2]. Hence, advances in bench research have elucidated much about the cellular and molecular pathways that govern the physiology and pathophysiology of HF. In the following paragraphs we will discuss the physiology of heart contractility, major pathologic pathways of HF, and role of calcium dysregulation in cardiomyocytes.

Physiology of heart contractility

The heart is made of cardiomyocytes, which are composed of contractile proteins (actin and myosin) and mitochondria. The contraction of the heart depends mainly on the coordinated action of individual cardiomyocytes. The beat-to-beat cycling of cardiomyocytes is dependent on intracellular Ca2+ cycling [6]. Calcium is released into the cytosol from the sarcoplasmic reticulum (SR) during systole resulting in the activation of actin and myosin coupling leading to contraction. Diastole is dependent on efflux of Ca2+ to the sarcoplasmic reticulum via sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) system. In other words, the contraction and relaxation of cardiomyocytes are dependent on the binding and dissociation process of Ca2+ from troponin protein [6] (Figure 1).

Major Pathophysiologic Pathways of HF

Over the past several decades, major advances in cellular and molecular biology have offered insights into pathogenesis of HF. The major pathognomonic processes of HF include adrenergic signaling abnormalities, alterations in calcium handling, disturbances cardiomyocyte relaxation, and activation of pathways that result in cell death [2,7]. The main focus of this paper is to explore the changes in the cardiomyocyte calcium dysregulation as targets for GT.

Role of SERCA2a in HF pathophysiology

The SERCA family is an intramembrane calcium channel pump that is composed of multiple domains. SERCA2a is the predominant isoforms that is found in the heart tissue and slow-twitch muscles. In order to demonstrate the role of SERCA2a in HF, several complete and partial knockout animal models were developed. While total knockout studies of SERCA2a were lethal to the mice embryos, the partial knockouts of SERCA2a predisposed these animals to HF. Other studies have shown that cardiomyocytes downregulate the expression of SERCA2a in the chronic HF model [6,8]. Importantly, Ca2+ cycling has been found to be dysregulated in HF with increased cytosol Ca2+ and decreased SERCA2a activity leading to a decrease in systolic function and abnormal diastolic functions [6,7].

The Ca2+ homeostasis and the tight control of SR Ca2+ levels are considered the key factors for the cardiomyocytes contractile function. Therefore, it is plausible that correction of SERCA2a activity levels could improve the contractility of the failing cardiomyocytes leading to clinical improvement and potentially better outcomes. As such, GT evolved as a promising therapeutic alternative that targets the cardiomyocyte calcium regulation. In animal models of HF, the treatment with gene transfer therapy using a viral vector to deliver the SERCA2a gene to the heart improved the symptoms of these animals [7,8].

Methods of gene transfer

Gene delivery determines the efficacy of GT. Because the current available technologies using intravenous route do not sufficiently transduce myocardium, direct cardiac delivery is necessary. Several methods of myocardial targeted gene delivery have been developed over the years as shown in Figure 4.

Intra-myocardium and endovascular delivery are the methods of choice in clinical applications. Accordingly, GT dose is delivered invasively using surgical methods or less invasively using endovascular catheters (Figure 4). These methods are limited by the systemic leak of the vectors through the venous drainage, lymph system, and from the injection needle holes [10].

When delivered into the circulation, the AAV particles bind to surface receptors and then incorporated into cardiomyocytes by endocytosis. Subsequently, the particles (SERCA2a gene) get released into the cytoplasm where they are transported to the nucleus. At the nuclear level, the vector is disassembled, and its genetic material is released (Figure 3). After double-stranded synthesis of the gene of interest is complete, transcription and translation begin leading to the production of the molecule of interest. The SERCA2a gene transfer enhances the contractility of the injected area, restore the energetic state of the heart both in terms of energy supply and utilization, decrease ventricular arrhythmias, and enhance coronary flow [10-12].

Clinical trials using SERCA2a gene transfer

Several clinical trials have been initiated using AAV1-SERCA2a in HF population. The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial was the first attempt to use AAV gene therapy to treat HF in human subjects. The CUPID trial involved a single intracoronary infusion of varying doses of the AAV1-SERCA2a vector to investigate the potential therapeutic benefit of increasing expression of SERCA2a in nine individuals with advanced HF [12-14].

CUPID 2 was a randomized, multinational, double-blind, placebo-controlled trial involving 250 subjects with advanced HF who received a high dose of AAV1-SERCA2a DNase-resistant particles [13]. Both trials improved the clinical symptoms of patients and exercise tolerance. Several other trials are going where the dose and methods of delivery are being modified [12,14].

Conclusion

HF is a global epidemic that continues to have poor prognosis. In spite of the advances of our understanding of the pathophysiology of HF and ongoing developments of new pharmacologic agents, the prognosis of HF remains poor. This necessitated new approaches and created an opportunity for GT in treating HF. GT appears to be a plausible strategy to approach such a complex pathophysiology seen in HF. Here we addressed the role of AAV1-SERCA2a gene transfer therapy in HF. Despite the disappointing results of CUPID trials, the field of cardiac gene therapy is moving forward. These trials proved the biosafety of AAV gene delivery, its ability to escape immune system and its affinity to heart tissue as demonstrated in the HF population. With improved vectors, broadening the gene therapy targets to include other pathophysiologic pathways, and enhanced gene delivery methods, the therapeutic benefits of gene therapy and its clinical applications will be upcoming in the near future. GT tools are already expanded to other diseases and organs making this field very exciting.

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Iris Publishers-Open access Journal of Complementary & Alternative Medicine | Integrative Approach

 

Authored by Viviana Siddhi*,

Short Communication

Each year, Americans spend more than $34 billion on complementary and alternative treatment methods and visit alternative practitioners more often than they see primary care doctors. Complementary therapies are those that are used along with conventional treatments. The most effective is integrative approach. It refers to the combined use of evidence-based proven therapies and complementary therapies. This is the term that many people in the field are using more frequently. Integrative medicine services are becoming part of hospitals across the country and cancer centers.

Holistic medicine focuses on how the physical, mental, emotional, and spiritual elements of the body are interconnected to maintain holistic health. When one part of the body is not healthy, it is believed to affect the whole person. Holistic approach concentrates on the whole body rather than focusing only on the disease or part of the body that is not working properly. A person should treat a whole self to reach a higher level of wellness. Patients treat disease by changing diet and behavior, taking botanical supplements, and undergoing various complementary therapies such as acupuncture, chiropractic, hypnosis, yoga, massage therapy. These approaches can be used along with conventional medicine such as surgery, radiation therapy, chemotherapy. By combining these different techniques, a person can take control of the disease and obtain a feeling of total wellness: spiritually, physically, and mentally.

The American Holistic Association says that healthy lifestyle habits will improve a person’s energy and vitality. Those habits include exercising, eating a nutritious diet, learning how to breath properly, yoga, acupuncture, and other alternative methods.

“Some doctors suggest that cancer pain and some side effects of treatment can be managed by incorporating different aspects of holistic medicine that include the physical, psychological, and spiritual factors involved with each individual. Health professionals realize that a person’s health depends on the balance of physical, psychological, social, and cultural forces. Adopting healthy habits related to diet, exercise, and emotional and spiritual well-being are considered important to maintaining good health [1].”

There is no scientific evidence that healthy habits such as humor can cure cancer or any other disease. It can reduce stress, promote health, and enhance the quality of life. Laughter has physiological effects that can stimulate the circulatory system, immune system, and other systems in the body.

Humor therapy is the use of humor or laughter for the relief of physical and emotional difficulties. It is used as a complementary tool to promote health and cope with disease, improve quality of life, provide some pain relief, encourage relaxation, and reduce stress. We have different types of humor. Passive humor is created by observing a comic film or reading a book. Humor production involves creating or finding humor in stressful situations. The physical effects of laughter on the body involve increased breathing, oxygen use, and heart rate, which stimulate the circulatory system. Many hospitals have incorporated special rooms where people with humorous materials, are there to help make people laugh. Laughter has many clinical benefits that include positive physiological changes and an overall sense of well-being.

Research has been done on the effects of humor on pain and stress relief. Laughter stimulates the release of special neurotransmitter substances in the brain that help control pain. Laughter increases stress-related hormones which provides support for the claim that humor can relieve stress.

Also, hypnosis helps to reduce stress, anxiety, and depression; manage pain; lower blood pressure; ease some of the side effects of chemotherapy; and create feelings in being in control.

“Physical exercise acts like a natural wonder drug for the brain; exercising is the single most important thing you can do to enhance brain function. It improves the heart’s ability to pump blood throughout the body, which increases blood flow to the brain. That supplies more oxygen, glucose and nutrients to the brain, which improves overall brain function. Research shows that exercise encourages the growth of new brain cells and enhances cognitive ability [2].

If you practice yoga, you will strengthen the immune system. The immune system is not a single, tangible part of the body like the lungs, heart, brain, or stomach. In one sense, the immune system includes all of the body’s parts and systems, being the interaction and union of all these systems. The goal of strengthening the immune system is to keep all the system working together, like working families in a large, healthy village. For example, if our bones are compromised from a break or osteoporosis, we will not be able produce new nourishing blood supply to feed our reproducing cells.

“Chemotherapy and other cancer treatments can compromise the immune system’s efficiency because they disrupt the development and balance of all cells, therefore stressing the body’s systems and increasing the risk of infection or other diseases. Specifically, treatments reduce white cells in the blood that are needed to form leukocytes, a natural immune protection. This is why it is so critical for active cancer patients to keep on “immune system alert”. Because yoga’s goal is to strengthen all body systems, the end product is an improved immune system [3].”

On the molecular level, we find further support that yoga boosts the immune system. Yoga causes an improvement in gene expression within lymphocytes, which are our cancer-fighting cells, often referred to as immune cells, that are being produced in our body all the time. Every yoga movement, position, or patterned breathing technique has one goal: to strengthen the immune system.

Yoga practice seeks to free the mind of negative thoughts and feelings about our bodies. Instead of looking into the mirror and making poor comparisons to magazine cover models, yoga teaches us how to turn the mirror around to find what is hidden on the inside. When we do something every day, even if it is a simple stretch, breathing exercise, or correcting our posture while walking down the street, we develop a healthier, more positive image of ourselves. Unfortunately, not everyone manages stress with the same success related to post-traumatic stress growth that requires self-discipline.

Blood purification is absolutely essential to keep “river of life” flowing and delivering nutrients and oxygen. “What makes ozone so special, in my view, is the way it merely catalyzes the delivery of oxygen, and ultimately energy, into the cells. Ozone stimulates the production of cytokines, or “messenger cells”, that set off a domino effect of positive energy changes throughout the immune system, delivering more oxygen to cells so they can perform the metabolic and detoxifying functions for which they’re designed [4].”

Interesting enough, Neil Schachter, M.D. is mentioning in his book particulate matter. “Doctors are particularly concerned about the very fine particle matter (less than 2.5 microns in diameter) that can be inhaled deeply into the airways. Studies throughout the world have linked “Particular Matter” to a range of serious health problems [5].”

During aerobic exercise, the body needs additional amounts of oxygen. The heart needs to pump more blood with each beat and with exercise it becomes more efficient. Doing this type of exercise allows muscle arteries to dilate so that more blood can be carried to the muscle. This makes it easier for the heart to move blood throughout the body, a change which also lowers blood pressure. All these factors assist the heart, allowing it to work better with less effort. For the lungs the most important benefits of aerobic exercise are that the muscles throughout the body become more efficient at absorbing oxygen from the blood. This means that the lungs do not have to work so hard to supply oxygen. With exercise, muscles can become more efficient and obtain more oxygen because of improved circulation. Increased oxygen levels provide more energy and relieve feelings of fatigue.

Chinese medical practitioner analyzes a patient’s energy, looking for signs of excess or deficiency, for indications that something is blocking energy flow, or for clues that there is an ambulance between the main types of energy in the body: the yin and the yang.

“The main underlying concept of Chinese medicine is qi (pronounced “chee”; also spelled chi). Qi is the fundamental life force that guides and controls all life processes, from breathing and the beating of the heart to digestion and sleep. Qi is produced by the metabolism of food and the intake of breath. Qi serves many functions throughout the body and exists in various types, such as protective qi and food qi. Too much or too little qi can lead to imbalance and illness, as can stagnation or blockage of qi [6].”

Ying and yang represent the primary opposing and counterbalancing forces that operate in the universe and, consequently, within each individual. Yin and yang are not merely opposites, like black and white. Instead, taken together, they represent a complete dynamic equilibrium, a constantly changing balance. Yin and yang are expressed in many ways hot and cold, inner and outer, moist and dry, dark and light, male and female. When there is a balance between the qualities of yin and yang, harmony and good health exist. If either becomes too predominant, then disharmony exists. Illness may result.

One yin quality is moisture. If too much is present, the body may experience edema (swelling) or diarrhea. But if dryness (yang) predominates, a person may experience dry mucous membranes, dry skin, or internal dryness leading to constipation. It isn’t a question which is better, yin or yang. Both are necessary. What’s important for good health is the balance between the two.

“As we move toward “Health, Happiness and Harmony”, we experience a greater sense of freedom in our lives” [7].

Asian body healing originated thousands of years ago in the villages and small communities in and around the countries of India, China, Japan and Korea. The actual techniques used began as instinctive responses to manifestations of imbalance in the body. The only tools they utilized were their senses. Each person they worked with represented a microcosmic manifestation of the macrocosmic world. Everyone was treated individually, even if they displayed the same outward indicators. Many aspects of a person’s lifestyle including diet, climate, exercise, type of work, family relations and ancestral influences were considered relevant in order to ensure successful therapy. For example, if two people suffered from fatigue and one lived in a cold area while the other came from a warmer island home, the methods utilized would have to be different for each of them.

After working with many people over thousands of years, certain observations were collected on how all the elements of the environment harmoniously interviewed and coexisted with each other. Eventually, they were able to describe how the ever-changing forces of nature influenced the human body. This system was based on heaven’s force originating from the constellations, interacting with the forces emanating from the earth: yin and yang.

We can supercharge our immune system to protect our bodies against disease – everything from the common cold to cancer. “Super immunity can be best defined as the body’s immune system working into its fullest potential. Modern science has advanced to the point where we have evidence that the right raw materials and nutritional factors can double or triple the protective power of the immune system. If you learn to fill every cell receptor lock with the right nutrient key and meet the demands of each cell, the body’s defenses take on superhero qualities – and you will hardly ever get sick again. More important, this change from average immunity to Super Immunity can save your life [8].”

Smoothies are the quickest and easiest way to incorporate a variety illness fighting nutrients into your diet. The drinks are rich in phytoestrogens from the soy and contain abundant amounts of antioxidants from the fruits and fruit juices.

Excellent source of beta-carotene and vitamin C are apricots and mangos. Place the banana, mango, orange juice, and soy yogurt in a blender. Blend ingredients until they are smooth. Antioxidant-rich beverage is smoothie made of kiwi, mango, apple juice and silken tofu. Smoothie made of mango, carrots, soy yogurt and orange juice are very rich source of beta-carotene.

“The brain is a beautiful thing. It’s deeply complex and intricate with so many neural pathways that it’s hard to know exactly which electrical impulses are being fired from where. Remember that you are the master of your mind. Know that you can and will accomplish all that you set out to do if you just believe that you can do it [9].”

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Iris Publishers-Open access Journal of Textile Science & Fashion Technology | Right-Sized Consumption: Should Doughnut Economics Inform the Textile and Apparel Industry?

 

Authored by Jana Hawley*,

Abstract

One of the toughest challenges the textile and apparel industry faces is how to Right-Size Consumption in a way that supports our environment while at the same time sustains profitable businesses. Companies are scrambling to find the right balance that meets this consumer shift while at the same time endures the demands of shareholders in a capitalist marketplace. Right-sized consumption is embedded in important economic, political, and social issues. Major corporations measure their success by stock market performance and constantly strive to sell more and more so that shareholders are happy. On the other hand, consumers are moving away from excessive consumption behavior to a more mindful approach that honors substance and sense of purpose [1]. As this shift occurs, a new economic model needs to be considered that allows businesses to flourish in an environment where sustainability becomes more important than quantity of sales. The purpose of this concept paper is to inspire a discussion on how ITAA scholars can begin to develop an economic model of sustainability where environment, economics, and humans not only co-exist- but thrive.

Keywords:Consumption; Sustainability; Behavioral Economics; Capitalism; Textiles; Apparel

Opinion

Depending on your point of view, often influenced by your political leanings, consumerism can be fundamental and benign or rampant and dangerous. No doubt, it is often a hot debate. A few years ago, the marketplace drove our consumption behavior with monikers such as “retail therapy” or “shop ‘til you drop”. More recently, however, consumers have begun to replace over-the-top consumption with mindful and intelligent consumption.

One of the toughest challenges the textile and apparel industry faces is how to Right-Size Consumption in a way that supports our environment while at the same time sustains business profitability. Companies are scrambling to find the right balance that meets this consumer shift while at the same time endures the demands of shareholders in a capitalist marketplace. Right-sized consumption is embedded in important economic, political, and social issues. Major corporations measure their success by stock market performance and constantly strive to sell more and more to satisfy shareholder expectations. On the other hand, consumers are moving away from excessive consumption to a more mindful approach that honors substance and sense of purpose [1]. As this shift occurs, a new economic model needs to be developed that allows businesses to flourish in an environment where sustainability becomes more important than quantity of sales. The purpose of this concept paper is to inspire a discussion on whether Raworth’s [2] doughnut economics theory can be used as a better economic model of sustainability where environment, economics, and humans not only co-exist can be--but thrive. I do not purport to be an economist, or even to understand it beyond the basic theories. However, I argue here that the basic teachings of economics fail to include the important concept of environment and nature. Here I have illustrated how two global apparel companies fit into Raworth’s Doughnut Economics model.

The Challenge of Neoclassical Economic Theory

Today’s dominate microeconomic theories is the neoclassical approach which relies on supply and demand to explain an individual’s rationality and ability to maximize utility or profit. For most of the 20th century, growth was widely thought to be the remedy for all economic problems. For example, to solve poverty, simply grow the economy and watch wealth trickle down. Unemployment issues are answered by increasing demand for goods and services thereby opening the job market. Environmental degradation is resolved with the Kuznets curve [3]. This approach to economics focuses on the determination of good, outputs, and income distribution. Originally introduced by Thorstein Veblen [4], neoclassical economics has three central assumptions:

1. People have rational preferences that are associated with values.

2. Individuals maximize utility and firms maximize profits.

3. People act independently based on full and relevant information.

From these three basic assumptions, neoclassical economists have built widely accepted theories that purport to explain the allocation of scare resources among alternative ends. Neoclassical economists have given us additional theories including the theory of the firm, demand curves, factors of production, and marginal productivity to name a few. Furthermore, neoclassical economists assert that human nature is self-interested, competitive, and calculating. This result is the goal of endless growth but with a result of those who win and those who lose.

For decades, critics have identified problems inherent in neoclassical economic theories, stating that too much emphasis is given to mathematical models without enough attention to whether these actually describe the real economy. Nobel Laureate Joseph Stiglitz argued:

“One cannot ignore the possibility that the survival of the [neoclassical] paradigm was partly because the belief in that paradigm, and the policy prescription, has served certain interests” [5].

Nordaus, the 2018 recipient of the Nobel Prize in Economic Sciences argued that nature dictates the main constraints on economic growth [6] and Dasgupta [7] argues that nature is fundamental to human well-being and thus, nature should be part of economic reasoning and theory development and Raworth argues that neoclassical economics has a sociological and ecological void [8]. She argues that instead of economic growth we should start our understanding with the fundamentals that we care about: People and planet. In other words, we should end the assumption that an environmental agenda is somehow separate or opposed to basic economic principles such as distribution of resources.

Conventional economic theory is rooted in the belief that there are no limits to growth. They believe that human ingenuity is infinitely substitutable for limited naturel resources. Traditional economic models are based on using up resources in ways that accurately reflect the tastes and preferences of individual consumers. Society, the environment, and even preferences for no-consumption goods are considered external to the economic decision-making process. These theories go back to the days of Rostow [9] where economic growth was outlined through 5 easy steps leading, finally, to high-mass consumption. However, the paradigm of the 20th century no longer holds true in today’s world. We must recognize that economies do not exist in a void. Rather the economy is part of a “subsystem of the finite biosphere that supports is” [3]. Furthermore, if economic expansion happens too quickly or without controls, the natural capital (fish, fossil fuels, waters) suffers. If we don’t heed the warnings, we may be faced with an ecological catastrophe. Daly HE [3] points out that conventional macroeconomists do not have an analogous ‘when to stop’ rule. They argue that growth is unlimited. But I contend that even though many economists still do not agree, we must make the transition to a sustainable economy- one that considers the limits of the natural environment .

A Sustainable Economy

Sustainability discussions have received much attention among ecologists, environmental engineers, textile and apparel scholars, and other members of the scientific and business community. In recent years, environmental sustainability has become a key managerial issue with both researchers and practitioners assigning attention to the issue as they face the challenge of achieving balance between economic needs and environmental concerns. Often times, these needs and concerns seem at loggerheads with each other. Yet, companies are held responsible for environmental and social problems and we must find a right-sized solution. Grimsley [10] defined a sustainable economy as one that “attempts to satisfy the needs of humans but in a manner that sustains natural resources and the environment for future generations”.

It is well documented that the textile and apparel industry has very high environmental and social impact. It accounts for 9.3% of the world’s employees [11] (World Trade Organization, 2008) and the production processes, in particular dyeing/drying/finishing, generate high environmental impact [12]. In addition, both natural and synthetic fibers have inputs (e.g. water, fertilizers, pesticides, petroleum, energy, toxic waste) that impact the environment. Significant impacts are also made when considering the global scale of the industry as the transport of goods from low-labor cost countries to consumers in US and Europe demands high inputs [13].

The emergence of sustainability as a major public issue reflects a fundamental challenge to the assumption of unlimited growth. Sustainability is people-centered [14]. It is about sustaining a desirable quality of life for future generations. The United Nations notes that climate change is now affecting every country on the continent, disrupting national economies, affecting lives, and costing people and communities [15]. The UN Sustainable Development Summit of 2020 adopted the 17 Sustainable Development Goals (SDGs) but placed in into a COVID recovery framework. It calls on facts, data, and opportunities we have as a human family to reimagine and reshape the future (https://www.un.org/ sustainabledevelopment/sustainable-development-goals/). A commentary in The Lancet argues that we must think about ‘wellbeing’ rather than sustainability where well-being depends on enabling every person to lead a life of dignity and opportunity, while safeguarding the integrity of Earth’s life-supporting systems [16].

Doughnut Economics: A New Economic Model of Sustainability

It has become clear that 20th century economic theories of unlimited growth no longer make sense in a world where environmental degradation warnings are commonplace. More and more consumers care about a healthy ecosystem. Yet, collectively, we have not made significant progress on reducing the damage business does across the globe. Reliable metrics that measure business impact on the environment have not been well-developed. We need to get to a point of “true cost accounting”- where successful companies are synonymous with sustainable business. In other words, we need to put a price on the priceless [17].

In an April 2018 TedTalk [18], Oxford economist, Kate Raworth proposed the Doughnut Economic Model for the 21st century. She argued that growth economics no longer work and proposed a new doughnut-shaped model. The doughnut model suggests that we transform our capitalist worldview obsessed with growth into a more balanced, sustainable perspective that allows both humans and our planet to thrive. The central premise to her theory is that we must meet the human rights of all people within the capacity of Earth’s life-support systems. She calls this the “sweet spot” between social and planetary boundaries [19]. While Raworth’s work certainly takes a giant step forward in rethinking economics, as professionals in textiles and apparel, we must ask whether the doughnut model fits with the sustainability and economic issues of the textile and apparel industry.

In Raworth’s [2] description of doughnut economics, she asks, “What enables human beings to thrive”. She calls on the 2015 United Nations Sustainability Goals to define the human social needs then surrounds this with the ecological ceiling. The result is the doughnut. Figure 1 Illustrates Raworth’s Doughnut Theory (Figure 1).

For most of the 20th century, economic thinking told us that GDP growth was the measure for progress, with upward trend lines that supported this claim. But with fair warning from climate scientists, we must change the direction of the trend lines and come into a ‘dynamic balance” [2] that supports human well-being and Earth’s boundaries.

Doughnut Economics for the Textile and Apparel Industry?

Textile and apparel companies are in constant negotiation between daily operating procedures and meeting shareholder expectations. Neoclassical theories would claim that markets determine what makes a firm efficient. This has often resulted in companies that push the limits of the law and the boundaries of our planet to maximize shareholder values.

The real challenge is to create a cultural shift where consumers consume less. In spring 2021, Levi Strauss & Co launched a new ad campaign that addresses a fundamental contribution that consumers can make to support environmental causes. At the same time, the “Buy Better, Wear Longer” campaign argues that better quality will also support the profits that Levi’s expects to run a successful business (https://www.levistrauss.com/2021/04/22/ levis-launches-buy-better-wear-longer-campaign/). To view a selection of their ads, please see https://www.levi.com/US/en_ US/. This campaign contradicts our long-held ideals of marketing and economic growth [20]

The conceptual idea of mindful consumption is embedded in ‘happiness’ literature. Sheth JN, et al. [21] (2011) found that happiness is not necessarily obtained from having more things or to consume more. Berntsson, et al. [22] argued that the millennial generation may provide the tipping point that moves consumption behavior to one that values sustainability over ‘shop ‘til you drop’.

It is time for textile and apparel scholars to come together to develop its own model of economic sustainability. Our programs are often deeply connected to industry as we prepare our students for careers. So how do we balance the need for new perspective at the same time we steward are relationships with industry? How do we nudge industry to make better decisions that support social and planetary needs? How do we muster the ethical courage required to make sure that our industry thrives well into a long-view of the future?

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Iris Publishers-Open access Journal of Neurology & Neuroscience | Kuru: The Neurodegenerative Disorder; Roles of PrPC and PrPSc in infection, Effects in Blocking Neural Synapses and its Comprehensive Observation

 

Authored by Ahnaf Ilman*,

Introduction

Professor Luisetto M et al. introduced that KURU, the first human transmissible spongiform encephalopathies, can be penetrated in humans. And can impact the brain and immune system by the primary process of the oral intake of affected materials by cannibalising. Also revealed that no boundaries of the genome had not been determined and added that the Kuru Disease efficient process works explicitly against the Brain and immune system as well as creates a fatal neurodegenerative disorder [1].

Methods & Materials

• Observation of the risk factors and impacts on the human body caused by KURU represented through the vigour of research articles.

• What are the must to alleviate the criticisms and analysis of pathogenesis?

• References have been referred based on the information collected from reliable and high impact journals, videos of related lectures by prominent professors of the world.

Results & Discussion

Background: Dr Collinge J. recently introduced that possibly, the disease and incubation somehow sign any future epidemic. Besides, oral intake is the principal factor of infection. It is regarded as a prion disease. The appearance of Kuru indicates the assumption of a disease which occurs rarely. Cannibalism can be the wherewithal to get rid of the prion disease infection [2]. Background: Dr Collinge J., et al. represented that the neurological and genetic analysis on some Kuru infected enlightened one person having Kuru infection in the tonsil biopsy. In the end, this relevance has created a firm belief that it is positively related to oral as a medium of disease [3].

Background: Dr Collinge J., et al. revealed that the incurable and neurodegenerative disorder created by Kuru disease attacks in the brain system. It is a disease caused by prions. Three echelons of Kuru infection - (i) Ambulant Stage, (ii) Sedentary Stage, and the most criticism, and the last stage is considered as (iii) Terminal Stage. The ambulant echelon represents the disorder in operating body organs, and synchronisation in speech can be found while speaking. Then, in the step of Sedentary, jerking in body, bursting out with laughter, and mental disabilities have been analysed. Besides, the infected become unable and cannot do any work without the support of anyone. Finally, in the last stage- Terminal Stage, infected become more incompetent, and other symptoms and orders turn more synchronised. Kuru disease was first identified in the tribal society of Papua New Guinea during the 1950s. As a disease which is rare and transmits positively from one to another, it transferred to several people. And sex variation analysis mentioned that the chance of the women and the children is very high because of cannibalism and getting a heightened touch to the corpses which can be attacked with Kuru [4].

Dr Liberski, PP. introduced that Kuru, the first transmitted prion disease had been manifested from Chimpanzees to humans. It has been considered acting as a neurodegenerative disease. Neurodegenerative disease is regarded as an illness in the human brain that mainly attacks neurons or creates neuron criticism. Neurons combination builds the nervous system- brain and spinal cord. Cannibalism is taken as a medium of infection [5].

Dr Kompoliti, K. mentioned that this very neurodegenerative disease infects the human body by an unconventional medium that acts against DeoxyRiboNucleic Acid and RiboNucleic Acid. And it has been created from the usual precursor protein and Cross Beta Pleated contamination. Since it is a brain system infecting disease, its presence in the very tiny neurons can be observed by only the microscopic system. One of the most common and fearful signs and symptoms alongside the risk factor of this disease is a disorder in regular movements. But soon after, it turns into a high fatal neurological disorder. It means criticism and synchronisation in the brain and the immune system. Consequently, brain and movement-related problems like coma and inabilities in activities are analysed. Women and children are having a high chance to get an infection and can have highly infected brain tissue through the following cannibalism in the regions of Papua New Guinea. Besides, they highly get contact with the Kuru infected- people and even animals. In some areas, ritual-like endocannibalism is a must to be followed by them as their culture, so like their culture, they consume the dead body of Kuru infected or non-infected. And this can be probably considered as the principal wherewithal transmission although a hypothesis found that people who don’t follow cannibalism, can get infected by Kuru Disease [6].

Ferguson-Smith, MA. and his study recently introduced that at the beginning of the disease transmission in 1957, 5%-10% infected patients were found in some regions. His study revealed that negative-fastness in movement, shivering while working had been effectively recognised. Alongside problems had been found while they talk- sometimes get muted and sometimes speak unsteadily. In the critical stage, patients sometimes go into a coma. Death took place within 1year of this disease. For consuming, preparing the fleshes, brains or other tissues of estimated cannibalising material; women do these processes. That’s why getting in touch with fluid of the materials, and they have a high chance of infection. And several studies revealed that the percentage of women is more than that of men. Besides, men do not involve themselves in this process. That’s a very relevant evidence of this study [7].

Structural Protein Effects

In the 20th century, researchers discovered that any disease could be caused by protein and the protein that causes disease-most often neurodegenerative illness, disorder and other diseases is called Prion Protein; in short PrP. PrP has two effective forms- PrPC that is called Cellular Prion Protein, and the other one is- PrPSc, which is called Scrapie Prion Protein [8]. In the chromosome number 20 of the human body, PRNP bears a protein called PrP [9]. PrPC is the normal protein and also found in heal the human body; it is formed as Alpha-helices form [10]. But because of the amino-acid formation and polypeptides, Alpha-helices of PrPC transform into PrPSc and beta sheets from the transforming receptacle named Molten Globule [11]. PrPSc is an abnormal and unstable phase that plays a role in mutation of PrP. PrPSc impacts on the standard and cellular prion protein-PrPC and it turns into PrPSc and creates a beta-sheet that is abnormal and misfolded/improperly folded [12]. The misfolded or PrPSc effects on the Central Nervous System and final cause is the failure of activities in the brain [13]. The centrum of the mind is Neuron. Neuron is consistent with axon, dendron, cellular body. Combination of Axon and Dendron features Neural Synapses. Due to the misfolded PrPSc, Neural Synapses get blocked and heal cells start to be deceased and damaged [14]. Microbials soon begin to kill the damaged cells, and the spongiform phase gets created.

Finally, death occurs by average 1year onset of the disease infection [15] (Figure 1).

In the above-added Figure: 01, two types of Prion Protein- PrPC and PrP Sc have been introduced by several signs and graphical work. In the figure, the regular phase of Cellular Prion Protein and abnormal phase of Scrapie Prion Protein have been accurately figured out with the accurate analysis and study on Alpha-helices and Beta-sheets. As beta-sheets belonged to an improper phase of protein, it contains a complicated gene-coding cycle that acts for mutation. And be ta-sheets containing Scrapie Prion Protein inspire other Alpha Helices normal prion protein. And if the appearance of one PrPSc is found in the human body, it transforms into many and many heal PrPC, and the brain and immune system get positively affected (Figure 2). A neuron is consistent with a cellular body, axon and dendron. PrPC or Cellular Prion Protein generally remains in the human body that does not play any dangerous role in the case of disease production. It has a connectivity to the human brain and its neurons. Cellular Prion Protein moves to the Neurons and the human brain through the Axon and axonal transport. So, axon is considered as the media [16]. Actually, PrPC plays a role in the comprehensive management and activities of the brain, body and immune system. If there remains any misfolded Prion Protein anyhow, that can cause life hampering disease.

Transmission

Kuru is a prion disease that is transmitted by practising cannibalism and consuming affected human brain [17] Or no other natural criticism and complications can be acknowledged as the wherewithal of the transmission of the protein-based disease. Principally, improperly appeared protein is the responsible because, through experiment, it has been revealed that the misfolded protein-based PrPSc blocks the neural synapses. Finally, it impacts the brain and immune system and causes death. Thus, kuru disease occurs and effects [18]. Besides, PrPSc contains scrapie and scrapie is positively related to the Transmissible Spongiform Encephalopathies [19]. In the 19 mid’s, it was revealed that Kuru is the first human prion disease transmitted to the Chimpanzees. For this reason, it was proved that the principal cause of transmission of Kuru is allowing and practising Cannibalism [20]. Later, cannibalistic people were found having the prion disease. And from then, Kuru started to transmit to humans. Finally, in 2004, when the government of Papua New Guinea and other infected regions headed to avoid the practice, the cases of Kuru were declined and discarded [21]. Kuru is under the section of Infectious TSE-Transmissible Spongiform Encephalopathies that effectively affects the brain and immune system. TSE is formed from Infectious, Sporadic and Familial features. Besides, Kuru cannot be defined in Sporadic and Familial Sections. As Kuru can be transmitted, it has been remarked under the Infectious TSE or Transmissible Spongiform Encephalopathies. After studies introduced that the patients who were infected in and died of Kuru Disease, they anyhow got contact with the brain and materials got contacted with PRPN. The pathophysiology of Kuru disease is quite unimaginable since it extracts growth hormones and central nervous system [22].

Death and Affected Analyses with Epidemiology

The cases of Kuru features fatality and left untreated for those patients who were infected because there was neither any proper treatment nor any kind of reliable and recommended medication. In the 20th Century, precisely in 1957-1959, frequency of cases of neurodegenerative disease-Kuru was about 2700, and mostly 200 infected died because of the lack of treatment [22]. A study by Alpers, MP., et al. revealed that during 1987-95, 66people died of being attacked by the neurodegenerative disorder creating Kuru Disease; in which 49 people were in female sex, and the rest 17 were male. Every year, about 3-12 people died from it. Including that in 1987, a one-year-old person and 1991, a 30 years person died from the suspected epidemic creating disease. In one study, the incubation period of the disease and its infection was introduced 30 years and here on this study, ranging to 1995, showed 35 years. The study by Alpers, MP., et al. also introduced that in 1987, overall 12 people died from the Kuru in which eight people were females and 4 were males. People ranging from 50-59 & 30-39 died most- 10(5people+ 5people=>50-59ages + 30-39ages) in number then in 1987. And 1death was found below 20, and ranging 20-29, 1 person died. In 1988, 8 people died; 7 were females, and 1 was male. In that year also, people aging 30-39 and 50-59 were mostly infected- 6people (3+3=>30-39+50-59). In 60-69 and 40-49, 2 deaths were found one by one in every range. In 1989, 11 patients died while female and male in number were respectively 6, 5. But in 1989, ages from 40 to 49 suffered most considering the death- 4 in number. For the people of 30-39 and 50-59 ages, death cases were respectively 3,3. And also in the year, among people aged 60-69, 1 death was caused. In 1990, death cases started to decline, occurring nine deaths; in which seven were female and 2 were male. People ageing from 40 to 49 faced five deaths. 50-59 aged people faced three deaths, and only one death was found in 30-39 aged people. But a flabbergasting feature is that in 1991, there were three deaths and three of them were female. In between 40-49 and 30-39 age, respectively 2 & 1 deaths were revealed. But death cases increased by 1992, causing seven new deaths. Here females and males were consecutively 5 and 2. In 50-59 ages, four deaths and 40-49 ages, three deaths were found. But death cases declined by 1993. Then, overall, four deaths were introduced and all of them from female gender. In age variation, it has been found that from 50 to 59 age, three people’s death were found and one additional death was found from the 40- 49 range. Five new deaths were newly started in 1994 in which four were female, and 1 was male. From the age range of 60-69, 1 new death; in 50-59 ages, three new deaths and 40-49 ages, one death were revealed. Seven new deaths were found in 1995. 1, 4, 2 deaths were found respectively in the age ranging of 40-49, 50-59, 60-69 [23].

Symptoms

Like other diseases, Kuru has several complicated and problematic symptoms which indicates the possibility of Kuru. Pain in the body and headache(especially in joint arms) is one of the symptoms in most cases [24] Serious management complications by improper movement in the human body, problems in activities performing, jerking in Human Body are also the effects and symptoms [25]. Random and unreasonable Laughing and brain working system complications [26] and Coma(in serious and final feature- not always happens) are the impacts on heal human body [27].

Prevention

As Kuru is a prion and rare disease caused from the infected brain tissue and spinal cord fluid [28], it is tough to get the proper medication as while the PrPC transforms into PrPSc(misfolded protein), PrPSc forms the Beta Sheets is the leading causing reason of complications due to its genomic abnormality. It is also a discovery that a disease can be occurred by any protein. So, currently, no medication has been accurately defined [29]. A study by Louisiana State University revealed that Kuru cases were clearly declined by unfollowing Cannibalism. So, avoiding cannibalism can be the wherewithal to prevent it [30].

Conclusion

Kuru has been identified as the first human TSE. It indeed penetrates the human body by oral intake-through practising cannibalism. As for citizens of Papua New Guinea practised cannibalism, the disease has been transmitted by the conduct; proved by experiment. Besides, it is also revealed that Chimpanzees are remarked as the media of transmission to humans. There were three stages- Ambulant, Sedentary and Terminal Stage in the discussion of Pathophysiology. Cellular Prion Protein remains in an ordinary human body that does not affect the human body by any disease. But on the contrary Scrapie (beta-sheet containing and abnormal) Prion Protein is the main reason for Kuru disease. And day by day, it modes Cellular Prion Protein into Scrapie Prion Protein. That finally plays a role in blocking the Neural Synapses, and then the brain gets affected. Later on, the condition of the patient attacked with Kuru gets complicated, and in the terminal stage, people worsen into Coma and then to Death. As currently, no vaccination or medication has been defined, there is no alternative of Prevention in our conducts while prevention is just to prohibit cannibalism. If cannibalism can be banned, the entire world can get rid of a suspected future epidemic.

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