In Ayurved for treating pain they explained Shoola Hara, Vedana. Sthapana Dravya ..... candle, till the patient can bear the heat. It works effectively ...... Clinical Sports Medicine-Peter Brukner and Karim Khan, 3rd Edition,. 2008. 10. .... Derangements in these normal secretory patterns are one of the earliest signs of beta cell ...
Research Trends in Medical Sciences Volume - 2
Chief Editor Sergiy Fedorov (MD, PhD, MBA, DSci) Professor of Therapy and Family Medicine Department of Postgraduate Faculty, Ivano-Frankivsk National Medical University, Ukraine
AkiNik Publications New Delhi
Published By: AkiNik Publications AkiNik Publications 169, C-11, Sector - 3, Rohini, Delhi-110085, India Toll Free (India) – 18001234070 Chief Editor: Sergiy Fedorov The author/publisher has attempted to trace and acknowledge the materials reproduced in this publication and apologize if permission and acknowledgements to publish in this form have not been given. If any material has not been acknowledged please write and let us know so that we may rectify it. © AkiNik Publications Pages: 124 ISBN: Price: ` 575/-
Contents Chapters 1.
Page No.
Ayurveda Sports Medicine: An Emerging Field for Ayurveda in the Management of Sports Injuries
01-42
(Dr. Bhangare Archana Nivrutti and Dr. Lahange Sandeep Madhukar)
2.
Review of Diabtes Mellitus and Complications
43-67
(Dr. Siva Rami Reddy E)
3.
Recent Amendments in Hippocratic Oath and Its Current Relevance
69-79
(Ganesh Singh Dharmshaktu and Tanuja Pangtey)
4.
Role of Nanomedicine: Therapeutic, Diagnostic and Pharmaceutical Research and Development
81-90
(Rohini Gupta)
5.
Autologous Platelet Orthopedics
Rich
Plasma
Therapy
in 91-101
(Madhan Jeyaraman, Naveen Jeyaraman and Prajwal GS)
6.
New Research Trends in Diabetes: The Islet Cell Transplantation in Type 1 Diabetics in India (Dr. Sarmistha Sarkar and Dr. Ajay Meshram)
103-124
Chapter - 1 Ayurveda Sports Medicine: An Emerging Field for Ayurveda in the Management of Sports Injuries
Authors Dr. Bhangare Archana Nivrutti Assistant Professor, Department of Kayachikitsa, Mahtma Jyotiba Fule Ayurved College and Hospital, Chomu Jaipur, Rajasthan, India Dr. Lahange Sandeep Madhukar Assistant Professor P. G. Department of Sharir Rachana NIA, Jaipur Rajasthan, India
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Chapter - 1 Ayurveda Sports Medicine: An Emerging Field for Ayurveda in the Management of Sports Injuries Dr. Bhangare Archana Nivrutti and Dr. Lahange Sandeep Madhukar
Introduction Sports medicine is a branch of medicine which can be defined precisely as medicines developed in response to the sportsmen needs and increasing their physical performance and prevents sports injuries. Sports medicine has two goals to achieve. Primarily physical and mental fitness of the sportsman and second goal is treating the sporting injuries of the sportsman. Ayurvedic treatment procedures like Panchakarma (purification & rejuventory system), yoga (meditation) Rasayana (Rejuvenation) and herbal compounds can do wonderful impacts in sports medicine. Sports medicine is the application of various medical principles to the sports activities, physical exercise and performance endeavors. It is related to the physiological as well as pathophysiological aspects of sports and athletics injuries. It is not only prevention and treatment of injuries, but it is a scientific investigation of training methods and practices in sports also. A sports injury can be defined as any kind of injury, pain, or physical damage that occurs as a result of sport, exercise or physical activity. Although the term sports injury can be used to define any injury sustained as a result of sport, it is most commonly used for injuries that affect the musculo-skeletal system, which include the muscles, bones, tendons, cartilage and associated tissue. The hinge joints are vital for movement and vulnerable to injury. It contains number of muscles, ligaments, tendons and bones. Hinge joint is involving in so many outdoor sports which causes various types of injuries such as fracture, dislocation, sprains, strains, inflammation and wound. Sports injuries are injuries that happen when playing sports or exercising. Some are from accidents. Other can results from poor training practices or improper gear. Some people get injured when they are not in proper condition. Not warming up or stretching enough before you play or exercise can also lead to injuries. According to Ayurveda, disease occurs in the body due to two factors Page | 3
one is Nija (within the body) and other is Agantuja (external factors),likewise sports injuries are also occurs mainly due to sudden impact or due to continues wear and tear. When an injury occur due to sudden impact, body respond to that condition which lead to immobility and other inflammatory responses, it's a protective mechanism of body, due to excessive body activity strained muscles, ligaments and tendons can get injured excess of toxin can accumulate in individual organ systems and can lower both mental and physical sharpness. In Samhita also, we find references of sport injuries under exogenous diseases (Aagantuja rogas) caused due to the contact of external factors like fire, poisonous substances and also due to trauma. In classifying diseases, Shusruta Samhita has included the category of diseases caused in a weak person due to fight with a stronger one (Sanghaatabala-pravrtta-vyadhi). This can be correlated with traumatic diseases such Shoola (pain), Shopha (swelling), Vranashopha (inflammatory swelling), Vrana (wound), Kandbhagna (fracture), Sandhimukata (dislocation), Sanayugatavata (ligament, tendon and nerve injuries) caused due to various games such as boxing, wrestling, martial arts etc. Acute (traumatic) and chronic (overuse) these are two types of sports injury. Acute injury is a sudden injury that is usually associated with a traumatic event such as clashing into another player during sports or a fall from a bike. You body undergo changes during this period and often it is a negative one. A traumatic impact can cause your bone to crack, muscles to tear or ligaments to snap. You will experience a sudden sharp pain that is often severe, immediate swelling and even cold purple regions in your body that indicates a lack of proper blood circulation in that injured part. You may even lose your stability if your knee ligaments are torn and you will be unable to place your body Weight on it. Chronic injuries can be also called overuse injuries as the name suggests, it is caused by overuse of particular part of body either through sports or exercises. They develop slowly and last a long time. Their symptoms are mild compared to acute injuries and the pain they cause are also little. This causes the patient to ignore the injury and carry on with their activities. Over time, it will build up and cause more problems. Some common Symptoms of chronic injuries include experiencing pain whenever you engage in sport activities, swelling after each game and constant aching when you are not doing anything. In other words, chronic injuries are lifestyle threatening as they restrict you from participating in many things. Some examples of chronic injuries are stress fractures caused by repeated loading of a particular part, causing tiny Cracks in your bone each time. Tennis players also commonly suffer from tennis Page | 4
elbow which is effectively pain near the elbow due to over use. There are so many sports injuries related to hinge joint like; tennis elbow, golfers elbow, wrist sprain, mallet finger, anterior knee pain lateral ligament injury, menisci injury, ankle sprain, Extensor tendinitis, tarsal tunnel syndrome, Achilles tendinopathy etc. The injury may be acute or chronic but it has to be treated immediately. In Ayurved Samhitas we can’t find any direct explanation of sport injuries but with the help of classics we can explain sport injuries. Usually most of the sport injuries occur in hinge joints due to exposure during various sports a part from emergency(head and injuries to spinal cord) and surgical conditions(ligament tear etc.,) based on Ayurved we can treat the conditions apart from these two. The common symptoms of sport injuries are pain, swelling, dislocation, fracture, wound and Hematoma in Ayurved we find detail description of these. The common among above mentioned symptoms is pain. In Ayurved for treating pain they explained Shoola Hara, Vedana Sthapana Dravya, Vata Chikitsa like Snehana, Swedana and Basti. If the injury is associated with swelling we use Shotha Hara Dravya such as Shoth Hara Mahakshaya Shoth Hara Lepa, and such herbal drugs which have antiinflammatory properties in it. If the sports injury is associated with skin injury such as abrasion, laceration, wound etc. in this condition we use Shodhan, Ropana Dravyas are use. In hematoma treatment is done by Agnikarma and Kshara Karma. In case of acute injury such as fracture, dislocation, treatment is done same as that of Bhagana Chikita as described in our classics. Acharaya Shusruta has given detailed description about Bhagna Chikitsa. Ayurveda plays an important role not only in treatment but also in prevention and control of sports injuries. To avoid injuries to sportsman Ayurveda has mentioned certain treatment modalities such as proper diet, Rasayan therapy, Abhayanga, exercise and yoga etc. yoga keeps strong as physically and mentally to every Sportsman as well as treats the various Sports injuries with the help of different techniques of yoga. Sports and Ayurveda Ayurveda is science of life which deals with the health, durability and quality life of each and every individual. In Ayurveda there is no direct description of sports and its related injuries but we find references of exogenous diseases (Aagantuja Rogas) caused due to the contact of external factors like fire, poisonous substances and also due to trauma. In classifying diseases, Susruta Samhita has included the category of diseases caused in a
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weak person due to fight with a stronger one (Sanghaatabala-pravrttavyadhi). This can be correlated with traumatic diseases such as sprain, muscle injuries, wounds, fractures, dislocation which caused due to various games such as boxing, wrestling, martial arts etc. Ayurveda gives enormous description of Vranashopha (inflammatory swelling), Vrana (wound), Kandabhagna (fracture), and dislocations (Sandhi-Mukta) and also their treatments are mentioned in Samhita which fall under the branch of Shalya-Tantra. There is also description of symptoms like Shoola (pain), Shopha (swelling), Snayugatvata (ligament and tendon injury) etc. and their Ayurvedic management. Sports medicine is a special branch of modern medicine. All the subjects of it are described in Ayurveda. A full description about Ayu, Vyayama, and good built of body, Dincharya and Ritucharya shows that over Ayurveda Acharya were very conscious about good health. Exercise has been an important part of the Ayurvedic routine for thousands of years before it becomes a modern aid. Through exercise one gets rid of heaviness and stiffness of the body because it burns Ama (digestion impurities) and creates more flexibility, lightness, smoothness and easiness. Other benefits include enhanced firmness, endurance, and ability to do work. It pacifies all three Doshas and creates balance suitable for the body type and season. It enhances the digestion, and if done properly, it dissolves impurities in the tissues. Exercise enhances immunity and capacity for food. It removes fatigue, sops early aging, and retards weight gain. The word Vyayama creates a sign sports in Ayurveda. The term ‘Ayu’ stands for the combination of the body, sense organs, mind and soul, and its synonyms are Dhari (the one that prevents the body from decay), Jiivit (which keeps alive), Nityaga (which serves as a permanent substratum of this body) and Anubandha (which transmigrate from one body to another [1]). Acharya Charaka has described the definition of Vyayama shows that for good sports fitness Vyayama how much needed. Such a physical action which is describe and is capable of bringing about bodily stability and strength is known as physical exercise [2]. This has to be practiced in moderation. Acharaya Sushruta explains physical exercise as a sense of weariness from bodily labour, and it should be taken every day. After taking physical exercise, the whole body should be massaged, until it gives rise to a comfortable sensation in the limbs. It makes the body stout and strong, helps the symmetrical growth of the limbs and muscles,
1
शरीरे न्द्रियसत्त्वात्मसंयोगो धारर जीवितम्| वित्यगश्चािुबन्धश्च पयाायैरायुरुच्यते|| ( च. सू. 1/42)
2
शरीरचेष्टा या चेष्टा स्थैयााथाा बलिवधािी| दे हव्यायामसङ्ख्याता मात्रया तां समाचरे त्|| ( च. सू. 7/31)
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improves the complexion and the digestive powers, prevents laziness and makes the body light and glossy, firm and compact [3]. Physical exercise causes physical development, luster, compactness of body parts, stimulation of digestive power, absence of idleness, firmness, lightness, cleanliness, tolerance to fatigue, exhaustion, thirst, heat, cold etc. and provides optimum immunity. There is no anti-obesity measure equal to physical exercise; one who performs physical exercise regularly can’t be overcome by enemies, he can’t be attacked and subdued suddenly by senility and his musculature becomes firm. Physical exercise brings about lightness, ability to work, stability, and resistance to discomfort and alleviation of Doshas (especially Kapha).it stimulates the power of digestion [4]. Acharya Charaka tells about the benefits of Vyayama that physical exercise brings about lightness, ability to work, stability, resistance to discomfort and alleviation of Doshas (especially Kapha). It stimulates the power of digestion [5]. Acharaya Vagbhatta says about the Vyayama the lightness of body, ability to do hard work, good appetite, and loss of excess fat, stable and constitute physique accrue from physical exercise [6]. Common Clinical Conditions Related to Sports Injuries in Ayurveda In Ayurveda we find the references of sport injuries under exogenous diseases (Aagantuja Rogas) caused due to the contact of external factors like fire, poisonous substances and also due to trauma. In classifying diseases, Susruta Samhita has included the category of diseases caused in a weak person due to fight with a stronger one (Sanghaatabala-pravrttavyadhi). This can be correlated with traumatic diseases such as Bhagna (bony injuries), Sandhimukta (joint injuries), Mansagatvata (sparin), Snayugatvata (ligament, nerve and tendon injuries), Vrana (wound), Shopha (inflammation) caused due to games such as boxing, wrestling, martial arts etc. The common symptoms of sport injuries are pain, swelling, dislocation, fracture; wound, sprain and strain in Ayurveda we find detail description of these symptoms like Shoola, Shopha, Vrana Shopha, Vrana, Bhagna and Snayugatvata. 3
् ् शरीरायासजननं कर्म व्यायार्सञ्ज्ञितर् ।तत कृ् त्वा तु स ुखं देहं ञ्ज्ञिर्ृद्गीयात सर्न्तत॥ (स ु.ञ्ज्ञि.24/36)
शरीरोपियः काञ्ज्ञन्तर्ामत्राणां स ुञ्ज्ञिभक्तता ।दीप्ताञ्ज्ञित्वर्नालस्यं ञ्ज्ञिरत्वं लाघिं र्ृजा॥ (स ु. ञ्ज्ञि.24/37) 4
लाघिं कर्मसार्र्थ्यं ि ैयं दःखसञ्ज्ञहष्णतु ा। दोषक्षयोऽञ्ज्ञििृञ्ज्ञिश्च व्यायार्ादपजायते ॥ (ि. सू. 7/32)
5
् (ि. सू. 7/1 ) स्वेदार्र्ः श्वासिृञ्ज्ञिर्ामत्राणां लाघिं तथा| हृदयाद्युपरोधश्च इञ्ज्ञत व्यायार्लक्षणर्||
6
लाघिं कर्मसार्र्थ्यं दीप्तोऽञ्ज्ञिर्ेदसः क्षयः| ञ्ज्ञिभक्तघनर्ात्रत्वं व्यायार्ादपजायते|| (अ.ह्र.सू. 10/2)
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Shopha (Swelling) In sports person traumatic injuries are more common and these injuries manifest as pain and swelling in involved tissues. Inflammation is the commonest in sports injuries such as bursitis, tendinitis, Bruise etc. Sports injuries can affect any part of the body, including the muscles, bones, joints and connective tissue (ligaments, tendons). Inflammation is the body’s reaction, towards any type of sports injuries. Swelling is a normal reaction of the body to an injury. It is an abnormal enlargement of a body part due to sports injury. Edema is described as fluid or swelling that has accumulated in the tissue outside the joint capsule. Effusion is described as that is inside the joint capsule, such as swollen ankle and knee. Inflammation can be correlated to Shopha in Ayurveda. Ayurvedic texts have two terms Shopha and Shotha to indicate inflammatory swelling and edema. It is of six kinds i.e. one each by Vata, Pitta, Kapha, Rakta, Sanipata and Aagantu [7]. Aagantuja (Produced by extraneous cause like blow, injury, insect bites, foreign bodies, poison etc,) symptoms of Pitta and Rakta kinds of oedema and red colour are its symptoms [8]. The Abhigataja type of swelling is caused by excision, incision, comminution, fracture, exposure to excessive pressure, grinding assault, grievous hurt, trying by rope act [9]. Shoola (Pain) Muscles strain and ligaments sprain are the most common injuries that cause pain in the young athlete. They can be caused by athletic overuse, improper body mechanics and technique, lack of proper conditioning, insufficient stretching as well as trauma. Pain is a protective body mechanism which alerts the person about the harmful condition or experience that occurs in the body. Pain can be somatogenic or psychological. The somatogenic pain occurs due to physiological cause or external injuries. Vitiated Vata starts destruction in joints by creating pain and inflammation in joints [10]. In Ayurveda, it is known as Shoola. Shoola can be in any region, but it is caused due to the aggravation of the Vata Dhosha. Vata Dhosha is 7
स षञ्ज्ञिधो िातञ्ज्ञपत्तकफशोञ्ज्ञणतसञ्ज्ञिपातार्न्तञ्ज्ञु नञ्ज्ञर्त्तः (स ु.सू.17/4)
……….ञ्ज्ञपत्तरक्तलक्षण आर्न्त ुलोञ्ज्ञहतािभासश्च || (स ु.सू.17/5)
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तत्रार्न्तिश्छेदनभेदनक्षणनभञ्जनञ्ज्ञपच्छनोत्पेषणप्रहारिधबन्धनिेष्टनव्यधनपीडनाञ्ज्ञदञ्ज्ञभिाम…… | (ि.सू.18/4)
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हञ्ज्ञन्त सञ्ज्ञन्धर्तः सञ्ज्ञन्धञ शूलाटोपौ करोञ्ज्ञत ि ॥ (र्ा.ञ्ज्ञन. पू. 22/21)
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responsible for every movement and action in the body. The hindrance in Vata flow leads to the pain, the obstruction in Vata flow cause pain. According to Acharya Sushruta without vitiated Vata there will be no pain, pain in any part of the body is caused by the Vata Dosha, without Pitta there is no ripening and without Kapha there is no pus, hence during the stage of ripening of the oedema (inflammatory) all the Dosha are involved [11]. Vrana (Wound) Common type of skin wounds in physical activity injuries includes abrasion, blisters and lacerations. Wounds of the integumentary system occur frequently in athletics. Wound can occur in many sports, and assessment and care of such trauma in an essential skill. The purpose of this is to do review of Vrana (wound) that may occur in sport and their acute management. Vrana is the commonest painful condition that every sports person being suffers in their life and skin is the largest organ in body. Vrana may be classified as Nija and Agantuja, where Agantuja Vrana or Sadhyovrana with a correlation to traumatic wound. Sandhi Gata Vrana (Ligament Injuries) The discharge does not appear even after pressure, when the wound is present over the joint (Sandhi) but when there is flexion, extension, elevation, depression or by running, coughing and straining it comes out. It will be slimy, sticky and appears as if churned with blood. Sushruta in his ChikitsaSthana 2nd chapter Sadyovrana Adhyaya explained the Sadyovrana in detail which comes under Aagantuja Vrana. Aagantuja Vrana is a fresh wound caused by various external agencies such as bites of animals, birds, snakes, trauma from sharp or blunt objects, Agni, Kshara, corrosive drugs, arrows etc. [12]. Sushruta has classified the Aagantuja Vrana into varieties according to their nature, depth, by the violence, surrounding tissue. These are Chhinnam (excised wound), Bhinnam (deep punctured wound), Viddham (superficially punctured wound), Kshathaja (incised wound), Pichchita (contusion), and Ghrista (lacerated wound) [13]. 11
िातादृते नाञ्ज्ञि रुजा न पाकः ञ्ज्ञपत्तादृते नाञ्ज्ञि कफाच्च पूयः |
् ् रपाककाले पिञ्ज्ञन्त शोफांस्त्रय एि दोषाः || (स ु.सू.17/12) तस्मात सर्िान पञ्ज्ञ 12
तयोः शारीरः पिनञ्ज्ञपत्तकफशोञ्ज्ञणतसञ्ज्ञिपातञ्ज्ञनञ्ज्ञर्त्तः; आर्न्त ुरञ्ज्ञप
प ुरुषपशुपञ्ज्ञक्षव्यालसरीसृपप्रपतनपीडनप्रहाराञ्ज्ञिक्षारञ्ज्ञिषतीक्ष्णौषधशकलकपालशृङ्गिक्रेष ुपरशुशञ्ज्ञक्तकु न्ताद्यायधु ाञ्ज्ञभघातञ्ज्ञनञ्ज्ञर् त्तः । (स ु.ञ्ज्ञि.1/3) 13
् (स ु.ञ्ज्ञि.2/9) ञ्ज्ञछिं ञ्ज्ञभिं तथा ञ्ज्ञििं क्षतं ञ्ज्ञपञ्ज्ञच्चतर्ेि ि ।घृष्टर्ाहुिथा षष्ठं तेषां िक्ष्याञ्ज्ञर् लक्षणर् ॥
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Bhagna (Fracture & Dislocation) Fracture and dislocations are both of the common hazards in sports injuries such as colle’s fracture, scaphoid fracture, phalangeal fracture, dislocations of the finger joints, Patella dislocation etc. Especially Sushruta has mentioned trauma is the major cause of bone injury & joint dislocations, in perceptive of Ayurvedic literature various references are available regarding Bhagna about their etiological factors and treatment. In such conditions our body requires assistance for healing assisting or helping an injured bony tissue/cartilaginous tissue is termed as Bhagna Chikitsa in ancient Ayurvedic literature. Ayurvedic Management of Sports Injuries Ayurveda is an intricate system of healing for treating chronic or acute ailments. The specialty is with the maintenance of physical, mental and social health of an individual and society as a whole. There is a lot of knowledge available regarding different treatment modalities for injuries, such as uses of drugs and dietetics as well as practices of rehabilitation. The fitness of the sportsman is not merely his healthy condition but it is a state of physical and mental endurance to extreme stress. Even though the injuries of any other kind do not distinctly vary from those of sports, the etiology and line of treatment may have to be considered with different view. Apart from the injuries, extreme fatigue, Stress and allied problems also have taken place in the field of sports medicine. As the sports buzz has risen in these days, at the same proportion propensity for sports injuries are inclining especially in the areas of joints like elbow, wrist, knee etc. particularly with outdoor games. Though the sports are professionalized and commercialized, the amateur sports are even now the main stay in India. Sports medicine, as a separate medical specialty has a fairly recent origin and it is quite pertinent to ask how a medical system, that is more than five thousand years old, can make any contribution in a field like sports medicine which, by stretch of imagination, is not more than a few decades old. In traditional medical system we definitely do not find direct references regarding a specially called sports medicine nor do we have readymade management plans for sports related ailments. It requires a lot of close observation and correct perception of this field. Hence a blind critique can easily shut the doors on any exploration on the topic concluding that “Ayurveda has nothing to do with sports medicine” but when we observe with the open mind of a curious scientist, we find enormous possibilities. It Page | 10
makes us appreciate a very significant contribution that Ayurveda can make to improve the effectiveness of sports medicine as a whole. This attempt aims at exploring the scope of Ayurveda in making very significant contribution to the field of modern sports injuries and thereby, could revolutionize and contributes a great deal to the Ayurvedic sports medicine. Aims of Ayurvedic Sports Medicine
Prakritisthaapana (Conditioning of Sports Person): to regain physical fitness of a sports person and send him back to the field as early as possible.
To evaluate the effect of various principles of Ayurvedic management in different sports injuries.
Objectives of Ayurvedic Sports Medicine
Prevention of injuries and illness related with sports and other activities.
Early treatment of sports related injuries and illness.
Improvement of physical fitness and performance of sportsperson.
Design of treatment, exercise and nutrition programs for maintaining peak physical performance.
Treatment of acute and chronic injuries.
Rehabilitation of sports injuries with Panchakarma treatment and exercises.
Conditioning by complementary physiotherapy and yoga
Better and quick result for post-operative and traumatic complication.
Early recovery and back to sports.
Special treatment to promote strength and tone of the muscles.
Ayurvedic herbal combination for better performance.
Yoga and Ayurveda make sports person physically and mentally fit to complete internal level.
therapy
of
Ayurveda,
Role of Ayurveda in Sports Medicine Panchakarma therapies and internal medications are highly beneficial and useful for sports person. There are different types of treatment for
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different activities, e.g. for endurance athlete, treatment and medicine will be different from a power training sports. This kind of scientific approach has to be adopted in sports, from the traditional medicine. Vaidya of Kalari Gurukul organization engaged in treating sports injuries by using conventional Marma Chikitsa (special treatment for injuries, contusion, sprain, dislocation and fractures). How to Maintain the Fitness and Prevention from Sports Injury Current sports medicines contain Supplementation with a multi-vitamin or anti-oxidant which appears to be safe; however large doses may result in serious toxicities. Ayurveda describes various rejuvenative therapies with the help of special class of medicinal preparations called Rasayana that are believed to rebuild the body and mind, prevent degeneration and postpone aging or rather reverse the aging process. Determining the frequency, intensity and duration of exercise is important. Running is most commonly associated activity; however other aerobic activities (e.g. swimming) and team sports (e.g. basketball) also have the potential for exercise addiction. Ayurveda has special directions regarding exercise which are mentioned under the daily regimen (Dinacharya) to keep fit and healthy. The aim of a sportsperson is to maintain 'positive health to achieve their goal in winning the game'. Hence sportspersons need to resort to a specific type of diet, exercise etc., without which achieving the goal will be impossible. Ayurveda maintains the health of the sportsperson by following the norms of daily regimen, seasonal Regimen (Dincharya, RituCharya) and good behavior (sadvritta). Ayurveda also cures the sports injuries through its unique measures, thereby serving both prevention and cure. Management of Clinical Conditions in Ayurveda Related Sports Injury Concepts of sports injuries and their management can be spotted in Ayurvedic Samhitas like- Bhagna (fracture & dislocations), Vrana (wound), Vranashopha (inflammatory conditions), Sadhyovrana (acute wounds), Snayugatavata (tendon &ligament injury) descriptions of Vata Vyadhi (chronic & painful conditions) related to musculoskeletal and neuro- motor system. Treatment Protocols in Ayurvedic Sports Medicine There are five main aim of Ayurvedic sports medicine asi.
Management of injuries Page | 12
ii. Rehabilitation of injuries iii. Active mobilization iv. Passive mobilization v.
Strengthening
The foremost aims of Internal Medication are i.
To boost up tissue healing
ii. To alleviate pain iii. In order to strengthen the injured part The foremost aims of External Therapies are i.
To alleviate pain
ii. Strengthens joints iii. To improve function The foremost aims of Lepa/Aalepa/Upanaha is i.
To alleviate pain
ii. To promote tissue healing A. Management of Shopha In Ayurveda the process of inflammation is known as Shopha. The basic line of treatment for the Shopha is of Sanshaman (Vatashamak and Vedanashamak drugs) by using local application of medicines and Shodhan Chikitsa. Alepa Poulticing is the first line of treatment for Shopha. It is common for all kinds of swelling which contain kalka (paste) of various Vatashamaka, Vedanashamaka drugs that applied on the site of swelling. Acharya Sushrut says the Apatarpana is the first, general and principal remedy in all types of Shopha (swelling) [14]. Blow Shloka clearly explains the indication of Lepa. It should be applied in acute swelling and in painful conditions. So in the acute management of Shopha, Lepa is the best option [15]. Bandha Bandha means bandaging due to which wound healing, and stability of 14 15
अपतप मणर्ाद्य उपक्रर्ः; एष सिमशोफानां सार्ान्यः प्रधानतर्श्च | (स ु.ञ्ज्ञि.1/11)
् (स ु.ञ्ज्ञि.1/14) ू रुजेष ु ि | यथास्वैरौषध ैले प ं प्रत्येकश्येन कारयेत || शोफे षूञ्ज्ञितर्ात्रेष ु व्रणेषग्र
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the bony joints is obtained [16]. In Abhigataj Shopha, symptoms start with pain and then bring about the vitiation of Doshas. Such swellings are cured when treated with such therapies as bandages including talisman, incantations, administration of medicines, and application of ointments, fomentation and cold sponging [17]. Anti-inflammatory drugs has been mentioned in Ayurveda like Shothahara Gana, Varana Shothhar Gana, Vishgna Dravyas (for allergic inflammatory conditions) etc. Patla, Agnimantha, Syonaka, Bilva, Kasmarya, Kantakarika, Brahati, Salaparni, and Prisniparni these ten drugs consist of anti-inflammatory contents which control inflammation [18]. Treatment of Vranashopha (Wound Along With Swelling) In ayurveda there are seven successive treatments for swelling leading to an wound [19] as follows1.
Vimlapana (softening by kneading with fingers)
2.
Avasechana (bloodletting)
3.
Upanaha (warm poultices)
4.
Patana (incising)
5.
Shodhana (cleaning)
6.
Ropana (healing)
7.
Vaikritapaha (moving/warding off the abnormalities)
B. Shoola (Pain Due to External Injuries) Snehana is preferred as a highly effective form of therapy for all sports of aliments. Massage helps reduce pain because it pacifies Vata, allay joint and muscle stiffness, increases circulation mobilizes toxins and relaxes the body. Based on Astanga Hridaya for the Vata, Pitta and Kapha Dosha of the body, Basti (enema), Virechana (purgation) and Vamana (emesis) are the best therapies respectively. Acharay Charak has described Shoola आलेप आद्य उपक्रर्ः एष सिमशोफानां सार्ान्यः प्रधानतर्श्च, तं ि प्रञ्ज्ञतरोर्ं िक्ष्यार्ः- ततो बन्धः प्रधानं,तेन
16
शुञ्ज्ञिव्रमणरोपणर्ञ्ज्ञिसञ्ज्ञन्धि ैयं ि |(स ु.सू.18/3) 17
…………..बन्धर्न्त्रार्दप्रलेपप्रतापञ्ज्ञनिामपणाञ्ज्ञदञ्ज्ञभश्चोपक्रर्ैरुपक्रम्यर्ाणाः प्रशाञ्ज्ञन्तर्ापद्यन्ते|| (ि.सू. 18/5)
18
पाटलाञ्ज्ञिर्न्थश्योनाकञ्ज्ञबल्वकाश्र्यमकण्टकाञ्ज्ञरकाबृहतीशालपणीपृञ्ज्ञिपणीर्ोक्षरु का इञ्ज्ञत दशेर्ाञ्ज्ञन श्वयथ ुहराञ्ज्ञण भिञ्ज्ञन्त
(ि.सू. 4/16) 19
् आदौ ञ्ज्ञिम्लापनं कु यामञ्ज्ञितीयर्िसेिनर् |् तृतीयर्ुपनाहं तु ितुथीं पाटनञ्ज्ञक्रयार् ||
् रोपणञ्ज्ञर्ष्यते । एते क्रर्ा व्रणस्योक्ताः सप्तर्ं िैकृतापहर् || ् (स ु.सू. 17/22-23) पञ्चर्ं शोधनं कु यामत षष्ठं
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Prashamana and Vedana Sthapana Mahakashaya. Pippli, root of Pippali, Chavya, Chitraka, Srigavera, Marica, Ajamoda, Ajaganda, Ajaji and Gandira are drugs for alleviating pain [20]. Saala, Katphala, Kadama, Padmaka, Tumba, Mocharasa, Sirisha, Vanjula, Elavaluka and Ashoka these ten drugs are sedatives and help in pain symptom [21]. Internal as well as external herbal drugs are also administered in pain. The drugs like Yavani, Ajmoda, Chandrashoor, Dhtura, Rasna, Kadamba, Vetus, Jalavatus, Suchi, Parsikyavani, Guggulu, eranda, Tagar, Rashon, Devdaru, Medask, Muchkunda etc. are Shoolhara in nature. Lepa The literally meaning of Lepa is application of paste of herbs on the affected area and leaves it to dry. It is usually applied in cases of swelling, injury, sprain etc. Panchkarma in Shoola Pain can be described as any physical suffering or discomfort caused by illness or injury. Frequent uses of pain killer lower the resistance power. Ayurveda explains the origin of pain is due to vitiated Vata Dosha, once Vata Dosha is treated efficiently the pain subsides automatically. In Ayurveda there are various panchakarma procedures explained for the Management of pain due to vitiation of vata in sports injuries as follows1.
Snehana and Swedana
The procedure includes application of medicated oil which is selected according to type of pain followed by sudation therapy (steam, dry heat, PatraPottali, Pinda Sweda, etc.) Usually done in cases of sprain, back ache, muscular injury as in sports injury. Lumbar pain can as well managed by various types of Basti therapy. Kati Basti, Janu Basti, Manya Basti are region related procedures performed at respective site to manage pain and at the same time strengthen them, for increased performance. Abhyantara Snehana (Internal oleation) is the best therapy to control Vata Dosha; 2-3 tsp of ghee everyday will serve the purpose. 2.
Agnikarma Agnikarma is basically performed in two ways like direct heat and
20
ञ्ज्ञपप्पलीञ्ज्ञपप्पलीर्ूलिव्यञ्ज्ञित्रकशृङ्गिेरर्ञ्ज्ञरिाजर्ोदाजर्न्धाजाजीर्ण्डीराणीञ्ज्ञत दशेर्ाञ्ज्ञन शूलप्रशर्नाञ्ज्ञन भिञ्ज्ञन्त ( ि. सू.
4/17) 21
शालकट्फलकदम्बपद्मकतुम्बर्ोिरसञ्ज्ञशरीषिञ्ज ुलैलिालुकाशोका इञ्ज्ञत दशेर्ाञ्ज्ञन िेदनािापनाञ्ज्ञन भिञ्ज्ञन्त ( ि. सू. 4/18)
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indirect heat. Most commonly we used indirect Agnikarma in which a small rod of Gold with a blunt end, specially designed for this purpose is placed on the affected area and the heat is transferred through the other end by a candle, till the patient can bear the heat. It works effectively and gives immediate relief. Usually done in conditions like joint pain, pain due to cervical or lumbar spondylosis, sciatica, the procedure is done along the path of the nerve, frozen shoulder. The other way (direct heat) is useful in pain at heels which is done by Mruttika Shalaka (earthen rod). 3.
Bloodletting
Bloodletting again is performed in various ways the common methods used in practice are as followsa) Jalaukavcharan (Leech Therapy) Leech only sucks the impure blood from the body. In conditions like painful cracked heels or soles and palms due to excessive dryness, swelling in various tissues or joints, pain due to contused wound where blood capillaries get ruptured and the blood gets accumulated under the skin resulting in pain. Leeches are usually used where the cause of pain lies in blood tissue. The moment the impure blood is sucked out the pain disappears. b) Bloodletting By Syringe or Scalp Vein In this method blood is removed by puncturing the vein in patients where blood pressure constantly remains high without any definite symptoms bloodletting plays an efficient role in local pain, redness, swelling etc. c)
Viddha Karma
This is a miniature of bloodletting; a very small puncture is done with the help of an insulin needle. During this process the knowledge of vital points and symptom related points is essential. C. Vrana (Wound) The healing process of Vrana is a natural process which starts immediate after injury. Sushruta has described the sixty mainfold measures (Shastivranopkarma) for a Vrana management from its manifestation to the normal rehabilitation of hairs in the scar tissue. He has divided the wound treatment as Aushadi Chikitsa and Shastra Chikitsa. There are six kinds of swellings (Shopha), and the following eleven measures commencing with Apatarpana and ending in Virechana, should be Page | 16
regarded as their cure. These are the proper remedies for a swelling and do not prove hostile to cases of swelling which are transformed into wound [22]. Treatment of Sadhyovrana (Acute Wound) Immediate general treatment is to pacifying the heat released at the site of injury due to Pitta aggravation by special cooling measures. Portions of Sneha (oily or fatty liquids) and using the same as a washing should be advised in such cases. Preparations of Veshavaras and other Krisharas largely mixed with oil or clarified butter should be used as poultices and fomentations with the Masha pulse, etc. and the use of oily unguents and emulsive Basti (enematas) prepared with decoctions of Vatashamaka drugs should be applied for first four Sadhyovrana [23]. Cold washes and cooling plasters should be used in these cases for the alleviation of the burning and suppuration as well as for the cooling of the heat for Pichcita and Ghrista. Vrana Bandhana Badhan plays an important role to keep the Vrana clean and facilitates to fasten the healing process. Bandhana is preventive measure to protect the Vrana from the secondary contamination of dust, Krimi etc. and give support to Asthi, Asthi- Bhanga, and Sandhi- Mukta and keep Vrana as Mradu (soft), promotes circulation and helps to avoid the displacement of Shodhana and Ropana- Dravya and keep the wound surface dry. Vrana Bandhana protects the Vrana while walking on uneven places, standing, sitting, and sleeping and during journey by vehicles. In case of a lateral and wide-mouthed wound on the extremities, the bone-joints should be duly set and joined together as instructed before and the wound should be sutured and speedily bandaged in the manner of a Vellitaka bandage (spiral bandage), or with a piece of skin tied in the Gophana (slig bandage) or such other form as would seem proper and beneficial and oil should be poured over it [24]. Raktamokshana Bloodletting should be resorted to in a case of newly formed swelling for its resolution and for alleviating the pain. Bleeding is recommended in 22
े षञ्ज्ञिधः प्रार्पु ञ्ज्ञदष्टः शोफः, तस्यक ै ादशोपक्रर्ा भिन्त्यपतप मणादयो ञ्ज्ञिरेिनान्ताः; ते ि ञ्ज्ञिशेषण
शोथप्रतीकारे ितमन्त,े व्रणभािर्ापिस्य ि न ञ्ज्ञिरुध्यन्ते; शेषाि ु प्रायेण व्रणप्रतीकारहेति एि || (स ु.ञ्ज्ञि. 1/10) 23
् स्नेहपानं ञ्ज्ञहतं तत्र तत्सेको ञ्ज्ञिञ्ज्ञहतिथा | िेशिारैः सकृ शरैः स ुञ्ज्ञस्नग्ध ैश्चोपनाहनर् ||
म ीयते || (स ु.ञ्ज्ञि. 2/24-25) धान्यस्वेदांश्च कु िीत ञ्ज्ञस्नग्धान्यालेपनाञ्ज्ञन ि |िातघ्नौषधञ्ज्ञसिैश्च स्नेहबै ञ्ज्ञम िञ्ज्ञिध 24
् शर् |् सीव्येत सम्यञ्ज्ञ ् म ः || शाखास ु पञ्ज्ञततांञ्ज्ञियमक ् प्रहारान ञ्ज्ञ् ििृतान भृ ििेश्याशु सन्ध्यिीन्यन ुपूिश
् ु.ञ्ज्ञि.2/ 34-35) बद्ध्वा िेञ्ज्ञितके नाशु ततिल ै ेन सेियेत |् िर्मणा र्ोफणाबन्धः कायो यो िा ञ्ज्ञहतो भिेत ||(स
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the case of a wound which is indurate, marked by a considerable swelling and inflammation and is reddish black or red coloured, extremely painful, gagged in its shape and considerably extended at its base (congested) [25]. Healing of Vrana has been an important problem since ancient time. Our Acharayas have given beautiful description about Vrana and Varnaropana. For good healing drug must have two properties i.e.
Vrana Shodhana for cleaning of wound
Vrana Ropana for healing of wound
Vrana Shodhana (Cleaning of Wound) The decoction of Haritaki, vibhitaka, Amalaki, Khadira, Daru-Haridra, drugs belonging to Nyagrodhadi group, Bala, Kusha and tender leaves of Nimba and Kola helps in the cleaning of wound [26]. Decoctions of Sankhini, Ankoth, Suman, Karavira, Suvarchala and drugs of Aragvadhadi group, are for cleaning of wound [27]. The wise physician should do fumigation of the wound by using Srivestaka, Sarjarasa, Sarala, Devdaru and piths (of trees like Sala, Sara etc.) for cleaning the wound [28]. Vrana Ropana (Healing of Wound) Acharya Charak has described Madhuka, Madhuparni, Prisniparni, Ambasthaki, Samanga, Mocarasa, Dhataki, Lodhra, Priyangu, and Katphala these ten drugs are healers of wounds [29]. Decoction, hot infusion or cold infusion prepared from barks of trees which are not in potency, is the best for healing. Paste of Samanga, Soma, Sarala, Somavalka, Candana and drugs of Kakolyadigana is best for healing the wounds [5]. Raskriya prepared from barks of drugs of Nayagrodhadi Gana and Triphala can also used for wound Healing [30]. ArkadiGana, mitigates Kapha, Medas and poison, alleviates worm, leprosy and heals wounds especially [31]. Kashaya, Varti, Kalka, ् िेदनोपशर्ाथामय तथा पाकशर्ाय ि । अञ्ज्ञिरोत्पञ्ज्ञतते शोफे कु यामच्छोञ्ज्ञणतर्ोक्षणर् ॥
25
सशोफे कञ्ज्ञिने ध्यार्े सरक्ते िेदनािञ्ज्ञत । संरब्धे ञ्ज्ञिषर्े िाञ्ज्ञप व्रणे ञ्ज्ञिस्रािणं ञ्ज्ञहतर्॥् (स ु.ञ्ज्ञि. 1/27-28) 26 27
ञ्ज्ञत्रफला खञ्ज्ञदरो दािी न्यग्रोधाञ्ज्ञदबमला कु शः| ञ्ज्ञनम्बकोलकपत्राञ्ज्ञण कषायाः शोधना र्ताः|| (ि.ञ्ज्ञि.25/84) शाञ्ज्ञिन्यङ्कोिस ुर्नःकरिीरस ुििमलाः । शोधनाञ्ज्ञन कषायाञ्ज्ञण िर्मश्चारग्िधाञ्ज्ञदकः ॥ (स ु.सू. 36/12)
् ् (स ु.सू. 36/22) श्रीिेष्टके सजमरसे सरले देिदारुञ्ज्ञण । सारेष्वञ्ज्ञप ि कु िीत र्ञ्ज्ञतर्ान व्रणधू पनर् ॥
28 29
ु र्धपु णीपृञ्ज्ञिपण्यमम्बष्ठकीसर्ङ्गार्ोिरसधातकीलोध्रञ्ज्ञप्रयङ्गक र्धक ु ट्फलानीञ्ज्ञत दशेर्ाञ्ज्ञन सन्धानीयाञ्ज्ञन भिञ्ज्ञन्त (ि.सू.4/9)
5सोर्ार्ृताश्वर्न्धास ु काकोल्यादौ र्णे तथा ।क्षीञ्ज्ञरप्ररोहेष्वञ्ज्ञप ि ितमयो रोपणाः स्मृताः॥ (स ु.सू. 36/24) 30 31
् (स ु.सू. 36/30) त्वक्ष ु न्यग्रोधिर्मस्य ञ्ज्ञत्रफलायािथ ैि ि ।रसञ्ज्ञक्रयां रोपणाथे ञ्ज्ञिदधीत यथाक्रर्र् ॥| अकामञ्ज्ञदको र्णो ह्येष कफर्ेदोञ्ज्ञिषापहः । कृ ञ्ज्ञर्कु ष्ठप्रशर्नो ञ्ज्ञिशेषाद्व्रणशोधनः॥ (स ु.सू. 38/17)
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Gharta, Taila, Rasa-Kriya and Avacurnana are the measures for the cleaning (Sodhana) of a wound and for helping its granulation (Ropana). The eight acts (from Chedana to Sivana) are surgical operations. Sonitasthapana, Ksara- Karma, Agni-Karma, Yantra, Ahara, Raksa- Vishodhana, Bandhana, Snehana, Vamana, Virechana and Basti are very cost-effective in management of Vrana [32]. A cut wound should be treated with its own specific measure and Remedies, while a bruised one should be treated as a case of Bhagna. The first line of treatment of a mangled or contused wound (Ghrsta) is to extinguish pain, after which it should be dusted with the power of proper medicinal drugs (such as Sala, Sarj, Arjuna, etc.) [33] Application of the paste of Manasila, Ela, Manjistha, Laksha, Haridra, and Daru Haridra along with ghee and honey helps in the promotion of healthy skin over the wound [34]. Pathya- Apathya Mithyahara- Vihara play an important role in the transformation of a Shudha- Vrana into Dusta- Vrana, Virudha- Ahara, Asatmaya- Ahara, Atibhuktha, Shoka, Krodha, diva- Swapana, sexual indulgence and other exercise etc. are the causes of Dusta- Varana by the vitiation of Dosha. A. Management of Bhagna (Fracture) Ayurvedic treatment for bone fracture and dislocation in its external and internal use for herbal medicines in various forms, which shows great results in reducing pain, healing wounds, and joining bones. Acharya Sushruta has described that depressed fracture hanging down should be set by raising it up, while an elevated and fractured joint should be reduced by pressing it down, by pulling it in its upward position in the event of its being lowered down. An intelligent physician should set all dislocated joints, whether fixed or movable, by the mode of reduction, known as Achana, Pidana, Sanksepa and Bandhana (bandaging) [35]. A crushed or dislocated joint should not be 32
तेष ु कषायो िञ्ज्ञतःम कल्कः सञ्ज्ञप मिल ै ं रसञ्ज्ञक्रयाऽििूणनम ञ्ज्ञर्ञ्ज्ञत शोधनरोपणाञ्ज्ञन, तेष्वष्टौ शस्त्रकृ त्याः, शोञ्ज्ञणतािापनं
ु क्षारोऽञ्ज्ञियमन्त्रर्ाहारोरक्षाञ्ज्ञिधानंबन्धञ्ज्ञिधानंिोक्ताञ्ज्ञन,स्नेहस्वेदनिर्नञ्ज्ञिरेिनबस्त्यत्तरबञ्ज्ञ िञ्ज्ञशरोञ्ज्ञिरेिननस्यधूर्किलधार णान्यन्यत्र िक्ष्यार्ः || ( स ु.ञ्ज्ञि.1/9) 33 34 35
क्षते क्षतञ्ज्ञिञ्ज्ञधः कायमः ञ्ज्ञपञ्ज्ञच्चते भििञ्ज्ञिञ्ज्ञधः । घृष्ट े रुजो ञ्ज्ञनर्ृह्याशु िूणरुै पिरेद्व्रणर्॥् (स ु. ञ्ज्ञि. 2/76)
र्नःञ्ज्ञशलैला र्ञ्ज्ञञ्जष्ठा लाक्षा ि रजनीियर्|् प्रलेपः सघृतक्षौद्रस्त्वञ्ज्ञग्िशुञ्ज्ञिकरः परः |(ि.ञ्ज्ञि 25/114) ् अिनाञ्ज्ञर्तर्ुिह्येदितं िािपीडयेत |् आञ्छेदञ्ज्ञतञ्ज्ञक्षप्तर्धो र्तं िोपञ्ज्ञर ितमयते ||
आञ्छ्ैः पीडन ैश्च ैि सङ्क्षेप ैबमन्धन ैिथा | सन्धीञ्छरीरे सिांि ु िलानप्यिलानञ्ज्ञप | एत ैि ु िापनोपाय ैः िापयेन्मञ्ज्ञतर्ान ञ्ज्ञ् भषक ् ॥ (स ु.ञ्ज्ञि.3/17-19)
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shaken and cold lotions or washes and medicated plasters (Pradeha) should be applied to the part. The fractured or dislocated part should be first covered with a piece of linen soaked in clarified butter. Splint should then be placed over it and the part properly bandaged [36]. The ancient Ayurvedic texts have described Asthibhagna Chikitsa’ thoroughly. This includes. 1) Principals of Bhagna Chikitsa. 2) General management of Bhagna. 3) Specific management for Kora Sandhi Bhagna. 4) Pathya- Apathya 5) Clinical criteria of fracture healing 1) Principals of Bhagna Chikitsa. 1) BhagnaSthapana (reduction) 2) KushaBandhana (retention) 3) Karmavarthana (rehabilitation) I.
Bhagna Sthapana (Reduction) BhagnaSthapana is not required in all the Bhagna. In case of incomplete fractures or when the fracture is of stable variety, reduction is not required. On the other hand it is very essential in fractures where the fracture fragment is unstable, like supracondylar fracture of humerus, femur etc. aim of Bhagnasthapana is to approximate the fracture ends and to achieve proper alignment. These are two main techniques mentioned in Shushruta Samhita for closed manipulation namely Anchana and Peedana. Anchana (Traction) It is a technique in which the wide gap between the fragments may be corrected. Anteriorly, medially, laterally or posteriorly displaced fragments can be brought in alignment by the application of traction. Peedana (Pressure) It is another technique where in fractured fragments are approximated through gentle and controlled pressure. The Vinamana and Unnamana 36
् ् हांश्चाििारयेत || ् उञ्ज्ञत्पष्टर्थ ञ्ज्ञिञ्ज्ञिष्टं सञ्ज्ञन्ध ं िैद्यो न घट्टयेत ।् तस्य शीतान परीषे कान प्रदे
अञ्ज्ञभघाते हृते सञ्ज्ञन्धः स्वां याञ्ज्ञत प्रकृ ञ्ज्ञत ं प ुनः | घृतञ्ज्ञदग्धेन पट्टेन िेष्टञ्ज्ञयत्वा यथाञ्ज्ञिञ्ज्ञध || ् पट्टोपञ्ज्ञर कु शान दत्त्वा यथािद्बन्धर्ािरेत॥् (स ु.ञ्ज्ञि.3/20-21)
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techniques can be incorporated within Peedana only. In case Vinamana (depressed) fracture; the fragment should be carefully lifted up. In case of Unnamana (elevated) the raised fragment should be pressed down. II. Kusha Bandhana (Retention) Kushabandhana is a technique that ancient Indian surgeons practiced for fracture immobilization. In this technique they have applied the barks certain plants like bamboo, banyan, and Pipal which were referenced regarding external applications of pastes of bamboo pith, latex of banyan, and Pipal like trees. This procedure was practiced based on the season, time constitution, and strength, of an individual. While manipulating the broken bones, Unnamana (elevation of depressed fragment) and Vinamana (depression of elevated fragment) were followed by traction and retention. The tree barks he has recommended are Ashwatha, Vamsha, Kakubha, Madhuka, Palasha, Sala, Udumbara, Vata trees should be used as splints (Kusha). [37] III. Karmavarthana (Rehabilitation) The importance of physiotherapy in a limb injury was also appreciated by Sushruta. After proper union it is desirable that that the joints or the fracture parts must regain normal functions and shape. For his Sushruta has given importance to rehabilitation. Various devices including exercise were being suggested by the Acharyas. In the fracture of carpal, metacarpal and phalangeal joints, initially the use of mud ball and at a later period the use of salt and the pieces of stone have been suggested [38]. This also suggests that an injured part should not be put into action immediately, but gradually the movements may be restored. After immobilization gentle massage with specific oils gradually restores the movements in the part and enhances circulation. 2) General treatment of Bhagna In case of fracture associated with the wound or a compound fracture locally a mixture of “Nyagrodhadi Gana Dravyas” in paste form, Madhu and Ghee should be applied [39]. Parishechana In this procedure a cold decoction of the drugs of the Nyagroghadi 37 38 39
् (स ु.ञ्ज्ञि.3/6) र्धूकोदम्बराश्विपलाशककु भत्विः | िंशसजमिटानां ि कु शाथर्म पु संहरेत ||
् िं लिणं ि ततः परर् |् हिे जातबले िाञ्ज्ञप कु यामत पाषाणधारणर् ् ् (स ु.ञ्ज्ञि.3/35) र्ृञ्ज्ञत्पण्डं धारयेत पू ||
् ु.ञ्ज्ञि.3/14) ू रैः ।प्रञ्ज्ञतसायम कषाय ैि ु शेष ं भििदािरेत ॥(स सव्रणस्य तु भिस्य व्रणं सञ्ज्ञपर्म धम त्त
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group should be used in washing (the affected part), whereas in the presence of (excessive) pain, (the part) should be washed with milk boiled with the drugs of the Pancha-Mula, or simply with the oil known as the chakra- taila made lukewarm [40]. By using Pariseka the body removes the sense of fatigue, and brings about the adhesion of broken joints. It alleviates the pain which usually attends of the burns, scalds, bruises and laceration, and subdues the actions of the deranged Vayu [41]. Lepana (Ointment or Plaster) It is carried on the fractured site. Lepana should be prepared using Manjisth, Madhuka, red sandal wood and Shali-rice mixed Shata-Dhauta clarified butter (i.e. clarified butter washed one hundred times in succession) should be used for plastering the fracture [42]. This Lepa reduces local pain and swelling. The ingredients get absorbed per cutenously and helps bone healing. After this the Anchana like procedures is to be followed. After completing the general measures Acharya has described the treatment part of various kinds of fractures occurring in the each bone of body. 3) Pathya-Apathya [43] A fractured patient must avoid the use of amla Lavana, KatuRasa, and Kshara and should follow the strictest continence, avoid over exposure to sun and physical exercises. 4) Clinical Signs of Ideally United Bone [44] 5) No swelling or hardness on palpation. 6) Absence of shortening and deformity. 7) Painless and easy movements All these are the signs of a healthy and complete healed bone that are always expected from every surgeon. In such a detailed, scientific manner, ancient Acharayas have described the condition of Asthibhadna. Acharya Sushruta has elaborately described types of bones, causes of bone injuries,
40
् दन॥ न्यग्रोधाञ्ज्ञदकषायं तु स ुशीतं पञ्ज्ञरषेिने । पञ्चर्ूलीञ्ज्ञिपक्वं तु क्षीरं कु यामत सिे
स ुखोष्णर्ििायं िा िक्रतल ै ं ञ्ज्ञिजानता ॥ (स ु.ञ्ज्ञि.3/11) 41 42 43 44
सेकः श्रर्घ्नोऽञ्ज्ञनलहृद्भिसञ्ज्ञन्धप्रसाधकः । क्षताञ्ज्ञिदग्धाञ्ज्ञभहतञ्ज्ञिघृष्टानां रुजापहः ॥ (स ु.ञ्ज्ञि 24/31) ् ु ं रक्तिन्दनर् ।शतधौतघृ आलेपनाथं र्ञ्ज्ञञ्जष्ठां र्धक तोञ्ज्ञन्मश्रं शाञ्ज्ञलञ्ज्ञपष्टं ि संहरेत॥् (स ु.ञ्ज्ञि.3/7) ् लिणं कटुकं क्षारर्म्लं र्ैथ ुनर्ातपर् |व्यायार्ं ि न सेिते भिो रूक्षािर्ेि ि|| (स ु.ञ्ज्ञि.3/4)
् (स ु.ञ्ज्ञि.3/70) भिं सञ्ज्ञन्धर्नाञ्ज्ञििर्हीनाङ्गर्न ुल्बणर् |् स ुखिेष्टाप्रिारं ि संञ्ज्ञहतं सम्यर्ाञ्ज्ञदशेत ||
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its clinical features, and dislocation and their management. In his text named Sushrut Samhita the principles of management of fracture mentioned by Sushruta has been never changing principles even after any advancement of techniques in modern surgery. Treatment of Snayugata Vata On the basis of its sign and symptoms, ligament, tendon and nerve injury can be correlated with the condition of Snayugata Vata described in Ayurveda. Acharya Sushruta has advocated various treatment modalities’ such as Snehana, Upanaha, Agnikarma, and Bandhana for Snayugata Vata [45] . Almost these, Agnikarma seems to be more effective in providing distinct and instant relief. Abhyanga (Massage) Ayurveda emphasizes the role of Abhyanga (massage) after the tenure of exercise. Abhyanga is beneficial for muscle fatigue and prevent small injuries affecting the muscle fibers. Acharya Charak has described as a pitcher, a dry skin, and an axis become strong and resistant by the application of oil, so by the massage of oil the human body becomes strong and smooth-skinned, it is not susceptible to the diseases due to Vata; it is resistant to exhaustions and exertions [46]. Advantage of Regular Massage One who practices Abhyanga (oil massage) regularly on the body, even if subjected to injuries or strenuous work is not much injured; his physique is smooth, flabby, strong and charming. By applying the oil massage regularly the onslaught of aging is slackened [47]. By massaging oil in the feet, roughness, immobility, dryness, fatigue and numbness are instantaneously cured; tenderness, strength and steadiness of feet are affected; the eye sight becomes clear and Vata is relieved thereby. Prevention from cracking of feet, constriction of vessels and ligaments of feet is ensured if massage is applied to the feet [48]. Charka says about Abhyanga” that a man constantly doing
45 46
ु न्ध्यञ्ज्ञिसम्प्राप्ते कु यामिायाितञ्ज्ञितः॥ (स ु.ञ्ज्ञि.4/8) स्नेहोपनाहाञ्ज्ञिकर्मबन्धनोन्मदमनाञ्ज्ञन ि । स्नायस स्नेहाभ्यङ्गाद्यथा कु म्भश्चर्म स्नेहञ्ज्ञिर्दमनात|् भित्य ुपाङ्गादक्षश्च दृढः क्लेशसहो यथा||
् (ि.सू.5/85-86) तथा शरीरर्भ्यङ्गाद्दृढं स ुत्वक् ि जायते| प्रशान्तर्ारुताबाधं क्लेशव्यायार्संसहर्|| 47
् न िाञ्ज्ञभघाताञ्ज्ञभहतं र्ात्रर्भ्यङ्गसेञ्ज्ञिनः| ञ्ज्ञिकारं भजतेऽत्यथं बलकर्मञ्ज्ञण िा क्वञ्ज्ञित||
स ुस्पशोपञ्ज्ञिताङ्गश्च बलिान ञ्ज्ञ् प्रयदशमनः| भित्यभ्यङ्गञ्ज्ञनत्यत्वािरोऽल्पजर एि ि|| (ि.ञ्ज्ञि.5/88-89) 48
् खरत्वं िब्धता रौक्ष्यं श्रर्ः स ुञ्ज्ञप्तश्च पादयोः| सद्य एिोपशाम्यञ्ज्ञन्त पादाभ्यङ्गञ्ज्ञनषेिणात||
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Abhyanga posses limbs which are smooth to touch and which are well developed. He will be too strong, handsome and will not be affected by early old age and who will not be affected by with external injuries even if he has to perform heavy and tiresome work”. This is the clear indication that Abhyanga can do a miracle in sports medicine. Generally, we can classify the effect of Abhyanga in sports medicine as follows1.
It increases the strength of the muscles
2.
Helps in the recovery of injuries
3.
Reduces the rate of injury comparable with others
4.
Prevents from fatigue
5.
Very effective for mental concentration
6.
Prevent muscle soreness, muscle pull, muscle cramps
Charaka advises the massage after exercises which would enable the body to endure extreme strain. It reduces fatigue after stress. He further emphasizes that by massage, one gets the power of endurance, if afflicted by injury. Modern medical science too agrees upon the advantage of massage. Dr. Peter N. Sparryn says it may help to drain inflammatory exudates from injuries in the early stages, valarie Steel notes that massage and transverse friction certainly have place. Vertebral and peripheral mobilization and manipulation technique are useful methods of treatment. Connective tissue massage is useful in the management of a person of the soft tissue lesions, seen in sport. It helps in re absorption of haematoma and stimulates blood flow in the affected parts. Some of the Ayurvedic massage techniques are as followsa) Udvartana: Upward and downward movements with oils and dry powders, with the help of palm of hand and also fingers [49] b) Udgharshana: more forceful rubbing creating greater friction generally with dry powders [50]. Sushruta advises Udgharshana with Phenaka (Samudraphena) to strength-then the calf and thigh
जायते सौकु र्ायं ि बलं ि ैयं ि पादयोः| दृञ्ज्ञष्टः प्रसादं लभते र्ारुतश्चोपशाम्यञ्ज्ञत||
ु ङ्कोिः पादाभ्यङ्गे न पादयोः|| (ि.सू.5/90-92) न ि स्याद्गध्रृ सीिातः पादयोः स्फु टनं न ि| न ञ्ज्ञसरास्नायस 49 50
् (स ु.ञ्ज्ञि.24/51-52) उितमन ं िातहरं कफर्ेदोञ्ज्ञिलापनर् |् ञ्ज्ञिरीकरणर्ङ्गानां त्वक्प्रसादकरं परर् || उिष मणर्स्नेहौषधिूणामञ्ज्ञदञ्ज्ञभघष मण्र् । (स ु. ञ्ज्ञि.24/52 डल्ह्ण कॄ त टीका)
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muscles [51]. c)
Utsadana: very gentle rubbing especially with medicated oils [52].
d) Mardana & Unmardana [53]: Vagbhata advises Mardane i.e. downward movements of hands while squeezing the muscles after exercise [54]. Sushruta recommends both Mardana and Unmardadana (Opposite to the former) in Mamsagata Vata. e)
Samvahana [55]: Gentle tingling massage with oils causes a pleasing sense and reduces fatigue. Samvahana helps on regaining the vitality in muscles.
f)
Padabhyanga [56]: Massage with feet to be more vigorous and emphasis on greater pressure and crushing effect. It is has been only after proper oelation, possibly muscles become more strong and stress resistant.
g) Peedana and Avapeedana: In this massage kneading of individual muscle is undertaken with the help of knuckles and fingers. Peedana is deep kneeding. One more Pari- Peedana is circular kneeding. h) Udveshtana & Upaveshtana: Massage applied to the limbs especially over shoulders, thighs and waist. Udveshtana is upward movement and Upaveshtana the opposite. Apart from all such techniques many more have been described like Latavestana (Spiral friction), Mandhana (Muscle rolling), Sandhi Chalalana (Joint movements), Samdanshika (Pulling), Harshana (Vibration) Praharshana (Percussion), Chedyam (Hacking) Tadana (Slapping), Samputaka (Boxing), Vadyam (Tapping) Asphalana (Clapping), Marjana (Sweeping) etc. [57]. The medicated oils, powders, pastes and such other 51 52 53
ऊिोः सञ्जनयत्याशु फे नकः ि ैयमलाघिे | ( स ु.ञ्ज्ञि.24/55))
सस्नेहकल्के नोउिष मणोत्सादनर्। (स ु.ञ्ज्ञि.24/53 डल्ह्ण कॄ त टीका)
् स्नेहाभ्यङ्गोपनाहाश्चर्दमनालेपनाञ्ज्ञनि|त्वङ्ांसासृञ्ज्ञिराप्राप्तेकुयामत्िासृञ्ज्ञग्िर्ोक्षणर्||
ु न्ध्यञ्ज्ञिसम्प्राप्तेकुयामिायाितञ्ज्ञितः|| ( स ु.ञ्ज्ञि.4/7-8) स्नेहोपनाहाञ्ज्ञिकर्मबन्धनोन्मदमनाञ्ज्ञनि|स्नायस 54 55 56
े सर्न्ततः| (अ. ह ्.स ु.2/12) तंकृत्वाऽन ुस ुखंदहे ं र्दमयच्च
् ( स ु.ञ्ज्ञि.24/83) संिाहनंर्ांसरक्तत्वक्प्रसादकरंस ुखर्|| ञ्ज्ञनद्राकरो देहस ुखश्चक्ष ुष्यः श्रर्स ुञ्ज्ञप्तन ुत ।्
पादत्वङ्ृदकारीिपादाभ्यङ्गःसदाञ्ज्ञहत॥ ( स ु.ञ्ज्ञि.24/70) Laxmipathi A: “Message” A text book of Ayurveda Vol. VI, Section I, Bezwada.
57
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materials used during massage have potentiality of improving the fitness of the sportsman and obviously have place in injury too. Role of Rasayana Therapy “Rasayana” means the way of obtaining good quality of Rasa. The word Rasa represents the seven Dhatus because they all are nourished by Rasa yield of Aahar Rasa (digestive product of food). The quality of the Rasa in the body directly governs the state of health of an individual. So the meaning of obtaining optimum standard of Rasa is to be Rasayana. The purpose of Rasayana is to obtain strength, immunity, Ojas, vitality, will power and determination and it also strengthen the sense. One of the results of Rasayana is Oja, which is the factor responsible for Vyasdhikshamtav (immunity). Ayurveda describes a variety of herbal and mineral mixtures, called Rasayanas. They contain not only highly concentrated nutrients, but also develop a unique effect on the mind and body by virtue of their specific compilation. Each of the different ingredients complement and reinforce each other synergistically, and can therefore be optimally absorbed by the body. Amla juice has been designated as sport Rasayana for physically active person. It has holistically nourishing and balancing as well as a natural anabolic (muscle building) effect. It supports the immune system in a holistic manner, and also has been proven to reduce cell-damaging substances known as free radicals. Free radicals are highly destructive molecular fragments that are increasingly produced at high levels of exertion. The physical and mental stamina of sportsman indicate perfect health with the help of balance condition of Tridosha and Saptdhatu. However for Dhatupachaya and Balavriddhi (strength) naturally the Rasayana therapy is most suitable and can be adopted during the training programme. For practical purpose Kuti Praveshika (indoor) type of Rasayana is prescribed in Ayurveda. Single Rasayana herb or formulation of various such herbs can be given for the physical as well as mental health, and specific formulations are indicated by choosing Such Rasayana drugs, which would improve the Mamsadhatu and Snayu (musculature). They may be selected as per the need and personality of the sportsman. There are so many formulation of Rasayana drugs like Ashwgnada (withania somnifera), Musali (asoaragys adscebdes), Sheerini (mimusps hexandra), Ala (sida cordifolia), Vidari (pueraria tuberose), Kushmanda (beninean sahispida), Shalaparani (desmodium ganetica), Khajura (phoenix sylvestric), Amra (manzifera indica), Kadali (musa paradisiacal), Amalaki, Madooka parni, Shatavari, Lashuna, Vacha, Bhallataka, Pippali, Haritaki, Guduchi, Bhibitaki etc. Page | 26
There are some mineral drugs like Shilajatu (bituman), Abhraka (mica), Loha, Tamra (copper), which are also important for improvement in physical and mental power of the sport person. The benefits of Rasayana are longevity, good memory and intelligence, freedom from disease, youthful age, and excellence of luster, complexion and voice, optimum strength, good functioning of sense organs. Rasayana creates new tissues in the body having optimum quality and it prevents ageing [58]. Importance of Rasayana Therapy 1.
It provides proper nutrition to each tissue.
2.
It increases Jataragni and as well as Dhatvagni and hence the function of Pancha Bhoutik Agni also gets improved.
3.
Hence all the tissues in the body are formed having their best qualities.
4.
It removes the Kleda, Ama and other waste products which are actually responsible for ageing process. These waste products are also called as free radicals and Rasayana removes these free radicals from the body. This action of Rasayana is known as antioxidant and it has now been found in most of the herbs having Rasayana action.
5.
It gives strength to the Srotas or channels in the body.
6.
It increases Ojas and strength of the body.
7.
It normalizes the Doshas in the body.
8.
It is also useful in maintaining the Satva quality of the mind. Hence the mind and the sense organs and the motor organs become optimum in their qualities. Thus, Rasayana therapy is the special treatment modality in Ayurveda. It improves durability as well as quality of the life.
Concept of Diet in Ayurveda and Its Importance in SportsDiet is one of the important and basic biological needs of sportsman. It is the foundation for good health. It is essential for life, growth and repair of human body, regulation of body mechanism and production of energy for Work. The above functions of diet can be achieved only through adequate nutrition which should consist of essential nutrients in the required proportion. These nutrients include Proteins, Carbohydrates, Fats, Minerals 58
् दीघमर्ायःु स्मृञ्ज्ञत ं र्ेधार्ारोग्यं तरुणं ियः| प्रभािणमस्वरौदायं देहञ्ज्ञे ियबलोदयर्||
् ॥ (अ.ह्र.सू.39/1-2) िाञ्ज्ञिञ्ज्ञिं िृषतां काञ्ज्ञन्तर्िाप्नोञ्ज्ञत रसायनात|् लाभोपायो ञ्ज्ञह शिानां रसादीनां रसायनर्||
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and Vitamins. Nutritious diet is always recommended for healthy body and mind. In case of Sportsman nutritious diet plays an important role in their performance. Because during sports training, the energy requirement of the players is high as such the diet should be accordingly planned otherwise the players Will not have the Stamina to Withstand the training and the player Will show the signs of fatigue which may result in internal and external injuries to the players. In the regimen of diet, Ayurvedic foods and food habits are noted and those suitable are adopted. There is a range of meats of flesh-eating animals and otherwise, given by Charaka which are said to be Mamsavardhaka in the treatment of Rajayakshma (tuberculosis) that may be screened for nonvegetarian food for sportsman [59]. In various sports activities mostly involved structures are Asthi for various locomotory activities by means of Mamsa (muscles) hence Asthiposhak and Mamsavardhaka foods mentioned in classics must be advised for sports person. Acharya Charak in Sutrastana 26th chapter said various food items these helps in proper nourishment of Mamsa and Asthi, in any injury there will be decrease in Rakta Dhatu to compensate this Acharya has advised to consume the Rakta of animals mentioned in Mamsa Varga eg: Mamsa Varga, Shaali Varga etc. Vyayama (Exercise) and Sports The training in sports is of prime importance for fitness, and involves physical exercise, which improves the tonicity and strength of muscles and also tones up cardiac and respiratory functions. Obviously our ancient Acharyas knew these benefits and have stressed upon regular Vyayama (exercise) not merely as a part of sports but as a daily regimen they also know that apart from many general advantages, Musculature is developed due to Vyayama. Sushrata and Vagbhata called it Suvibhaktata and Vibhakta Gatratvam [60]. Endurance to high amount of stress is indicated by Charaka as Duhkha Sahishnuta [61] and by Vaghhata as Karma Samarthya [62] i.e. capacity to strain to maximum extent. In fact, strength is a function of Neuro-Musculo-Skeletal system and closely related to muscle crosssectional area. Its development is indispensable for success in sports. 59 60
् (ि.ञ्ज्ञि.8/154) दद्यान्मञ्ज्ञहषशब्देन र्ांस ं र्ांसाञ्ज्ञभिृिये | र्ांसने ोपञ्ज्ञिताङ्गानां र्ांस ं र्ांसकरं परर् || ् शरीरायासजननं कर्म व्यायार्सञ्ज्ञितर् |् तत कृ् त्वा तु स ुखं देहं ञ्ज्ञिर्ृद्गीयात सर्न्ततः |
शरीरोपियः काञ्ज्ञन्तर्ामत्राणां स ुञ्ज्ञिभक्तता | दीप्ताञ्ज्ञित्वर्नालस्यं ञ्ज्ञिरत्वं लाघिं र्ृजा |
श्रर्क्लर्ञ्ज्ञपपासोष्णशीतादीनां सञ्ज्ञहष्णतु ा | आरोग्यं िाञ्ज्ञप परर्ं व्यायार्ादपजायते || (स ु.ञ्ज्ञि.24/37-40) 61
लाघिं कर्मसार्र्थ्यं ि ैयं दःखसञ्ज्ञहष्णतु ा । दोषक्षयोऽञ्ज्ञििृञ्ज्ञिश्च व्यायार्ादपजायते॥ (ि.सू.7/32)
62
लाघिं कर्मसार्र्थ्यं दीप्तोऽञ्ज्ञिर्ेदसः क्षयः। ञ्ज्ञिभक्तघनर्ात्रत्वं व्यायार्ादपजायते ॥ (अ.ह्र.सू.2/10)
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Yoga and Sports According to Ayurveda, the human body contains Asthi, Sandhi, Snayu, Peshi etc. This supports and helps in movement and locomotion. Every sports person in his career suffers from various sports injuries, specially of Golfer`s elbow, Tennis elbow, Wrist strain, Sprained ankle, planter fasciitis, rotator cuff tear, iliotibial band syndrome etc. the extensive use of a joint cause tears, stretching, inflammation, trauma etc. in athletes, cricketers, long jumpers etc. Here treatment required is faster and long lasting. Recently research studies proved that Yogas are very effective in sports, health and fitness related fields such as aerobic training, strength training, body building, and endurance sports. A combined approach of Ayurveda, physiotherapy and yoga can be in successfully employed sports, for training sports person, treating injuries and rehabilitation. Yoga is useful for all type of sports to help prevent injuries. One gets extra agility which helps avoid damage, provides more strength and improves a player’s ability to react to a situation. Yoga works not only at physical level but also at psychological level, ensuring well-rounded development. Yoga is both preventive and therapeutic and has shown to offer both physical and mental benefits to the body and mind. Although most poses are not aerobic in nature, they do in fact send oxygen to the cells in the body by way of conscious deep breathing and sustained stretching and contraction of different muscle groups. Whatever sport choose to practice, yoga can enhance and complement your ability. Most sports build muscular strength and stamina, often in specific areas of the body. Yoga can help to check any imbalance in muscular development and will enable both your body and your mind to function more efficiently. If your body is flexible and supple you will be less prone to sports injuries, as your joints will be kept lubricated. Skiing demands mental alertness as well as good balance. Importance of Yoga in Sports i.
Improved Strength
Routine and consistent practice of the various yoga Asanas has helped me build strength and improve lean muscle mass. Most notably with respect to several muscle groups under-utilized in my chosen athletic disciplines of swimming, cycling and running. These gains have enhanced core body stability and supportive but otherwise under-developed muscles surrounding the more utilized muscles, creating a more balanced and optimally functional overall strength. Page | 29
ii. Balance: Through a consistent yoga practice, coordination the balance has improved immensely. iii. Flexibility Yoga invariably improves joint and muscular flexibility, which is crucial to the body’s overall structural soundness. Enhanced joint and muscle pliancy translates to a greater range of a motion, or an increase in the performance latitude for a particular movement or series of movements. iv. Free Your Mind The ability to create a stress free mind is a significant benefit of yoga practice. The physical practice is used as a tool to enhance breath control. This helps improve focus and concentration, allowing clarity of thought and clear decision making. Mental practice in any sport will teach you how to gain control of your emotional states. So arousal levels and anxiety don’t impede your performance. Thus yoga improves our body as follows
Strengthens deep connective tissue preventing or minimizing injury.
Creates an overall body flexibility. Increases range of motion and mobility.
Dramatically enhances physical balance by developing the athlete's awareness of his body's center place, thus keeping their body balanced in action, moment by moment, giving the ability to recover from or prevent falls, while enhancing agility and maneuverability.
Improves circulation, massages internal organs and glands for optimum health.
The yoga breath circulates and detoxifies the lymph fluid to speed up recovery time from training 15% faster, eliminating fatigue.
The yoga breath builds up increases one's life force energy.
Enhances sensory acuity, mental focus, concentration, mental clarity, will power, and determination.
Dissolves pre competition anxiety and stress. Helps to balance & manage emotions that could cloud focus, concentration & judgment.
Trains the athlete gets and stays in the mental zone.
Discussion and Conclusion In Ayurveda there is no direct description of sports and its related Page | 30
injuries but we find some references of exogenous diseases (Aagantuja Rogas) caused due to the contact of external factors like fire, poisonous substances and also due to trauma. In classifying diseases, Sushruta Samhita has included the category of diseases caused due to Sanghaatabala- pravrtta- vyadhi. This can be correlated with traumatic diseases such as sprain, abrasion, muscle injuries, wounds, fractures, dislocation etc. which caused due to various games such as boxing, wrestling, running, martial arts etc. A full description about Ayu, Vyayama, and good built of body, Dincharya and Ritu Charya shows that over Ayurveda Acharya were very conscious about good health. Exercise has been an important part of the Ayurvedic routine for thousands of years before it becomes a modern fad. Exercise gets rid of heaviness and stiffness of the body because it burn Ama (digestion impurities) and creates more flexibility, lightness, smoothness and easiness. Other benefits include enhanced firmness, endurance, and ability to do work. It pacifies all three Doshas and creates balance when suitable for the body type and season. It enhances the digestion, and if done properly, it dissolves impurities in the tissues. Exercise enhances immunity and capacity for food. It banishes fatigue, sops early aging, and retards weight gain. In Charaka Samhita the definition of Vyayama shows that for good sports fitness Vyayama how much needed. Such a physical action which is described and is capable of bringing about bodily stability and strength is known as physical exercise. According to Acharya Charak the definition of Vayayama crate a sign of sports in Ayurveda. There is also no direct description of sports and sports injuries related to Sandhi. But Acharya Sushruta has described the Lakshana of Sandhi Vidhha. When the joints, either movable or immovable are injured, there will be increased swelling, very severe pain, loss of strength of the joints; splitting pain; edema and loss of function of the joints. These Lakashana has similar to symptoms of sports injuries. Because these symptoms are found in all type of sports injury related to Sandhi. In Ayurveda common conditions included under sports injury are, Shoola (pain), Shopha (inflammation), Vrana (wound), Bhagna (fracture/dislocation) and Snayugatvata (ligaments, tendons and nerves injuries). Every sports injuries have pain condition is almost present during any type of sports injuries like fracture, inflammation, dislocation and wound etc. In ancient time also there were many sports just like modern era, both having same motto of physical plus intellectual fitness and entertainment. Page | 31
Sports of modern era are like Cricket, Football, and Volley Ball, Badminton etc. while sports of ancient era were like Horse Riding, Hunting, Wrestling, Running, and Sword Fighting etc. This proves that in ancient era also many sports were played, to maintain physical plus psychological health and to increase stamina, flexibility and stability. Sports injuries are the injuries that occur during participating in any sporting events. In many cases, these types of injuries are due to overuse of a part of the body when participating in a certain activity. For example runner’s knee is a painful condition generally associated with running, while tennis elbow is a form of repetitive stress injury at the elbow, although it does not often occur with tennis players. Other types of injuries can be caused by a hard contact with something. This can often cause a broken bone or torn ligament or tendon. Sports injuries can be broadly classified as either traumatic or overuse injuries. Traumatic injuries account for most injuries in contact sports such as Association football, rugby league, rugby union, Australian Rules football, Gaelic football and American football because of the dynamic and high collision nature of these sports. These injuries range from bruises and muscle strains, to fractures and head injuries. A bruise or contusion is damage to small blood vessels which causes bleeding within the tissues. A muscle strain is a small tear of muscle fibers and a ligament sprain is a small tear of ligament tissue. The body’s response to these sports injuries is the same in the initial five day period immediately following the traumatic incident is inflammation. According to modern all of these sign and symptoms are also present in any type of sports injuries, so we can say that indirectly sport injuries are also mentioned in Ayurveda. According to Ayurveda disease occurs in the body due to two factors one is Nija (within the body),other is Aganthu (external factors), sports injuries mainly occur due to sudden impact or due to continues wear and tear. When an injury occur due to sudden impact, body respond to that condition which lead to immobility and other inflammatory responses, it's a protective mechanism of body, due to excessive body activity strained muscles, ligaments and tendons can get injured excess of toxin can accumulate in individual organ systems and can lower both mental and physical sharpness. There are so many sports injuries related to hinge joint like; tennis elbow, golfer’s elbow, wrist sprain, mallet finger, anterior knee pain lateral ligament injury, menisci injury, ankle sprain, Extensor tendinitis, tarsal tunnel syndrome, Achilles tendinopathy etc. Sports medicine is the specially branch of modern medicine while Ayurveda is a Holistic system of healing that originated in India thousands of Page | 32
years ago. The specialty of this science is that it deals not only with the cure of disease but also with the maintenance of physical, psychological and social health of an individual and society as a whole. Ayurvedic treatment procedures like Panchkarma (purificatory & rejuventory) can do wonderful impact in sports medicine. Recently research studies proved that Ayurvedic medicine and treatment are very effective in sports, health& fitness related fields such as aerobic training, strength training, bodybuilding, endurance sports, games like football, volley ball, basketball, cricket and tennis etc. A combined approach of Ayurveda, physiotherapy and yoga ‘can be in successfully employed sports, for training sports person, treating injuries and rehabilitation. Today’s Modern world has given priority to sports. During the sports events, injuries are common. Injuries to soft and hard tissues are the problems faced by sports persons as they have to undergo physical strain or stress in the field. If Ayurveda can provide a remedy which is cost effective, easily available and free from side effects, it would be a great boon in the field of sports. In Ayurveda management of sports injury has not been mentioned separately. But sports injury can be managed on the basis of Ayurvedic principles, but it has separate branch in modern science, which is more costly and has many adverse effects. Ayurveda Acharya gives vast description of wounds (vrana), fractures (Bhagna), and dislocations (SandhiMukta) and also their treatments are mentioned in Samhita which fall under the branch of Shalya-Tantra. There is also description of symptoms like Shoola (pain), Shopha (swelling), Snayugatvaat (ligaments, tendons and nerves injuries) etc. and their Ayurvedic management. When we consider Symptoms of sports injuries from external to internal, 1st symptom produced will be muscular pain/spasm, swelling, then tendon tear, ligament tear, bursitis, fracture ultimately all these conditions effects the a joints which are involved in those particular sport activities. Sports injuries happen in any joint or part of the body during sports activities shows same common symptoms like pain, swelling, spasm, fracture etc. only the name of injury may be differ according to structures involve, name of the sports or site of common injury in particular sport like tennis elbow, golfers knee etc. So here we discussed only several common injuries that can go on very frequently in any types of sport activities. Sports injuries are classified under two categories on the basis of onset like acute, chronic and according to severity mild, moderate, severe. Ayurveda Acharya also explained various acute and chronic clinical conditions regarding Shoola (pain), Shopha (swelling), Vrana (wound) etc. Page | 33
Since sport injuries related to Kora Sandhi (hinge joint) are same as sports injuries at any joint or part of the body we included only most common sports injuries in this study. In all these sports injuries the common conditions observed are pain, swelling, inflammation, wound, strain and sprain, fracture, dislocation etc. we can interpret these conditions with Shoola, Shopha, Vranashopha, Vrana, Snayugatavata, Kandabhagna and Sandhimukata respectively and based on these the treatment protocol has been designed. Pain is the first and foremost symptom seen in all kind of injuries, in modern sciences they advise analgesics, anti-inflammatory and steroids produces instant relief but prolong use of this causes several side effects as the age progresses like osteoarthritis, gout, osteoporosis etc, hence to avoid these complications we must follow Ayurveda protocol which is beneficial for sports person in any sports injuries. Pain is produced as a result of irritation to nerve ending, here Vata refers to Vatavaha Sansthana i.e. nervous system without irritation or involvement of this Shoola and Ruja cannot be produced. Treatment of Shoola /Ruja is categorized under 2 types these are Shodhana and Shamana. In Shamana therapy Lepa, Alepa, Taila etc. are used externally, whereas single drugs, Churna, Vati, Aasava and Arista, Kwatha, Gutika, Guggulu, Ras Aushdhi etc. are used internally while in Shodhana therapy Snehana, Swedana, Basti, Agnikarma, Raktamokshana is done. The best treatment for Vata is by Taila (Shamana) and Basti (Shodhana). By application of Taila it relives Shoola/Vedana, when we see the properties of this it has Ushna (heat), Sthira (stable), Yonivishodhanam, by Ushna quality it penetrates the skin there by producing sedative effect and Yonivishodhanam refers to it helps in eliminating the toxins pertaining to that region. Depending on the cause of pain the appropriate medicine has to be choosed from above protocol. Shopha resulting after sports injuries comes under Aagantuja type of Shopha. Aagantuja Shopha arises due to Abhi (trauma), Bheda (splitting of tissues), and Kshata (injury). Swelling will be hot in touch, red in color and will have similar symptoms as those of Pittaj and Raktaj Shopha. The commonly traumatic joint disorders are fracture, dislocation, strain, and sprain. In all such conditions initial complaint of sportsman will be pain associated with swelling with or without deformity. Pain and swelling are the primary sign and symptom of any kind of sports injuries. While looking for a natural treatment to reduce swelling; we must go for
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Ayurvedic treatment. Ayurveda offers some excellent natural medicine and therapies such as Ayurvedic oil, Lepa, Alepa and massage that reduces swelling, pain and inflammation of joints. Many herbals have documented anti-inflammatory properties without side effect of commonly prescribed medications. Application of oil is the important because of the action of medicine is very fast, and can penetrate the skin layers. Lepa along with reducing pain and swelling also helps in proper healing of wound and management of its complications. So Lepa is highly useful in reducing the swelling and also to control the pain. In Ayurveda, Alepa is the first line of treatment advised for every Shopha due to Raktaprasandana Karma and hot potency (Ushna Veerya) of many Lepas (like Manjisthadi Lepa) help to penetrate into the local tissue that will dilation the peripheral vessels, thus resulting in venous dilation followed by increased peripheral arterial blood flow. This may be the reason for reduction of the swelling at the affected area. Ushana Guna, Madhura Rasa of the Lepa Dravya probably act as Vata Shamaka, thus result in reliving the pain, the Madhura and Snigdha properties of this act as anti-inflammatory. After Alepa, Bandhana Karma is advised in Shopha because it helps in Shodhana (purify by disinfecting), Ropana (healing) and stabilized the bones and joints. The Vranashopha is described as earlier phase of Vrana (wound). Sushruta has mentioned detail description of inflammatory swelling under the heading of Vranashopha which has 3 stages. Sushruta explains sixty procedures for management of Vranashopha (inflammatory swelling) and Vrana (wound). Out of these first eleven from Virechana were mentioned for Vranashopha specially and rest other forty eight procedures were truly for Vrana. It is very important to know all about Vranashopha as treatment in this stage can prevent hazardous complications occur by infected wound. According to Ayurveda different kinds management are required in different stages of Vranashopha like in early stage (Amawastha) only rubbing (Vimlapana), olation (oil massage), application of medicated paste (Alepa), Upanaha (poultice), are needed while in suppurative stage (Pakwawastha) surgical procedure like incision (Bhedana) after this Shodhana (antiseptic measures), Ropana (healing measures), and Vaikritapaha (to restore normalcy to the scar) are required. When Vranashopa is not treated in proper way it is converted in to Vrana (wound) in chronic stage. Wounds are the result of injuries to the skin that disrupt the other soft tissue. Wound healing is a complex and protracted process of tissue repair and remodeling in response to injury. Various plants products have been used in treatment of wounds over the years. Wound healing herbal extracts promote blood clotting, fight infection, and accelerate the healing of wounds. Several Page | 35
herbal, mineral, and animal originated drugs are described in the Ayurveda for their Vranaropaka (wound healing) properties. Wound healing procedures described by Sushruta still holds its place today. The faster the wound healing, the faster is the recovery of the sport person enabling him to resume his daily routine. These included various purification therapies (Shodhana) and local applications (Ropana) of natural resources, which are available very easily and heal the wound faster without any sepsis. Some Ayurvedic medicinal plants has described in Ayurveda, which have wound healing properties, for example Madhu has Vranaropaka properties as per the principles of the sixty Upakaramas of Vrana management described in the Sushruta Samhita. It has excellent properties to heal the wound by virtue of its Sodhana (purification), Ropana (healing), and Sandhana (union) actions. Even though healing is a natural process, it is inhibited by various factors. Deranged Doshas cannot be treated with a single drug all the times. Therefore number of herbal drugs having different properties has been described as Vrana Shodhaka and Vrana Ropaka Karma in the management of Vrana. Shodhana has been two types, Abhyantra Shodhana (internal purification) included Vamana, Virechana, Basti and Shirovirechana while Bahya Shodhana (external purification) incorporated Raktamokshana, Vrana Prakshalana, Vrana Pichu, Vrana Lepa, and Vrana Bast these are also very essential in healing of Vrana (wound). Ropana Karma means to promote or quickens the healing process. At present the modern system of medicine could not find such Karma which promotes the process of healing except anti-infective and debriding agents, Ropana drugs has been used in the form of Kalka, Kashaya, Varti, Ghrita, Taila, Churna etc. Fractures are incredibly common in sport, particularly in contact sports such as football, rugby etc. Stress fractures are also very common in sports which involve repetitive movements and forceful movements such as long distance runners’ often suffer from stress fracture in the foot, wrists, and hands. Contact sports such as football or an activity which involve excessive stretching or falling can cause dislocations. The most common joints that are dislocated are the shoulder, fingers and hand. Elbows, knee can be dislocated but are less common. General symptoms presents in fractures include swelling, redness and pain. Treatment generally depends on the fracture but rest is universally recognized as the most important form of treatment. Initially ice will usually be applied to the affected area; this will help to reduce swelling. Anti-
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inflammatory medication and pain relief will also be prescribed to ease pain and further reduce swelling. In many cases, the fractures bone will be immobilized for a period of time; this may involve having a plaster cast fitted, wearing a sling or using crutches it will allow minimum time to heal the fracture. Treatment depends on site of joint which has been dislocated and the severity of the injury. It might include manipulations to reposition your bones, medicine, a splint or sling, and rehabilitation. When all these are properly done than only the recovery of the joint will occur quickly. Ayurveda has mentioned different types of fracture and dislocations without any diagnostic interventions such as radiological investigations along with treatment according to severity of wound. Sushruta has explained 12 types of fracture and 6 types of dislocations which are same as modern orthopedic contexts. In addition to this he also divided these classifications according to the Nidana (etiology) of fracture such as fall, strike, compression etc. There is not only similarity of types of fracture and dislocations but principle of treatment is also same to that of modern era modalities. So we also used these modalities for the management of Bhagna which are very valuable and cost effective. Acharya Sushruta has mentioned four principles of skeletal injuries which are almost same as that of modern aspect of treatment like Anchana Karma which is very much similar to traction as modern aspect of treatment, Pidana karma which means manipulation is done by local pressure on the injured part so that nature of dislocation or fracture of joint part is examined properly, Sankshepana karma in which opposition and stabilization of dislocated and fractured part has been adjusted accurately and lastly Bandana karma has been done for immobilization of the injured part by applying or sprinkling various measures like use of different medicated Lepa, decoctions and oils followed by uses of splits to support the injured part for better results. In modern science also same procedure has been done with the help of modern techniques. Acharya Sushruta has already described the treatment for fracture and dislocations of Kora Sandhi. We can interpret these treatments for fracture and dislocation of sports injuries. A dislocation of (Kurpara Sandhi) elbow joint should be first rubbed with the thumb, after which it should be pressed with a view to set it in its right place by fixing and expanding the same. After that the affected part should be sprinkled over with any oleaginous substance. The same measures are also adopted in the case of a dislocation of the knee joint (Janu Sandhi), the ankle joint (Gulpha Sandhi) and the wrist joint (Mani-Bandha). In case of the phalanx fracture or dislocation, it should be first set in its natural position and bandaged with pieces of thin linen and should be then sprinkled with ghee. This ancient method resembles with Page | 37
modern management, in which the affected part is supported by bandaging it along with a splint or adjoining finger. One of the main advantages of Ayurvedic treatment for bone fracture and dislocation is it’s both external and internal use of different herbal medicines in various forms, such as paste, barks, decoctions, Ghritas, oil form etc, which shows enormous results in reducing pain, healing wounds, and re-joining the fractured bones. Chakra Taila, Ghandha Taila oil massage therapies are also a popular method adopted in Ayurveda, in shaping the bones back to their original from and Panchkarma has been also given depending on the conditions of the patient. The sports man is advised to consume Shali rice, meat soup, milk, ghee, pea soup and weight promoting food and liquids. This is not only nourishes the body but also bestow sturdiness to the joints. Sushruta has been also explained various types of bandage like Swastika, Anuvellita, Kosha etc. in fracture or in dislocation of joints. Acharya Sushruta’s line of treatment is very much similar to the modern treatment which is practiced today. There are also different types of tendon, nerve, and ligament injuries in sports like Golfer’s elbow, tennis elbow, carpal tunnel syndrome, ankle sprain, and wrist sprain etc. which shows common symptoms resembling pain, swelling, redness etc. In ayurveda all these symptoms or conditions has been occur due to vitiation of Vata named as Snayugatavata. It has been occurred due to Atichehsta, Ativayayama, i.e. injuries due to overuse or over exercise. In Snayugatavata, Snehana, Upnaha, Agnikarama, and Bandhana has been done simultaneously. Snehana followed by Upanaha followed by Agnikaram it is best remedy for reducing pain and finally Bandhan is done to stabilize the injured body component. In classics to avoid injury some principle treatment are also explained by which physical and psychological fitness of sports person ensured. In Ayurveda we have some concepts like Rasayan, Aahar, Abhayanga, yoga for improving the strength and immunity of every individual due to which injuries may be minimized or avoided. These therapies have important role in before, during and after sports injuries as these therapies keep the body strong physically and spiritually to avoid or fight against any sport injury. Role of Rasayana in Sports Rasayana anti-oxidant property and removes free radicals and has a major role in preventing complications of post injury. In sports injuries the physical and mental fitness of the person will be impaired which affect the natural performance of the sport person. So to get rid from injuries or fitness one must use Rasayan therapy. Rasayan therapy is a boon to mankind.
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Different Rasayana like Naimittik, Aachar and Kutipraveshik etc. has been explained in the classics, which are responsible for Vyasdhikshamtav (immunity) of the body. Apart from this it has been also shown its utility in provide proper nutrition to each tissue, gives strength to the Srotas or channels in the body, normalized the Doshas in the body, increase Ojas (mental strength), physical strength of the body, maintaining the Satva quality of mind and improves durability as well as quality of the life so to enchase fitness of body and mind we must consume Rasayana or rejuvenation therapy. Herbal drugs like Aswagandha, Satavari, Kushmanda, Vidarighnada etc. by its Rasayana properties produces Shresta/Preshasta Bhava of Rasadi Dhatu, prevents the aggravation or vitiation of Vata and also due to its anti-oxidant properties they help in scavenging the free radicals produced during physical activities, thus increase the metabolic rate of the body. Role of Aahara in Sports In case of sportsman nutritious diet plays an important role in their performance. During sports training, the energy requirement of the players is relatively high therefore the diet should be accordingly planned otherwise the players will shows the signs of fatigue which may result in internal and external injuries to the players. Sport person must need a balanced food to maintain their stamina. Good food habit provides them energy to perform their activities in a better way. The relation between diet and Bala is already well explained in the Ayurvedic classics. Ahara Sampata is described as one of the Bala Vridhikara and Sharir Vridhikara Bhava. Either vegetarian or mixed type of diet if it digested properly can produce strength in the body. Different types of Ahara Varga have been described in Ayurvedic classics. Acharyas have mentioned Pathya-Apathya concerning conditions of Vrana, Bhagna, Shotha etc. If Pathya is followed it helps in speedy recovery, whereas Apathya delays recovery. In injuries there is Dhatukshya so intake of Dhatuposhaka Ahara helps in recovery of injuries. Every sportsman should take Aahara according to its own Parkariti. Ayurveda gives comprehensive descriptions of food substances which increases muscle mass and physical ability. In Ayurveda Nutritious food should be taken according to eight factors such as nature of food, processing of food, combination, quantity, place, time dietetic rules and constitution i.e. genetic makeup. An Ayurvedic practitioner can play significant role in developing a detailed nutritional plan which will support these eight factors in accordance with the individual goals. Role of Abhayanga in Sports In sports injuries major affected body structures are muscles, nerves, Page | 39
tendons, ligaments etc. hence to increase the strength of all these components Abhayanga plays a prime role. By Abhayanga one attains strength, stability flexibility to muscles, nerves, tendons, ligaments etc. So every sports person must apply Abhayanga regular way for muscles sprain, muscles fatigue, improve mental concentration and fast recovery of damage. Role of Yoga in Sports Yoga focuses on harmony between mind and body. Yoga consists of various movements, breath techniques, postures of relaxation and mediation in order to establish a healthy, lively and balanced approach to life. Yoga plays an important role in games and sports also. Yoga improves near about all physical fitness and wellness components required by sportsman. Yoga works on strength, flexibility, balance, agility, endurance, core, stability, recovery and overall strength, among other things. Yoga is able to mobilize joints, stretch tissue and ligaments, tone muscles, bring flexibility to the spine and strengthen internal organs. Yoga exercises are based on the formula of stretching, relaxation, deep breathing, and increasing circulation and can play a key role in cultivating mind control and concentration which helps a sportsperson to perform at their peak level. Many Yoga poses has been explained in this dissertation related to Kora Sandhi for their strengthening. Sports injuries happen in any joint or part of the body during sports activities shows same common symptoms like pain, swelling, spasm, fracture etc. Only the name of injury may differ according to structures involved, name of the sports or common site of injury in particular sports like tennis elbow, golfers knee etc. So here we discussed only several common injuries that can go on very frequently in any types of sport activities like Shoola, Shopha, Vranashopha, Vrana, Kandabhana, Sandhimukta, Snayugata Vata etc. and its management on the basis of Ayurveda knowledge explained in Samhita and relevant Ayurveda literature. References 1.
Ashtanga Hridaya of Vagbhatta with the commentaries Sarvangasundara of Arundutta & Ayurved Rasayana of Hemadri edited by Pt. Bhisagacharya Hari Shadashiv Shastri Paradkar Vaidya, Chaukhamba Surbharati Prakashan, Varanasi, Reprint, 2007.
2.
Ashtanga Samgraha of Vagabhatta edited by Pandit Lalchandra Shastri Vaidya, Shri Vaidyanath Ayurveda Bhawan, Nagpur, 1st edition, 1989.
3.
Ashtanga Samgraha of Vagabhatta with the Shashilekha Sanskrit commentary edited by Indu Chowkhambha Sanskrit Series office. Page | 40
4.
Bhaishajya Ratnavali, Commentary by Ambika Dutta Shastri, 16th Ed., Chaukhambha Sanskrit Sansthan, Varanasi (India), 2002.
5.
Bhavprakash, Bhav Mishra 5th ed. Vidyotini Commentary by Brahma Shankar Shastri, Chaukhamba Sanskrit Series, Varanasi, 1969.
6.
Charak Samhita with 'Ayurvedadipika' sanskrit commentary by Sri Chakrapanidutta, 'Tattvaprakasini' hindi commentary of 'Ayurvedadipika' and on some places hindi commentary of 'Jalpakalpataru' of Gangadhar edited by Dr. Lakshmidhar Dwivedi part 1&2, Published by Chowkhambha Krisnadas Academy, Varanasi.
7.
Charak Samhita with Charak Chandrika Hindi commentary by Pt. Dr. Brhamnand Tripathi foreword by Dr. Ganga Sahay Pandey part 1, Published by Chaukhamba Surbharati Prakashan, Varanasi.
8.
Charaka Samhita of Agnivesha revised by Charaka & supplemented by Dridhabala with Ayurveda Dipika commentary by Chakrapanidatta edited by Vaidya Yadavaji Trikaji Acharya, Chukahmba Surbharati Prakashan Varanasi, Reprint, 2009.
9.
Clinical Sports Medicine-Peter Brukner and Karim Khan, 3rd Edition, 2008.
10. Dravyaguna Vijnana, by Dr. Gyanendra Pandey, 2nd edition, Chaukhambha Krishnadas Academy Varanasi, 2002, I, II, III. 11. Derek Armfield MD, Patrick J, McMahon MD. Editor; Current Diagnosis & Treatment in Sports Medicine, 1st Edition; McGraw-Hill, 2007. 12. Domhnall McAuley, Thomas M Best. Editor; Evidence-based Sports Medicine, London, BMJ Books, 2002. 13. Essentials of Medical Physiology- Third Edition, (K. Sembulingam & Prema Sembulingam)-Jayреe Brothers Medical Publishers (P) Ltd. New Delhi. 14. Evidence Based Sports Medicine- Domhnall Macanley & Thoms M. Best-Bmj Books. 15. Gray's Anatomy-the anatomical basis of medicine and surgery, PL Williams, Bannister LH, Berry MM Collins P, Dussek JE, Ferguson MWJ. (eds): 38th ed. New York, Churchill Livingstone, 1995. 16. Human Anatomy; Regional and Applied Dissection and Clinical, ed. Fifth, B.D. Chaurasia; CBS Publishers and Distributors Pvt. Ltd, New Delhi, 2010, 2. Page | 41
17. Kashyapa Sahmhita of Vriddha Jivaka revised by Vatsya with Sanskrit Intoducation by Pandit Hemaraja Sharma, Chaukhamba Sanskrit Series, 2002. 18. Manav Sharir Rachana by Prof. D.G. Thatte, 1st ed. Ayurved and Unani Tibbi Academy, Lucknow. 19. Medical Dictionary, 23rd edition, Williams and Witkins com. Stedman, Calcutta, Indian Reprint III, 1982. 20. Sharangadhara samhita of Sharangadhara with the commentaries Aadhamallas dipikas And kasiramas gudhartha-dipika edited by Pt. Parashuramshatri Vidyasagar, introduction by Prof. C.B. Jha, 1st edition, published by Chaukhamba Surbharati Prakashan, Varanasi, 2006. 21. Sports injuries hand book diagnosis and management-Christer Rolf A & C Black 1st Edition, 2007. 22. Sushruta Samhita of Sushruta with the Nibhandhasangraha commentary of Sri Dalhanacharya and the 'Nyayachandrika Panjika' of Sri Gayadasacharya on Nidanasthana edited by Vaidya Yadavji Trikamji Acharya, Chaukhamba Surbharati Prakashan, Varanasi, 2012. 23. Vaidhya Shabdasindhu, Chowkhambha Sanskrit Series, Varanasi. 24. Yoga for sports: a journey towards health and healing. -BKS Lyengar, 2015.
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Chapter - 2 Review of Diabtes Mellitus and Complications
Author Dr. Siva Rami Reddy E Faculty of Homoeopathy, Tantia University, Sri Ganga nagar, Rajasthan, India
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Chapter - 2 Review of Diabtes Mellitus and Complications Dr. Siva Rami Reddy E
Abstract Diabetes Mellitus (DM) is a clinical syndrome characterized by hyperglycemia due to absolute or relative deficiency of insulin. This can arise in many different ways. Lack of insulin affects the metabolism of carbohydrate, protein and fat and causes a significant disturbance of water and electrolyte homeostasis. Death may result from acute metabolic decompensation while long standing metabolic derangement is frequently associated with permanent and irreversible functional and structural changes in the cells of the body, with those of the vascular system being particularly susceptible. Keywords: Diabetes mellitus, pathophysiology. Introduction Diabetes mellitus (DM) comprises a group of common metabolic disorders that share the phenotype of hyperglycemia. Several distinct types of Diabetes mellitus exist and are caused by a complex interaction of genetics, environmental factors, and life style choices [1, 6]. Depending on the etiology of the Diabetes Mellitus, factors contributing to hyperglycemia may include reduced insulin secretion, decreased glucose utilization, and increased glucose production. The metabolic dysregulation associated with Diabetes mellitus causes secondary pathophysiologic changes in multiple organ systems that impose a tremendous burden on the individual with diabetes and on the health care system. In the United States, Diabetes Mellitus is the leading cause of end stage renal disease (ESRD), nontraumatic lower extremity amputations, and adult blindness [7, 10]. With an increasing incidence worldwide, Diabetes Mellitus will be a leading cause of morbidity and mortality for the foreseeable future [11] The pancreas (meaning all flesh) lies in the upper abdomen behind the stomach. The pancreas is part of the gastrointestinal system that makes and secretes digestive enzymes into the intestine, and also an endocrine organ Page | 45
that makes and secretes hormones into the blood to control energy metabolism and storage throughout the body. It is worthwhile to mention a few definitions for key terms as used in the context of the pancreas: Exocrine pancreas, the portion of the pancreas that makes and secretes digestive enzymes into the duodenum. This includes acinar and duct cells with associated connective tissue, vessels, and nerves. The exocrine components comprise more than 95% of the pancreatic mass. Endocrine pancreas, the portions of the pancreas (the islets) that make and secrete insulin, glucagon, somatostatin and pancreatic polypeptide into the blood. Islets comprise 1-2% of pancreatic mass. Since we are dealing with a three dimensional solid structure, the aphorism that “a picture is worth a thousand words” seems to pertain. Accordingly, this chapter will largely consist of images with extended legends. The images range from classic work of skilled medical artists to original drawings and photomicrographs from leaders in the study of pancreatic anatomy and structure. Gross Anatomy of Pancreas The gross anatomy of the pancreas and its relationship to surrounding organs in adults. It is customary to refer to various portions of the pancreas as head, body, and tail. The head lies near the duodenum and the tail extends to the hilum of the spleen. When the terms anterior, posterior, front and back are used, they pertain to relationships in the human, standing erect. Superior and inferior are used in the same context so that they mean toward the head and toward the feet, respectively. These usages obviously do not pertain in quadraped animals where dorsal, ventral, cephalad, and caudad are more useful terms.
Fig 1: Anatomy of pancreas Page | 46
Use of the terms left and right can be problematic. For example, the spleen is located in the upper portion of the abdomen on the left side of the body. When the abdomen is pictured from the front, this places the spleen on the viewer’s right hand side. We will adopt the convention that right and left (unqualified) will be used in the first sense in the legends for gross anatomy.
Fig 2: Histology of Pancreas
The tail of the pancreas and spleen are in the left upper quadrant of the abdomen and the head of the pancreas is in the right upper quadrant just to the right of the midline. If you place your right hand over your upper abdomen with fingers extending to the left over the lower portion of your rib cage and the tip of your thumb extended up over the lower portion of the sternum, then your pancreas lies behind your hand in the back (retroperitoneal) portion of the abdomen. The pancreas is about the size of the half of your hand that includes the index and third fingers excluding the thumb. The pancreas weighs about 100 grams and is 14-20 cm long. Epidemiology The worldwide prevalence of Diabetes Mellitus has risen dramatically over the past two decades. Likewise, prevalence rates of IFG are also increasing. Although the prevalence of both type 1 and type 2 Diabetes mellitus is increasing worldwide, the prevalence of type 2 Diabetes mellitus is expected to rise more rapidly in the future because of increasing obesity and reduced activity levels. Diabetes Mellitus increases with aging. In 2000, the prevalence of Diabetes mellitus was estimated to be 0.19% in people 20 years old and 8.6% in people 20 years old. In individuals 65 years the prevalence of Diabetes Mellitus was 20.1%. The prevalence is similar in men and women throughout most age ranges but is slightly greater in men 60 years. There is considerable geographic variation in the incidence of both type 1 and type 2 Diabetes Mellitus. Scandinavia has the highest incidence of Page | 47
type 1 Diabetes Mellitus (e.g., in Finland, the incidence is 35/100,000 per year). The Pacific Rim has a much lower rate (in Japan and China, the incidence is 1 to 3/100,000 per year) of type 1 Diabetes Mellitus; Northern Europe and the United States share an intermediate rate (8 to 17/100,000 per year). Much of the increased risk of type 1 Diabetes Mellitus is believed to reflect the frequency of high risk HLA alleles among ethnic groups in different geographic locations. The prevalence of type 2 Diabetes Mellitus and its harbinger, IGT, is highest in certain Pacific islands, intermediate in countries such as India and the United States, and relatively low in Russia and China. This variability is likely due to genetic, behavioural, and environmental factors. Diabetes Mellitus prevalence also varies among different ethnic populations within a given country. In 2000, the prevalence of Diabetes Mellitus in the United States was 13% in African Americans, 10.2% in Hispanic Americans, 15.5% in Native Americans (American Indians and Alaska natives), and 7.8% in non-Hispanic whites. The onset of type 2 Diabetes Mellitus occurs, on average, at an earlier age in ethnic groups other than non-Hispanic whites. Insulin Biosynthesis, Secretion, and Action Biosynthesis Insulin is produced in the beta cells of the pancreatic islets. It is initially synthesized as a single chain 86 aminoacid precursor polypeptide, preproinsulin. Subsequent proteolytic processing removes the aminoterminal signal peptide, giving rise to proinsulin. Proinsulin is structurally related to insulin like growth factors I and II, which bind weakly to the insulin receptor [12] . Cleavage of an internal 31 residue fragment from proinsulin generates the C peptide and the A (21 amino acids) and B (30 amino acids) chains of insulin, which are connected by disulfide bonds. The mature insulin molecule and C peptide are stored together and cosecreted from secretory granules in the beta cells. Because the C peptide is less susceptible than insulin to hepatic degradation, it is a useful marker of insulin secretion and allows discrimination of endogenous and exogenous sources of insulin in the evaluation of hypoglycemia [13, 15]. Human insulin is now produced by recombinant DNA technology; structural alterations at one or more residues are useful for modifying its physical and pharmacologic characteristics [16]. Secretion Glucose is the key regulator of insulin secretion by the pancreatic beta cell, although amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin secretion. Glucose Page | 48
levels 3.9 mmol/L (70 mg/dL) stimulates insulin synthesis, primarily by enhancing protein translation and processing. Glucose stimulation of insulin secretion begins with its transport into the beta cell by the GLUT2 glucose transporter. Glucose phosphorylation by glucokinase is the rate limiting step that controls glucose regulated insulin secretion. Further metabolism of glucose-6- phosphate via glycolysis generates ATP, which inhibits the activity of an ATP sensitive K channel. This channel consists of two separate proteins: one is the receptor for certain oral hypoglycemics (e.g., sulfonylureas, meglitinides); the other is an inwardly rectifying K channel protein. Inhibition of this K channel induces beta cell membrane depolarization, which opens voltage dependent calcium channels (leading to an influx of calcium), and stimulates insulin secretion. Insulin secretary profiles reveal a pulsatile pattern of hormone release, with small secretary bursts occurring about every 10 min, superimposed upon greater amplitude oscillations of about 80 to 150 min. Meals or other major stimuli of insulin secretion induce large (four to fivefold increase versus baseline) bursts of insulin secretion that usually last for 2 to 3 h before returning to baseline. Derangements in these normal secretory patterns are one of the earliest signs of beta cell dysfunction in Diabetes Mellitus. Action Once insulin is secreted into the portal venous system, 50% is degraded by the liver. Unextracted insulin enters the systemic circulation where it binds to receptors in target sites. Insulin binding to its receptor stimulates intrinsic tyrosine kinase activity, leading to receptor auto phosphorylation and the recruitment of intracellular signalling molecules, such as insulin receptor substrates (IRS). These and other adaptor proteins initiate a complex cascade of phosphorylation and dephosphorylation reactions, resulting in the widespread metabolic and mitogenic effects of insulin. As an example, activation of the phosphatidylinositol-3-kinase (PI-3-kinase) pathway stimulates translocation of glucose transporters (e.g., GLUT4) to the cell surface, an event that is crucial for glucose uptake by skeletal muscle and fat. Activation of other insulin receptor signalling pathways induces glycogen synthesis, protein synthesis, lipogenesis, and regulation of various genes in insulin responsive cells. Glucose homeostasis reflects a precise balance between hepatic glucose production and peripheral glucose uptake and utilization. Insulin is the most important regulator of this metabolic equilibrium, but neural input, metabolic signals, and hormones (e.g., glucagon) result in integrated control of glucose supply and utilization. In the fasting state, low insulin levels increase glucose production by promoting hepatic gluconeogenesis. Page | 49
Pathophysiology Type 2 Diabetes mellitus is characterized by three pathophysiologic abnormalities: impaired insulin secretion, peripheral insulin resistance, and excessive hepatic glucose production. Obesity, particularly visceral or central (as evidenced by the hip waist ratio), is very common in type 2 Diabetes mellitus. Adipocytes secrete a number of biologic products (leptin, TNF free fatty acids, resistin, and adiponectin) that modulate insulin secretion, insulin action, and body weight and may contribute to the insulin resistance. In the early stages of the disorder, glucose tolerance remains normal, despite insulin resistance, because the pancreatic beta cells compensate by increasing insulin output. As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemic state. IGT, characterized by elevations in postprandial glucose, then develops. A further decline in insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting hyperglycemia. Ultimately, beta cell failure may ensue. Markers of inflammation such as IL 6 and C-reactive protein are often elevated in type 2 diabetes. Insulin Resistance The decreased ability of insulin to act effectively on peripheral target tissues (especially muscle and liver) is a prominent feature of type 2 Diabetes mellitus and results from a combination of genetic susceptibility and obesity. Insulin resistance is relative, however, since supernormal levels of circulating insulin will normalize the plasma glucose. Insulin dose response curves exhibit a rightward shift, indicating reduced sensitivity, and a reduced maximal response, indicating an overall decrease in maximum glucose utilization (30 to 60% lower than normal individuals). Insulin resistance impairs glucose utilization by insulin sensitive tissues and increases hepatic glucose output; both effects contribute to the hyperglycemia. Increased hepatic glucose output predominantly accounts for increased FPG levels, whereas decreased peripheral glucose usage results in postprandial hyperglycemia. In skeletal muscle, there is a greater impairment in nonoxidative glucose usage (glycogen formation) than in oxidative glucose metabolism through glycolysis. Glucose metabolism in insulin independent tissues is not altered in type 2 Diabetes mellitus. The precise molecular mechanism of insulin resistance in type 2 Diabetes mellitus has not been elucidated. Insulin receptor levels and tyrosine kinase activity in skeletal muscle are reduced, but these alterations are most likely secondary to hyperinsulinemia and are not a primary defect. Therefore, postreceptor defects are believed to play the predominant role in insulin resistance. Page | 50
Polymorphisms in IRS-1 may be associated with glucose intolerance, raising the possibility that polymorphisms in various postreceptor molecules may combine to create an insulin resistant state. The pathogenesis of insulin resistance is currently focused on a PI-3-kinase signaling defect, which reduces translocation of GLUT4 to the plasma membrane, among other abnormalities of note, not all insulin signal transduction pathways are resistant to the effects of insulin [e.g., those controlling cell growth and differentiation and using the mitogen activated protein (MAP) kinase pathway. Consequently, hyperinsulinemia may increase the insulin action through these pathways, potentially accelerating diabetes related conditions such as atherosclerosis. Another emerging theory proposes that elevated levels of free fatty acids, a common feature of obesity, may contribute to the pathogenesis of type 2 Diabetes mellitus. Free fatty acids can impair glucose utilization in skeletal muscle, promote glucose production by the liver, and impair beta cell function. Impaired Insulin Secretion Insulin secretion and sensitivity are interrelated. In type 2 Diabetes mellitus, insulin secretion initially increases in response to insulin resistance to maintain normal glucose tolerance. Initially, the insulin secretory defect is mild and selectively involves Glucose stimulated insulin secretion. The response to other non-glucose secretagogues, such as arginine, is preserved. Eventually, the insulin secretory defect progresses to a state of grossly inadequate insulin secretion. The reason(s) for the decline in insulin secretory capacity in type 2 Diabetes mellitus is unclear. Despite the assumption that a second genetic defect-superimposed upon insulin resistance leads to beta cell failure, intense genetic investigation has so far excluded mutations in islet candidate genes. Islet amyloid polypeptide or amylin is cosecreted by the beta cell and likely forms the amyloid fibrillar deposit found in the islets of individuals with long standing type 2 Diabetes mellitus. Whether such islet amyloid deposits are a primary or secondary event is not known. The metabolic environment of diabetes may also negatively impact islet function. For example, chronic hyperglycemia paradoxically impairs islet function (“glucose toxicity”) and leads to a worsening of hyperglycemia. Improvement in glycemic control is often associated with improved islet function. In addition, elevation of free fatty acid levels (“lipotoxicity”) and dietary fat may also worsen islet function. Acute Complications of Diabetes Mellitus Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state are Page | 51
acute complications of diabetes. DKA was formerly considered a hallmark of type 1 Diabetes mellitus, but it also occurs in individuals who lack immunologic features of type 1A Diabetes mellitus and who can subsequently be treated with oral glucose lowering agents (these individuals with type 2 Diabetes mellitus are often of Hispanic or African American descent). HHS is primarily seen in individuals with type 2 Diabetes mellitus. Both disorders are associated with absolute or relative insulin deficiency, volume depletion, and acid base abnormalities. Diabetic ketoacidosis and HHS exist along a continuum of hyperglycemia, with or without ketosis. The metabolic similarities and differences in Diabetic ketoacidosis. Both disorders are associated with potentially serious complications if not promptly diagnosed and treated. Diabetic Ketoacidosis (DKA) Clinical Features The symptoms and physical signs of Diabetic ketoacidosis are usually developed over 24 hours. Diabetic ketoacidosis may be the initial symptom complex that leads to a diagnosis of type 1 Diabetes mellitus, but more frequently it occurs in individuals with established diabetes. Nausea and vomiting are often prominent, and their presence in an individual with diabetes warrants laboratory evaluation for Diabetic ketoacidosis. Abdominal pain may be severe and can resemble acute pancreatitis or ruptured viscous. Hyperglycemia leads to glucosuria, volume depletion, and tachycardia. Hypotension can occur because of volume depletion in combination with peripheral vasodilatation. Kussmaul respirations and a fruity odour on the patient’s breath (secondary to metabolic acidosis and increased acetone) are classic signs of the disorder. Lethargy and central nervous system depression may evolve into coma with severe Diabetic ketoacidosis but should also prompt evaluation for other reasons for altered mental status (infection, hypoxia, etc.). Cerebral oedema, an extremely serious complication of Diabetic ketoacidosis, is seen most frequently in children. Signs of infection, which may precipitate Diabetic ketoacidosis, should be sought on physical examination, even in the absence of fever. Tissue ischemia (heart, brain) can also be a precipitating factor. Laboratory Abnormalities and Diagnosis The timely diagnosis of Diabetic ketoacidosis is crucial and allows for prompt initiation of therapy. Diabetic ketoacidosis is characterized by hyperglycemia, ketosis, and metabolic acidosis (increased anion gap) along with a number of secondary metabolic derangements. Occasionally, the serum glucose is only minimally elevated. Serum bicarbonate is frequently Page | 52
10 mmol/L, and arterial pH ranges between 6.8 and 7.3, depending on the severity of the acidosis. Despite a total body potassium deficit, the serum potassium at presentation may be mildly elevated, secondary to the acidosis. Total body stores of sodium, chloride, phosphorous, and magnesium are also reduced in Diabetic ketoacidosis but are not accurately reflected by their levels in the serum because of dehydration and hyperglycemia. Elevated blood urea nitrogen (BUN) and serum creatinine levels reflect intravascular volume depletion. Interference from acetoacetate may falsely elevate the serum creatinine measurement. Leukocytosis, hypertriglyceridemia, and hyperlipoproteinemia are commonly found as well. Hyperamylasemia may suggest a diagnosis of pancreatitis, especially when accompanied by abdominal pain. However, in Diabetic ketoacidosis the amylase is usually of salivary origin and thus is not diagnostic of pancreatitis. Serum lipase should be obtained if pancreatitis is suspected. The measured serum sodium is reduced as a consequence of the hyperglycemia [1.6 mmol/L (1.6 meq) reduction in serum sodium for each 5.6 mmol/L (100 mg/dL) rise in the serum glucose]. Normal serum sodium in the setting of Diabetic ketoacidosis indicates a more profound water deficit. In “conventional” units, the calculated serum osmolality [2 (serum sodium serum potassium) plasma glucose (mg/dL)/18 BUN/2.8] is mildly to moderately elevated, though to a lesser degree than that found in HHS. In Diabetic ketoacidosis, the ketone body, hydroxybutyrate, is synthesized at a threefold greater rate than acetoacetate; however, acetoacetate is preferentially detected by a commonly used ketosis detection reagent (nitroprusside). Serum ketones are present at significant levels (usually positive at serum dilution of 1:8 or greater). The nitroprusside tablet, or stick, is often used to detect urine ketones; certain medications such as captopril or penicillamine may cause false positive reactions. Serum or plasma assays for hydroxybutyrate more accurately reflect the true ketone body level. The metabolic derangements of Diabetic ketoacidosis exist along a spectrum, beginning with mild acidosis with moderate hyperglycemia evolving into more severe findings. The degree of acidosis and hyperglycemia do not necessarily correlate closely since a variety of factors determine the level of hyperglycemia (oral intake, urinary glucose loss). Ketonemia is a consistent finding in DKA and distinguishes it from simple hyperglycemia. The differential diagnosis of Diabetic ketoacidosis includes starvation ketosis, alcoholic ketoacidosis (bicarbonate 15 meq/L) and other increased anion gap acidosis. Chronic Complications of Diabetes Mellitus The chronic complications of diabetes mellitus affect many organ Page | 53
systems and are responsible for the majority of morbidity and mortality associated with the disease. Chronic complications can be divided into vascular and nonvascular complications. The vascular complications of diabetes mellitus are further subdivided into microvascular (retinopathy, neuropathy, nephropathy) and macrovascular complications (coronary artery disease, peripheral arterial disease, cerebrovascular disease). Nonvascular complications include problems such as gastroparesis, infections, and skin changes. The risk of chronic complications increases as a function of the duration of hyperglycemia; they usually become apparent in the second decade of hyperglycemia. Since type 2 diabetes mellitus often has a long asymptomatic period of hyperglycemia, many individuals with type 2 diabetes mellitus have complications at the time of diagnosis. The microvascular complications of both type 1 and type 2 diabetes mellitus result from chronic hyperglycemia. Large, randomized clinical trials of individuals with type 1 or type 2 diabetes mellitus have conclusively demonstrated that a reduction in chronic hyperglycemia prevents or delays retinopathy, neuropathy, and nephropathy. Other incompletely defined factors may modulate the development of complications. For example, despite long standing Diabetes mellitus, some individuals never develop nephropathy or retinopathy. Many of these patients have glycemic control that is indistinguishable from those who develop microvascular complications, suggesting that there is a genetic susceptibility for developing particular complications. Evidence implicating a causative role for chronic hyperglycemia in the development of macrovascular complications is less conclusive. However, coronary heart disease events and mortality are two to four times greater in patients with type 2 Diabetes mellitus. These events correlate with fasting and postprandial plasma glucose levels as well as with the A1C. Other factors (dyslipidemia and hypertension) also play important roles in macrovascular complications. Mechanisms of Complications Although chronic hyperglycemia is an important etiologic factor leading to complications of Diabetes mellitus, the mechanism by which it leads to such diverse cellular and organ dysfunction is unknown. Four prominent theories, which are not mutually exclusive, have been proposed to explain how hyperglycemia might lead to the chronic complications of Diabetes mellitus. One theory is that increased intracellular glucose leads to the formation of advanced glycosylation end products (AGEs) via the nonenzymatic glycosylaton of intra and extracellular proteins. Nonennenzymatic glycosylation results from the interaction of glucose with Page | 54
amino groups on proteins. AGEs have been shown to cross link proteins (e.g., collagen, extracellular matrix proteins), accelerate atherosclerosis, promote glomerular dysfunction, reduce nitric oxide synthesis, induce endothelial dysfunction, and alter extracellular matrix composition and structure. The serum level of AGEs correlates with the level of glycemia, and these products accumulate as glomerular filtration rate declines. A second theory is based on the observation that hyperglycemia increases glucose metabolism via the sorbitol pathway. Intracellular glucose is predominantly metabolized by phosphorylation and subsequent glycolysis, but when increased, some glucose is converted to sorbitol by the enzyme aldose reductase. Increased sorbitol concentration alters redox potential, increases cellular osmolality, generates reactive oxygen species, and likely leads to other types of cellular dysfunction. However, testing of this theory in humans, using aldose reductase inhibitors, has not demonstrated significant beneficial effects on clinical endpoints of retinopathy, neuropathy, or nephropathy. A third hypothesis proposes that hyperglycemia increases the formation of diacylglycerol leading to activation of protein kinase C (PKC). Among other actions, PKC alters the transcription of genes for fibronectin, type IV collagen, contractile proteins, and extracellular matrix proteins in endothelial cells and neurons. A fourth theory proposes that hyperglycemia increases the flux through the hexosamine pathway, which generates fructose-6-phosphate, a substrate for O linked glycosylation and proteoglycan production. The hexosamine pathway may alter function by glycosylation of proteins such as endothelial nitric oxide synthase or by changes in gene expression of transforming growth factor (TGF) or plasminogen activator inhibitor-1 (PAI-1). Growth factors appear to play an important role in Diabetes mellitus related complications, and their production is increased by most of these proposed pathways. Vascular endothelial growth factor (VEGF) is increased locally in diabetic proliferative retinopathy and decreases after laser photocoagulation. TGF is increased in diabetic nephropathy and stimulates basement membrane production of collagen and fibronectin by mesangial cells. Other growth factors, such as platelet derived growth factor, epidermal growth factor, insulin like growth factor I, growth hormone, basic fibroblast growth factor, and even insulin, have been suggested to play a role in Diabetes mellitus related complications. A possible unifying mechanism is that hyperglycemia leads to increased production of reactive oxygen species or superoxide in the mitochondria; these compounds may activate all for of the pathways described above. Although hyperglycemia serves as the initial Page | 55
trigger for complications of diabetes, it is still unknown whether the same pathophysiologic processes are operative in all complications or whether some pathways predominate in certain organs. Ophthalmologic Complications of Diabetes Mellitus DM is the leading cause of blindness between the ages of 20 and 74 in the United States [17, 21]. The gravity of this problem is highlighted by the finding that individuals with Diabetes mellitus are 25 times more likely to become legally blind than individuals without Diabetes mellitus. Blindness is primarily the result of progressive diabetic retinopathy and clinically significant macular edema. Diabetic retinopathy is classified into two stages: non-proliferative and proliferative. Nonproliferative diabetic retinopathy usually appears late in the first decade or early in the second decade of the disease and is marked by retinal vascular microaneurysms, blot hemorrhages, and cotton wool spots [22, 24]. Mild nonproliferative retinopathy progresses to more extensive disease, characterized by changes in venous vessel caliber, intraretinal microvascular abnormalities, and more numerous microaneurysms and hemorrhages. The pathophysiologic mechanisms invoked in nonproliferative retinopathy include loss of retinal pericytes, increased retinal vascular permeability, alterations in retinal blood flow, and abnormal retinal microvasculature, all of which lead to retinal ischemia. The appearance of neovascularization in response to retinal hypoxia is the hallmark of proliferative diabetic retinopathy. These newly formed vessels appear near the optic nerve and macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment [25]. Not all individuals with nonproliferative retinopathy develop proliferative retinopathy, but the more severe the nonproliferative disease, the greater the chance of evolution to proliferative retinopathy within 5 years. This creates an important opportunity for early detection and treatment of diabetic retinopathy. Clinically significant macular edema can occur when only nonproliferative retinopathy is present. Fluorescein angiography is useful to detect macular edema, which is associated with a 25% chance of moderate visual loss over the next 3 years. Duration of Diabetes mellitus and degree of glycemic control are the best predictors of the development of retinopathy hypertension is also a risk factor. Nonproliferative retinopathy is found in almost all individuals who have had Diabetes mellitus for 20 years (25% incidence with 5 years, and 80% incidence with 15 years of type 1 Diabetes mellitus). Although there is genetic susceptibility for retinopathy, it confers less influence than either the duration of Diabetes mellitus or the degree of glycemic control. Page | 56
Renal Complications of Diabetes Mellitus Diabetic nephropathy is the leading cause of ESRD in the United States and a leading cause of Diabetes mellitus related morbidity and mortality. Proteinuria in individuals with Diabetes mellitus is associated with markedly reduced survival and increased risk of cardiovascular disease. Individuals with diabetic nephropathy almost always have diabetic retinopathy. Like other microvascular complications, the pathogenesis of diabetic nephropathy is related to chronic hyperglycemia [26]. The mechanisms by which chronic hyperglycemia leads to ESRD, though incompletely defined, involve the effects of soluble factors (growth factors, angiotensin II, endothelin, AGEs), hemodynamic alterations in the renal microcirculation (glomerular hyperfiltration or hyperperfusion, increased glomerular capillary pressure), and structural changes in the glomerulus (increased extracellular matrix, basement membrane thickening, mesangial expansion, fibrosis). Some of these effects may be mediated through angiotensin II receptors [27, 31]. Smoking accelerates the decline in renal function. The natural history of diabetic nephropathy is characterized by a fairly predictable sequence of events that was initially defined for individuals with type 1 Diabetes mellitus but appears to be similar in type 2 diabetes mellitus. Glomerular hyper perfusion and renal hypertrophy occur in the first years after the onset of Diabetes mellitus and cause an increase of the glomerular filtration rate (GFR). During the first 5 years of Diabetes mellitus, thickening of the glomerular basement membrane, glomerular hypertrophy, and mesangial volume expansion occur as the GFR returns to normal. After 5 to 10 years of type 1 Diabetes mellitus, 40% of individuals begin to excrete small amounts of albumin in the urine. Microalbuminuria is defined as 30 to 300 mg/d in a 24 h collection or 30 to 300 g/mg Creatinine in a spot collection (preferred method). The appearance of Microalbuminuria (incipient nephropathy) in type 1 Diabetes mellitus is an important predictor of progression to overt proteinuria (300 mg/d) or overt nephropathy. Blood pressure may rise slightly at this point but usually remains in the normal range [32, 33]. Once overt proteinuria is present, there is a steady decline in GFR, and 50% of individuals reach ESRD in 7 to 10 years. The early pathologic changes and albumin excretion abnormalities are reversible with normalization of plasma glucose. However, once overt nephropathy develops, the pathologic changes are likely irreversible. The nephropathy that develops in type 2 Diabetes mellitus differs from that of type 1 Diabetes mellitus in the following respects: (1) microalbuminuria or overt nephropathy may be present when type 2 Page | 57
Diabetes mellitus is diagnosed, reflecting its long asymptomatic period;(2) hypertension more commonly accompanies microalbuminuria or overt nephropathy in type 2 Diabetes mellitus and (3) microalbuminuria may be less predictive of diabetic nephropathy and progression to overt nephropathy in type 2 Diabetes mellitus. Finally, it should be noted that albuminuria in type 2 Diabetes mellitus may be secondary to factors unrelated to Diabetes mellitus, such as hypertension, congestive heart failure, prostate disease, or infection. Diabetic nephropathy and ESRD secondary to this develop more commonly in African Americans, Native Americans, and Hispanic individuals than in Caucasians with type 2 Diabetes mellitus. Neuropathy and Diabetes Mellitus Diabetic neuropathy occurs in approximately 50% of individuals with long standing type 1 and type 2 diabetes mellitus [34, 37]. It may manifest as polyneuropathy, mononeuropathy or autonomic neuropathy. As with other complications of Diabetes mellitus, the development of neuropathy correlates with the duration of diabetes and glycemic control; both myelinated and unmyelinated nerve fibers are lost. Because the clinical features of diabetic neuropathy are similar to those of other neuropathies, the diagnosis of diabetic neuropathy should be made only after other possible etiologies are excluded [38, 40]. Polyneuropathy/Mononeuropathy The most common form of diabetic neuropathy is distal symmetric polyneuropathy. It most frequently presents with distal sensory loss. Hyperesthesia, paresthesia, and dysesthesia also occur. Any combination of these symptoms may develop as neuropathy progresses. Symptoms include a sensation of numbness, tingling, sharpness, or burning that begins in the feet and spreads proximally. Neuropathic pain develops in some of these individuals, occasionally preceded by improvement in their glycemic control. Pain typically involves the lower extremities, is usually present at rest, and worsens at night. Both an acute (lasting 12 months) and a chronic form of painful diabetic neuropathy have been described. As diabetic neuropathy progresses, the pain subsides and eventually disappears, but a sensory deficit in the lower extremities persists. Physical examination reveals sensory loss, loss of ankle reflexes, and abnormal position sense. Diabetic poly radiculopathy is a syndrome characterized by severe disabling pain in the distribution of one or more nerve roots. It may be accompanied by motor weakness. Intercostal or truncal radiculopathy causes pain over the thorax or abdomen. Involvement of the lumbar plexus or Page | 58
femoral nerve may cause pain in the thigh or hip and may be associated with muscle weakness in the hip flexors or extensors (diabetic amyotrophy). Fortunately, diabetic poly radiculopathies are usually self-limited and resolve over 6 to 12 months. Mononeuropathy (dysfunction of isolated cranial or peripheral nerves) is less common than polyneuropathy in DM and presents with pain and motor weakness in the distribution of a single nerve. A vascular etiology has been suggested, but the pathogenesis is unknown. Involvement of the third cranial nerve is most common and is heralded by diplopia. Physical examination reveals ptosis and opthalmoplegia with normal pupillary constriction to light. Sometimes cranial nerves IV, VI, or VII (Bell’s palsy) are affected. Peripheral mononeuropathies or simultaneous involvement of more than one nerve (mononeuropathy multiplex) may also occur. Cardiovascular Morbidity and Mortality Cardiovascular disease is increased in individuals with type 1 or type 2 Diabetes mellitus. The Framingham Heart Study revealed a marked increase in peripheral arterial disease, congestive heart failure, coronary artery disease, myocardial infarction (MI) and sudden death (risk increase from one to fivefold) in Diabetes mellitus. The American Heart Association recently designated Diabetes mellitus as a major risk factor for cardiovascular disease (same category as smoking, hypertension, and hyperlipidemia). Type 2 diabetes patients without a prior MI have a similar risk for coronary artery related events as non-diabetic individuals who have had a prior myocardial infarction [41, 44]. Because of the extremely high prevalence of underlying cardiovascular disease in individuals with diabetes (especially in type 2 Diabetes mellitus), evidence of atherosclerotic vascular disease should be sought in an individual with diabetes who has symptoms suggestive of cardiac ischemia, peripheral or carotid arterial disease, a resting electrocardiogram indicative of prior infarction, plans to initiate an exercise program, proteinuria, or two other cardiac risk factors (ADA recommendations). The absence of chest pain (“silent ischemia”) is common in individuals with diabetes, and a thorough cardiac evaluation is indicated in individuals undergoing major surgical procedures [45]. The prognosis for individuals with diabetes who have coronary artery disease or myocardial infarction is worse than for non-diabetics. Coronary artery disease is more likely to involve multiple vessels in individuals with Diabetes mellitus. The increase in cardiovascular morbidity and mortality appears to relate to the synergism of hyperglycemia with other cardiovascular risk factors. For example, after controlling for all known cardiovascular risk factors, type 2 Page | 59
Diabetes mellitus increases the cardiovascular death rate two fold in men and fourfold in women. Risk factors for macrovascular disease in diabetic individuals include dyslipidemia, hypertension, obesity, reduced physical activity, and cigarette smoking. Additional risk factors specific to the diabetic population include microalbuminuria, gross proteinuria, an elevation of serum creatinine, and abnormal platelet function. Insulin resistance, as reflected by elevated serum insulin levels, is associated with an increased risk of cardiovascular complications in individuals with and without Diabetes mellitus. Individuals with insulin resistance and type 2 Diabetes mellitus have elevated levels of plasminogen activator inhibitors (especially PAI-1) and fibrinogen, which enhances the coagulation process and impairs fibrinolysis, thus favoring the development of thrombosis. Diabetes is also associated with endothelial, vascular smooth muscle, and platelet dysfunction. Proof that improved glycemic control reduces cardiovascular complications in Diabetes mellitus is lacking; in fact, it is possible that macrovascular complications may be unaffected or even worsened by such therapy. Concerns about the atherogenic potential of insulin remain, since in nondiabetic individuals, higher serum insulin levels (indicative of insulin resistance) are associated with a greater risk of cardiovascular morbidity and mortality. In the DCCT, the number of cardiovascular events did not differ between the standard and intensively treated groups. However, the duration of Diabetes mellitus in these individuals was relatively short, and the total number of events was very low. An improvement in the lipid profile of individuals in the intensive group [lower total and low density lipoprotein (LDL) cholesterol, lower triglycerides] suggested that intensive therapy may reduce the risk of cardiovascular morbidity and mortality associated with Diabetes mellitus. In the UKPDS, improved glycemic control did not conclusively reduce cardiovascular mortality. Importantly, treatment with insulin and the sulfonylureas did not appear to increase the risk of cardiovascular disease in individuals with type 2 Diabetes mellitus, refuting prior claims about the atherogenic potential of these agents. Lower Extremity Complications Diabetes mellitus is the leading cause of nontraumatic lower extremity amputation in the United States. Foot ulcers and infections are also a major source of morbidity in individuals with Diabetes mellitus. The reasons for the increased incidence of these disorders in Diabetes mellitus involve the interaction of several pathogenic factors: neuropathy, abnormal foot biomechanics, peripheral arterial disease, and poor wound healing. The peripheral sensory neuropathy interferes with normal protective mechanisms Page | 60
and allows the patient to sustain major or repeated minor trauma to the foot, often without knowledge of the injury. Disordered proprioception causes abnormal weight bearing while walking and subsequent formation of callus or ulceration. Motor and sensory neuropathy lead to abnormal foot muscle mechanics and to structural changes in the foot (hammer toe, claw toe deformity, prominent metatarsal heads, Charcot joint). Autonomic neuropathy results in anhidrosis and altered superficial blood flow in the foot, which promote drying of the skin and fissure formation [47, 49] . Peripheral arterial disease and poor wound healing impede resolution of minor breaks in the skin, allowing them to enlarge and to become infected. Treatment The optimal therapy for foot ulcers and amputations is prevention through identification of high risk patients, education of the patient, and institution of measures to prevent ulceration. High risk patients should be identified during the routine foot examination performed on all patients with Diabetes mellitus [50, 55]. Patient education should emphasize: (1) careful selection of footwear, (2) daily inspection of the feet to detect early signs of poor fitting footwear or minor trauma, (3) daily foot hygiene to keep the skin clean and moist, (4) avoidance of self-treatment of foot abnormalities and high risk behavior (e.g., walking barefoot), and (5) prompt consultation with a health care provider if an abnormality arises. Patients at high risk for ulceration or amputation may benefit from evaluation by a foot care specialist. Interventions directed at risk factor modification include orthotic shoes and devices, callus management, nail care, and prophylactic measures to reduce increased skin pressure from abnormal bony architecture. Attention to other risk factors for vascular disease (smoking, dyslipidemia, hypertension) and improved glycemic control are also important [56, 58]. Infections Individuals with Diabetes mellitus have a greater frequency and severity of infection. The reasons for this include incompletely defined abnormalities in cell mediated immunity and phagocyte function associated with hyperglycemia, as well as diminished vascularization. Hyperglycemia aids the colonization and growth of a variety of organisms (Candida and other fungal species). Many common infections are more frequent and severe in the diabetic population, whereas several rare infections are seen almost exclusively in the diabetic population. Examples of this latter category includes rhinocerebral mucormycosis, emphysematous infections of the gall bladder and urinary tract, and “malignant” or invasive otitis externa. Invasive Page | 61
otitis externa is usually secondary to P. aeruginosa infection in the soft tissue surrounding the external auditory canal, usually begins with pain and discharge, and may rapidly progress to osteomyelitis and meningitis. These infections should be sought, in particular, in patients presenting with HHS. Pneumonia, urinary tract infections, and skin and soft tissue infections are all more common in the diabetic population. In general, the organisms that cause pulmonary infections are similar to those found in the nondiabetic population; however, gram negative organisms, S. aureus, and Mycobacterium tuberculosis are more frequent pathogens. Urinary tract infections (either lower tract or pyelonephritis) are the result of common bacterial agents such as Escherichia coli, though several yeast species (Candida and Torulopsis glabrata) are commonly observed. Complications of urinary tract infections include emphysematous pyelonephritis and emphysematous cystitis. Bacteriuria occurs frequently in individuals with diabetic cystopathy. Susceptibility to furunculosis, superficial candidal infections, and vulvovaginitis are increased. Poor glycemic control is a common denominator in individuals with these infections. Diabetic individuals have an increased rate of colonization of S. aureus in the skin folds and nares. Diabetic patients also have a greater risk of postoperative wound infections. Strict glycemic control reduces postoperative infections in diabetic individuals undergoing CABG and should be the goal in all diabetic patients with an infection. Dermatologic Manifestations The most common skin manifestations of Diabetes mellitus are protracted wound healing and skin ulcerations. Diabetic dermopathy, sometimes termed pigmented pretibial papules, or “diabetic skin spots,” begins as an erythematous area and evolves into an area of circular hyperpigmentation. These lesions result from minor mechanical trauma in the pretibial region and are more common in elderly men with Diabetes mellitus. Bullous diseases (shallow ulcerations or erosions in the pretibial region) are also seen. Necrobiosis lipoidica diabeticorum is a rare disorder of Diabetes mellitus that predominantly affects young women with type 1 Diabetes mellitus, neuropathy, and retinopathy. It usually begins in the pretibial region as an erythematous plaque or papules that gradually enlarge, darken, and develop irregular margins, with atrophic centers and central ulceration. They may be painful. Acanthosis nigricans (hyperpigmented velvety plaques seen on the neck, axilla, or extensor surfaces) is sometimes a feature of severe insulin resistance and accompanying diabetes. Generalized or Page | 62
localized granuloma annulare (erythematous plaques on the extremities or trunk) and scleredema (areas of skin thickening on the back or neck at the site of previous superficial infections) are more common in the diabetic population. Lipoatrophy and lipohypertrophy can occur at insulin injection sites but are unusual with the use of human insulin. Xerosis and pruritus are common and are relieved by skin moisturizers. References 1.
JE Shaw, Sicree RA, Zimmet PZ. Diabetes Research and Clinical Practice. 2010; 87:4-14.
2.
Gilroy M. World health organization. 2017; 1(3):4-9.
3.
Wild S, Roglic G, Green A et al. Diabetes Care. 2004; 27(5):1047-1053.
4.
Juliana Chan CN, Vasanti M, Weiping J et al. JAMA. 2009; 301(20):2129-2140.
5.
Kate VA, Brian MF, Mark WJS. European Journal of Pharmacology. 2004; 490:169-175.
6.
Maureen IH, Katherine MF, Catherine CC et al. Diabetes Care. 1998; 21:518-524.
7.
Waleed MS, Ansam FS, Sa’ed HZ et al. Pharmacy Practice (Internet). 2009; 7(1):40-46.
8.
Lipin Cort Charles, Craig R, Robert ES. Modern Pharmacology with Clinical Applications. Fifth edition, 763-776.
9.
Iraj, Vida R, Sara R et al. International Journal of Diabetes Mellitus. 2010; 2:61-63.
10. Subrata C, Zia Ali K, Mark C et al. Int. Jnl Experimental Diab. Res. 2002; 3:217-231. 11. Michael. Clinical Diabetes. 2008; 26(2):357. 12. Rhodes CJ. Processing of the insulin molecule. In Diabetes Mellitus, D. LeRoith, S.I. Taylor, and J.M. Olefsky, eds. (Philadelphia, PA: Lippincott Williams & Wilkins), 2004, 27-50. 13. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 2000a, 1099-1108. 14. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk2/2 mice Page | 63
reveals a role for translational control in secretory cell survival. Mol. Cell 7, 2001, 1153-1163. 15. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, Zhao H et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity. 2004; 21:81-93. 16. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 2002; 16:1345-1355. 17. Fong DS, Aiello LP, Ferris FL 3rd, Klein R. Diabetic retinopathy. Diabetes Care. 2004; 27:2540-53. 18. Rema M, Premkumar S, Anitha B, Deepa R, Pradeepa R, Mohan V. Prevalence of diabetic retinopathy in urban India: The Chennai Urban Rural Epidemiology Study (CURES) eye study, I. Invest Ophthalmol Vis Sci. 2005; 46:2328-33. 19. Raman R, Rani PK, Reddi Rachepalle S, Gnanamoorthy P, Uthra S, Kumaramanickavel G, et al. Prevalence of diabetic retinopathy in India: Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetics Study report 2. Ophthalmology. 2009; 116:311-8 20. Raman R, Ganesan S, Pal SS, Kulothungan V, Sharma T. Prevalence and risk factors for diabetic retinopathy in rural India. Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Study III (SN‑DREAMS III), report no 2. BMJ Open Diabetes Res Care 2014; 2:e000005. 21. Nirmalan PK, Tielsch JM, Katz J, Thulasiraj RD, Krishnadas R, Ramakrishnan R, et al. Relationship between vision impairment and eye disease to vision‑specific quality of life and function in rural India: The Aravind Comprehensive Eye Survey. Invest Ophthalmol Vis Sci. 2005; 46:2308-12. 22. Nirmalan PK, Tielsch JM, Katz J, Thulasiraj RD, Krishnadas R, Ramakrishnan R, et al. Relationship between vision impairment and eye disease to vision specific quality of life and function in rural India: The Aravind Comprehensive Eye Survey. Invest Ophthalmol Vis Sci 2005; 46:2308-12. 23. Wong TY, Klein R, Couper DJ, Cooper LS, Shahar E, Hubbard LD, et Page | 64
al. Retinal microvascular abnormalities and incident stroke: The atherosclerosis risk in communities study. Lancet. 2001; 358:1134-40. 24. Fuller JH, Stevens LK, Wang SL. Risk factors for cardiovascular mortality and morbidity: The WHO mutinational study of vascular disease in diabetes. Diabetologia. 2001; 44(2):S54-64. 25. Kalofoutis C, Piperi C, Kalofoutis A, Harris F, Phoenix D, Singh J. Type II diabetes mellitus and cardiovascular risk factors: Current therapeutic approaches. Exp Clin Cardiol. 2007; 12:17-28. 26. Adler AI, Stevens RJ, Manley SE, Bilous WR, Cull AC, Holman RR. Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney int, 225-232. 27. Vrhovac B, Jakšić B, Reiner Ž, Vucelić B. Interna medicina. Zagreb: Naklada Ljevak, 2008, 1258-1259. 28. Kimmelstiel P, Wilson C. Benign and malignant hypertension and nephrosclerosis. A clinical and pathological study. Am. J pathol. 1936; 12:45-8 29. Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H. Microalbuminuria as a predictor of clinical nephropathy in insulin dependent diabetes mellitus. Lancet. 1982; 1:1430-1432. 30. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity onset diabetes. New eng. J med. 1984; 310:356360. 31. Orchard TJ, Dorman JS, Maser RE, Becker DJ, Drash AL, Ellis D. Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes. 1990; 39:1116-1124. 32. Chaturvedi N, Bandinelli S, Mangili R, Penno G, Rottiers RE, Fuller JH. Microalbuminuria in type 1 diabetes: rates, risk factors and glycemic threshold. Kidney int. 2001; 60:219-227. 33. Hovind P, Tarnow L, Rossing P, Jensen BR, Graae M, Torp I, et al. Predictors of the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study. Brit. med. J. 2004; 328:1105-1108. 34. Tripathi BK, Srivastava AK. Diabetes mellitus: complications and therapeutics. Med Sci Monit. 2006; 12(7):RA130-47. 35. Kamijo M, Cheian PV, Sima AAF. The preventive effect of aldose Page | 65
reductase inhibition on diabetic optic neuropathy in the BB/W rat. Diabetologia. 1993; 36(10):893-8. 36. Mooradian AD. Central nervous system complications of diabetes mellitusaPerspective from blood brain barrier.Brain Res Rev. 1997; 23:210-18. 37. Northam EA, Rankins D, Lin A, Wellard RM, Pell GS, Finch SJ et al. Central nervous system function in youth with type 1 diabetes 12 years after disease onset. Diabetes Care. 2009; 32:445-450. 38. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology. 1999; 53(9):1937-42. 39. Jason D Huber, Reyna L Van Gilder, Kimberly A. Houser. Streptozotocin induced diabetes progressively increases blood brain barrierpermeability in specific brain regions in rats. Am J Physiol Heart Circ Physiol. 2006; 291:2660-68. 40. Huang TJ, Price SA, Chilton L, Calcutt NA, Tomlinson DR, Verkhratsky A et al. Insulin prevents depolarization of the mitochondrial inner membrane in sensory neuronsof type 1 diabetic rats in the presence of sustained hyperglycemia. Diabetes. 2003; 52(8):212936. 41. Tsai EC, Hirsch IB, Brunzell JD, Chait A. Reduced plasma peroxyl radical trapping capacity and increased susceptibility of LDL to oxidation in poorly controlled IDDM. 1994; 43:1010-1014. 42. Enkins AJ, Klein RL, Chassereau CN, Hermayer KL, Lopes Virella MF. LDL from patients with well controlled IDDM is not more susceptible to in vitro oxidation. 1996; 45:762-767. 43. Diwadkar VA, Anderson JW, Bridges SR, Gowri MS, Oelgten PR. Postprandial low density lipoproteins in type 2 diabetes are oxidized more extensively than fasting diabetes and control samples, Proc Soc Exp Biol Med. 1999; 222:178-184. 44. Chisholm DJ, Campbell LV, Kraegen EW. Pathogenesis of the insulin resistance syndrome (syndrome X). Clin Exp Pharmacol Physiol. 1997; 24:782-784. 45. Thornalley PJ. Cell activation by glycated proteins; AGE receptors; receptor recognition factors and functional classification of AGEs. Cell Mol. Biol. 1998; 44:1013-1023. Page | 66
46. Robert. American Diabetes Association. Diabetes Care. 2008; 31(1):S12-S54. 47. Wild S, Roglic G, Green A et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004; 27:1047-53. 48. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005; 293:217-28. 49. Prompers L, Huijberts M, Apelqvist J et al. Optimal organization of health care in diabetic foot disease: introduction to the Eurodiale study. Int J Low Extrem Wounds. 2007; 6:11-7. 50. Levin ME. Foot lesions in patients with diabetes mellitus. Endocrinol Metab Clin North Am. 1996; 25:447-62. 51. Boulton AJ, Meneses P, Ennis WJ. Diabetic foot ulcers: A framework for prevention and care. Wound Repair Regen. 1999; 7:7-16. 52. Apelqvist J, Ragnarson Tennvall G, Larsson J et al. Long term costs for foot ulcers in diabetic patients in a multidisciplinary setting. Foot Ankle Int. 1995; 16:388-94. 53. Gordon PA. Effects of diabetes on the vascular system: current research evidence and best practice recommendations. J Vasc Nurs. 2004; 22:211. 54. Jeffcoate WJ, Price P, Harding KG. Wound healing and treatments for people with diabetic foot ulcers. Diabetes Metab Res Rev. 2004; 20(1):S78-89. 55. Widatalla AH, Mahadi SE, Shawer MA et al. Implementation of diabetic foot ulcer classification system for research purposes to predict lower extremity amputation. Int J Diabetes Dev Ctries. 2009; 29:1-5. 56. Armstrong DG, Lavery LA, Vela SA. et al. choosing a practical screening instrument to identify patients at risk for diabetic foot ulceration. Arch Intern Med. 1998; 158:289-92. 57. Lipsky BA, Polis AB, Lantz KC et al. The value of a wound score for diabetic foot infections in predicting treatment outcome: a prospective analysis from the SIDESTEP trial. Wound Repair Regen. 2009; 17:6717. 58. Cruciani M, Lipsky BA, Mengoli C. Are granulocyte colony stimulating factors beneficial in treating diabetic foot infections: A meta-analysis. Diabetes Care. 2005; 28:454-60. Page | 67
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Chapter - 3 Recent Amendments in Hippocratic Oath and Its Current Relevance
Authors Ganesh Singh Dharmshaktu Dr. Ganesh Singh Dharmshaktu, M.S. (Orthopaedics) Assistant Professor, Department of Orthopaedics Government Medical College, Haldwani, Uttarakhand, India Tanuja Pangtey Dr. Tanuja Pangtey, M.D. (Pathology) Assistant Professor, Department of Pathology Government Medical College, Haldwani, Uttarakhand, India
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Chapter - 3 Recent Amendments in Hippocratic Oath and Its Current Relevance Ganesh Singh Dharmshaktu and Tanuja Pangtey
Abstract The new amendments in the Hippocratic Oath that now better identifies as the physician’s pledge has certain additional points that are very relevant in the contemporary medicine. The concern for the autonomy of the patient, the health of the doctors themselves and the need for sharing the knowledge for greater common good are three key elements that are briefly acknowledged in this article. The article highlights the importance of embracing the change through simple, practical and logical manner to reap rich dividends in the future. These guiding lights not only make the doctors a better professional and human being but more importantly have positive bearing on the treatment of patient. A healthy doctor, who cares for the autonomy and consent of the patient and is ready to share the knowledge through various avenues for the larger benefit, is the need of the hour. Keywords: Hippocratic Oath, medical ethics, ethical documents, physician’s pledge. Social media, physician-patient communication, health care policy. Introduction Hippocrates is considered ‘the father of medicine’ and his legendary knowledge, skill and teachings have been instrumental in the evolution of medical science. He is known for many treatment methods, innovations and treatises. The Hippocratic Oath is an eponymous tribute to the man himself who was true flagbearer of modern medicine [1]. The medicine has grown by leaps and bounds since that time but his legacy and values of empathy resonate with the Hippocratic Oath that medical personnel swear by. It has been a beacon of hope for determined souls to treat the ailing humanity abiding the core principles that form the bedrock of the oath. The completion of making of a physician is not complete till the oath is taken with a pure intent to follow it in letter and spirit. Recently modifications were made to the Hippocrates oath, that was first Page | 71
adopted in 1948, with few additions and renaming it ‘The Physician’s pledge’ by World Medical Association (WMA) Declaration of Geneva (updated in Oct 14,2017) [2]. This article is about three key value added principles and how they matter more now than ever. 1.
Respecting Patient's Autonomy ‘I WILL RESPECT the autonomy and dignity of my patient’.
The autonomy of the patient is key concept that is better preached and lesser understood. It is high time a universal approach and guidelines are developed and practiced by us all to acknowledge the importance of patient’s autonomy. There is global consensus about inculcating values related to high standards of ethical and legal aspects of medicine be strengthened in graduate courses [3]. Certain key areas in contemporary medicine requiring stringent directives to respect patient’s autonomy and consenting in clinical participation are briefly described here. In Clinics Respecting the fact that the patient is the sole proprietor of his/her body is the basic tenet of the healthcare delivery. No physical or abstract intervention can be exercised in an unwilling patient and while a thorough informed consent is taken for all invasive or surgical procedures usually, its requirement is taken for granted in other aspects of healthcare. The patient is hardly explained about the disease, procedures, investigation with respect to its objective, risks and complication etc. that are now considered as part of shared decision making (SDM). In most instances the consent is not well written and lakes necessary specifications. A common consent form is used for all practical purposes despite the fact that it may not be suitable for every discipline. Lack of staff and manpower is cited as the excuse behind the most important document in the healthcare setup to be taken for granted. But establishing a standard operating procedures and following it requires lesser time to assimilate and once done makes life and work easier for all. Tailormade consent forms for various requirements should be made with provisions for periodic revision and updates if need be. We should make specific forms according to the departmental and procedural basis and practice the drill till it becomes a habit. Proper consent is an important element in safeguarding patient autonomy that has been given due respect through this amendment [4]. In Clinical Trial In large scale activities like clinical trials where consent process has Page | 72
gained dubious and opaque distinction. There are reports of flouted norms and poor adherence to standard procedures resulting in significant impact on study subjects especially if mishaps and compensation issues raise head. Better steps are required to improve knowledge of trial related information among participants through proper communication in an understandable manner.5 researchers also take note of the fact that illiteracy, poverty and language barrier may affect comprehension issues of consent process. Authorities have issued guidelines to include audiovisual consent process for each participants in standardized manner for drug trials among other stringent policies. Use of multimedia, computers and other means may improve the consent process and should be utilized as per the scenario [6]. Apart from it, conducting randomized controlled trials or other research involving human subjects, proper guidelines are described by regulatory authorities and should be adhered to. In Social Media, Internet Etc. In current era of connected world where internet has widened the reach and impact of shared content to an enormous proportion. The consent and respecting the autonomy of the patient often takes a backseat in camerahappy settings. Lots of patient images, their data and medical records are clicked and shared among colleagues for educative discussions and thus endanger the confidentiality and autonomy of the patient regarding the use of his personal data without proper consent [7]. Recently launched General data protection regulation (GDPR) is one collective initiative in this regard for responsible and transparent data usage across systems [8]. More and more universal regulatory measures will be required in the future across geopolitical boundaries. WhatsApp and other platforms of data sharing are highly popular for their user-friendly interface. Despite encrypted sharing between persons, the possibility of patient privacy being leaked in the group messaging can never be ruled out [9]. In developing countries there is less effort to conceal vital identifying information of patients by the users and lack of proper knowledge and etiquettes may form the basis of such rampant behavior. This is sheer invasion of patients right to privacy and confidentiality. Besides it, HIPPAA (Health Insurance Portability and Accountability Act, 1996) compliant messaging/texting services are not prevalent in many developing countries unlike some developed nations. HIPPA-compliant messaging services segregate personal and health information, require special authentication for gaining access, encrypt, enable secure sharing and prevent copying or leaking of data among other features [10]. This gray area requires amelioration of these burning issues with international consensus and collaboration. Page | 73
Big Data, Internet of the Things, Artificial Intelligence (AI) Etc. The advent of numerus groundbreaking technological advances like internet of the things (IoT), Big Data and AI are considered the next big thing with potential to change the face of healthcare delivery through engaging connected matrices of information and analytics to solve many prevalent problems and promising better care, diagnosis and treatment. But with Big data comes bigger responsibilities [11]. There is growing concern regarding data protection, theft and other unimaginable complication of the technology [12]. The worrying concern is valid owing to the fact that many highly secured institutions and organizations have witnessed security breaches and successful hacking attempts. Great inventions in AI like IBM Watson® are increasingly used in healthcare owing to superb ability of data crunching and providing valuable inputs in diagnosing and treating ailments like cancer [13]. Better protocols, ethical consideration and strengthening of data protection is the need of the hour and future will show how these things fare and clear their status of boon or bane. Concern for patient autonomy here calls for universally accepted norms and principles to be put into the place. Living Will, Do-Not-Resuscitate and End-of-Life Issues Reams of news stories and anecdotal reports make rounds whenever words ‘euthanasia’, ‘do not resuscitate (DNR)’ or ‘living will’ are pronounced in print or electronic media. This are highly debated areas with patient autonomy constantly under question. The laws around the globe are different in countries but these topics off and on raise their head in developing world’s regarding their sanctity [14]. Expert opinion from leading authorities of legal and ethical arm should prescribe a workable solution to address these morally difficult questions in the future world for better clarity on ethical options. 2.
Care of Own Health to Serve With Best Ability
‘I WILL ATTEND TO my own health, well-being, and abilities in order to provide care of the highest standard.’ It is not uncommon to see a specialist to suffer from same ailment he/she routinely prescribes preventive plans about. For example, many heart specialists themselves are found to be neglecting their own heart care by failing to avoid regular checkups and subsequently suffering or in unfortunate cases succumb to the condition. The neglection on their part for their own well-being has many reasons and grave implications to doctor himself, the patient and the society at large [15]. The added element has Page | 74
rightfully advocated healthy living for doctors to ‘heal thyself’. The objective to stay fit has profound bearing on better patient care and certain aspects of it are briefly recalled here. Lack of Exercise and Sleep Ill-defined workhours and hectic schedule have its own untoward repercussions. Night shifts not only disturbs sleep cycle but affects melatonin physiology apart from decrease performance. As the doctors are well trained for these occupational hazards, long term cumulative effects may be bad for some [16]. Lack of sleep and exercise is making doctors sick and it leads to premature ageing, stress and decline in clinical performances that at times alter crucial decision making. Stress, Burnout, Job Dissatisfaction Various factors are related to increased stress in the life of people today and doctors are no exceptions. This is major determinant of physician burnout and that have great impact on patients and healthcare [17]. Part of this may relate to aloofness and lack of social and interpersonal communication among doctors themselves and with the society. Bad communication affecting the doctor –patient rapport and commercialization has put the profession in bad light. Besides it, corporatization of hospitals has turned doctors into mere employee with targets and return of investment agenda. Lack of passion and absence of growth opportunities also decrease the morale especially in government setup. All these have cumulative effect in causing mental disorders [18]. Positive outlook of life, healthy family and active social life and passion for the work may to some extent thwart its progression that may become occupational epidemic. Positive societal cooperation is also required to achieve this. Violence at Workplace and Occupational Injuries Recent spates of attack on doctors or hospitals in both government or private setup have created a sense of insecurity among the medical fraternity [19] . Lack of strong association and fear of defamation is a hurdle for doctors and thus mostly do not protest. Essential services maintenance act (ESMA) is another obstacle for government doctors who are mostly affected. Ethical practice with explanation of every detail of treatment and outcome to patient and relative is the least one can do to safeguard himself along with developing good communication skills. Work-Life Imbalance Quality time with family, a great stress buster, is affected by late night Page | 75
shifts and erratic duty schedules. Doctors should make a point to devote good amount of time with family as it rejuvenates and one can be active participant in the growth of children. It is not uncommon to see renowned doctors earning money only to be wasted by their spoilt kids on mundane stuffs. Money is of no use when good education, parenting and values are not implanted into the younger generation. It is no possible that doctors who manage so complicated cases won’t be skillful in managing time and love with good efforts [20, 21]. Suicidal Thoughts and Other Mental Demons Suicidal ideation is the culmination of cumulative sense of despair and hopelessness and many doctors embrace this abominable act [22]. It is through proper self-evaluation and regular assessment that a preventive and prohibitive attempt can be taken. Friends, family and attitude of society is important to counter mental disorders for everyone including doctors. 3.
Sharing the Knowledge For The Benefit of Patients and Advancement of Medical Science.
‘I WILL SHARE my medical knowledge for the benefit of the patient and the advancement of healthcare.’ Doctors see patient all through their lives and accumulate wealth of knowledge which in turn is transferred to students in medical colleges and subordinates in working hospitals. As the experience enriches their clinical acumen, the need for its benefit reaching to larger audience is warranted [23]. Generally, doctors serving at teaching institutions are supposed to indulge in teaching and research while rest of the doctors achieve professional excellence as they age. In the both scenario, numerus interesting cases and research opportunities pass through them and only handful of those is transferred to the other colleagues or scientific community leading to missed opportunity. We all should be researcher in whichever capacity we work in and try to share our knowledge with the peers. Besides it, we should be trained to perform good critical appraisal of scientific articles so that valuable information can be extracted for better patient care [24]. Various avenues exist to be an audience to interesting tales and tricks you learned through life. Peer/Non Peer Reviewed Publications Good observations when formulated into a manuscript can be sent to peer-reviewed journals of respective national or international societies. These not only provide credibility to the author but serve as important Page | 76
foundation for future work and thus add value to the scientific community. Promotion may be initial reason for teachers to indulge in publication juggernaut but love of the craft and passion for the discipline shall be the guiding light for lasting creative spirit. Besides it, local or national newspapers, magazines, journals are another non peer-reviewed arenas to display health related articles that shall be useful to general public as well. Local Meetings, Events, Clubs Etc. Presentation of work in national/international meetings, seminars, conferences of medical or related field can be planned. These meeting also serve a platform of networking with like-minded people and also the enrich and gain newer perspectives by witnessing other researchers. Internet Internet is the ultimate Pandora’s Box full of the articles, videos of surgeries or clinical examinations, journals, online learning platforms, webinars etc. [25]. Besides it there are new age online education tools like massive open online courses (MOOCs) on offer [26]. It is great source of knowledge on virtually every topic and we can not only binge on it but contribute to it with the help of blogs, videos on you tubes, tutorials and educative presentations. Conclusion The above described three key newer additions are relevant today and hold greater potential to impact the healthcare tomorrow. As a pledge, all doctors should embrace these principles as they have power to change both the patients and doctors. Keeping a healthy body by respecting own health, a healthy mind by continuous learning and sharing and a big heart to care for the patient as dignified soul; the new age doctor should look forward a better future for us all. References 1.
Bailey Ian. Who wrote Hippocratic Oath? West Engl Med J. 1991; 106(4):91-92.
2.
Parsi-Parsa RW. The revised declaration of Geneva. A modern day Physician’s pledge. JAMA. 2017; 318(20):1971-1972.
3.
Stirrat GM, Johnston C, Gillon R, Boyd K. Medical education working group of institute of medical ethics and associated signatories. Medical ethics and law for doctors of tomorrow: The 1998consensus statement updated. J Med Ethics. 2010; 36:55-60. Page | 77
4.
Kinnersley P, Phillips K, Savage K, Kelly MJ, Farrell E, Morgan B et al. Interventions to promote informed consent for patients undergoing surgical and other invasive healthcare procedures. Cochrane Database Syst Rev. 2013; 7:CD009445.
5.
Kadam RA. Informed consent process: a step further towards making it meaningful. Perspect Clin Res. 2017; 8(3):107-112.
6.
Kim L, Young AJ, Neimeyer RA, Baker JN, Barfield RC. Keeping users at the center: Developing a multimedia interface for informed consent. Tech Commun Q. 2008; 17:335-57.
7.
Denecke K, Bamidis P, Bond C, Gabarron E, Househ M, Lau AYS et al. Ethical issues of social media in healthcare. Yearb Med Inform. 2015; 10(1):137-147.
8.
Rumbold JMM, Pierscionek B. The effect of general data protection regulation on health research. J Med Internet Res. 2017; 19(2):e47.
9.
Mars M, Scoitt RE. WhatsApp in clinical practice: A literature review. Stud Health Technol Inform. 2016; 231:82-90.
10. Giordano V, Koch H, Godoy-Santos A, Belangero WD, Pires RES. WhatsApp messenger as an adjunctive tool for telemedicine: An overview. Interact J Med Rews. 2017; 6(2):e11. 11. Lee CH, Yoon HJ. Medical big data: promise and challenges. Kidney Res Clin Pract. 2017; 36(1):3-11. 12. Santoro E. Artificial intelligence in medicine: limits and obstacles. Recenti Prog Med. 2017; 108(12):500-502. 13. Kohn MS, Sun J, Knoop S, Shabo A, Carmelli B, Sow D et al. IBM’s health analytics and clinical decision support. Yearb Med Inform. 2014; 9(1):154-162. 14. Kuwahar RT. More on living wills, death and dying. West J Med. 2001; 175(1):18. 15. George S, Hanson J, Jackson JL. Physicians, heal thyself: a qualitative study of physician health behaviors. Acad Psychiatry. 2014; 38(1):1925. 16. Howard SK. Sleep deprivation and physician performance: Why should I care? Proc (Bayl Univ Med Cent). 2005; 18(2):108-112. 17. Kumar S. Burnout and doctors: Prevalence, prevention and intervention. Healthcare (Basel). 2016; 4(3):37. Page | 78
18. Imo UO. Burnout and psychiatric morbidity among doctors in the UK: a systemic review of prevalence and associated factors. BJ Psych Bull. 2017; 41(4):197-204. 19. Kapoor MC. Violence against medical profession. J Anasthesiol Clin Pharmacol. 2017; 33(2):145-147. 20. Purdie DR. Work- life balance: True failure is in not trying. Front Padiatr. 2016; 4:37. 21. Vliagoftis H. Work-life balance: How can we achieve it within the work environment? Front Padiatr. 2016; 4:40. 22. Gold KJ, Sen A, Schwenk TL. Details on suicide among U.S. Physicians: Data from the National Violent Death Reporting System. Gen Hosp Psychiatry. 2013; 35(1):45-49. 23. Asemahagn MA. Knowledge and experience sharing practices among health professionals in hospitals under the Addis Ababa health bureau, Ethiopia. BMC Health Serv. Res. 2014; 14:431. 24. Jiwa M. Doctors and medical science. Australas Med J, 2012; 5(8):462467. 25. Masic I. E-learning as new method of medical education. Acta Inform Medica. 2008; 16(2):102-117. 26. Dharmshaktu GS, Pangtey T. Strengthening clinical research education in India: The massive open online course. Digit Med. 2016; 2:127-8.
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Chapter - 4 Role of Nanomedicine: Therapeutic, Diagnostic and Pharmaceutical Research and Development
Author Rohini Gupta Lecturer, Department of Pharmacology & Therapeutics, Government Medical College, Jammu and Kashmir, India
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Chapter - 4 Role of Nanomedicine: Therapeutic, Diagnostic and Pharmaceutical Research and Development Rohini Gupta
Abstract In the present scenario of ongoing research in the area of nanotechnology, designing of materials at atomic and molecular level have raised an optimistic hope of developing a new drug delivery system in the field of medicine with an added advantage in the diagnosis and treatment of disease. The field of nanomedicine is the science and technology of diagnosing, preventing and treating disease and traumatic injury, relieving pain, preserving and improving human health, using molecular tools and molecular knowledge of the human body. Alongwith nanoscale drugs and their precise targeted controlled release, other applications of nanomedicine include anti-microbial medical dressings including textiles, in vivo imaging, bone substitutes and dental materials, coatings for in vivo implants and tissue repair structures. Tools are being structured using nanotechnology to help in the identification and understanding of biomarkers involved in the different stages of diseases. Futuristic agenda of nanomedicine involves providing solutions to many of modern medicine’s unsolved problems by focusing on personalised, targeted and regenerative medicine. Introduction Nanoparticles are organic or inorganic structures (sizes 1-100 nm) similar to antibodies and DNA [1]. Nanomedicine is defined as application of nanotechnology to medicine. It encompasses the use of nano-sized drug particles for the diagnosis, prevention and treatment of diseases for better understanding the complex underlying pathophysiology of diseases and for improving the quality of life of patients [2]. With the emergence of 21st century, nanotechnology has revolutionised physics, chemistry, biology, medicine, electronics and information techology. Nanobiotechology encompasses molecular intra and intercellular processes which is extremely important for nanotechnology applications in medicine [3]. With applications of nanophase and nanostructures in biomedicine, nanobiotechnology acts as a bridge between physical and biological aspects of science [4]. Significant Page | 83
efforts have been made in the past few years in the nanomedicine field and a number of nanomedicine formulations have been developed which have shown a considerable potential for enabling more effective and less toxic diagnostic and therapeutic interventions [5]. 1.1 Types of Nanoparticles in Medicine Generally, nanoparticle may be composed of polymeric or inorganic materials. Polymeric nanoparticles are made from biocompatible and biodegradable materials and a variety of natural (gelatin, albumin) and synthetic polymers (polylactides, poly alkyl cyanoacrylates) whereas inorganic nanoparticles include silica nanoparticles, quantum dots, metal nanoparticles (Gold, copper and silver) and lanthanide nanoparticles. Other particles which can be used as noanoparticles are dendrimers and liposomes [6] . Various types of nanoparticles employed in medicine are illustrated as follows: Polymeric Materials: Polymeric nanoparticles, made from biocompatible and biodegradable materials and a variety of natural polymers like gelatin and albumin and synthetic polymers like polylactides, poly alkyl cyanoacrylates are considered as the most promising drug carrier as compared to liposomes [7]. There are several polymers available for the synthesis of nanoparticles. Polylactide– polyglycolide copolymers, polyacrylates and polycaprolactones, etc. are synthetic polymers whereas albumin, gelatin, alginate, collagen and chitosan used as natural polymers [8]. Polylactides and poly (DL-lactide-coglycolide) polymers undergo hydrolysis upon implantation, form biologically compatible fragments, and are mostly investigated for drug delivery [9]. Release of drugs from nanoparticles and biodegradation are important parameters to be considered for developing successful formulations. Therefore, the diffusion characteristics and breakdown properties of the nanoparticles at the drug delivery site need to be carefully mapped to achieve effective therapeutic capabilities [10]. Inorganic Materials: Nanoparticles offers important multifunctional platforms for biomedical applications. Varieties of nanoparticles, such as silica nanoparticles, quantum dots, metal nanoparticles and lanthanide nanoparticles, have unique properties which are adapted for different applications in the bio-analysis field [11, 12]. A nanoparticle does not only indicate drug delivery but confirmation of target delivery is also important. Tracking of nanomedicine from the systemic to sub-cellular level becomes essential. Many florescent markers are available; however, nanoparticles have not only advantage of showing improvement in fluorescent markers Page | 84
for medical imaging and diagnostic applications but also in imaging of tumors and other diseases in vivo [13]. Quantum Dots Are small-sized (1-10 nm) semiconductor nanocrystals composed of inorganic elemental core like cadmium and selenium, surrounded by a metallic shell (zinc sulphide). They are widely used in biological research and can also be used as drug carriers or simply as fluorescent labels for other drug carriers [14]. Among the broad diversity of nanoparticles, iron oxide and gold nanoparticles are the most intensively studied [15]. Due to the presence of surface plasmons, gold, copper and silver nanoparticles strongly absorb light in the visible region, making it possible to study their sizedependent light absorption through surface plasmon resonance. Gold nanoparticles and nanorods have many unique properties, which have been explored for potential applications in bio-molecular detection. In terms of biocompatibility and non-cytotoxicity, gold nanoparticles have distinct advantages over other metallic particles and can also be utilized as a favorable carrier for delivery of drugs. These nanoparticles can be conjugated with amino acid and proteins. Fabrication of gold nanoparticles and functionalization with organic molecules to interact with any physiological system are more important. These functionalized nanoparticles are a promising candidate for drug delivery as biomarkers of drug resistance cancer cell. Reported application of gold nanoparticles includes insulin delivery by nasal route, improved antimicrobial action against E. coli strains and ciprofloxacin-protected nanoparticles for better drug release [16]. Dendrimers: These are highly branched macromolecules with controlled near monodisperse three-dimensional architecture emanating from a central core. Polymer growth starts from a central core molecule and growth occurs in an outward direction by a series of polymerisation reactions. Hence, precise control over size can be achieved by the extent of polymerisation, starting from a few nanometers. Cavities in the core structure and folding of the branches create cages and channels. The surface groups of dendrimers are amenable to modification and can be tailored for specific applications. Therapeutic and diagnostic agents are usually attached to surface groups on dendrimers by chemical modification. Polymeric Micelles: Micelles are formed in solution as aggregates in which the component molecules (e.g., amphiphilic AB-type or ABA-type block copolymers, where Aand B are hydrophobic and hydrophilic components, respectively) are generally arranged in a spheroidal structure with hydrophobic cores shielded from the water by a mantle of hydrophilic Page | 85
groups. These dynamic systems, which are usually below 50 nm in diameter, are used for the systemic delivery of water-insoluble drugs. Drugs or contrast agents may be trapped physically within the hydrophobic cores or can be linked covalently to component molecules of the micelle [17]. Liposomes: Various forms of liposomes have long been and remain among the most successful drug careers. They include lipids, proteins, albumin, vesicles and related biopolymers and can involve combined drugs such as anti-cancer agents. Combination of imaging agents for diagnostics and drugs for therapy are examples called theranostics [18]. Nanospheres: These are spherical objects, ranging from tens to hundreds of nanometers in size, consisting of synthetic or natural polymers (collagen, albumin). The drug of interest is dissolved, entrapped, attached or encapsulated throughout or within the polymeric matrix. Depending on the method of preparation, the release characteristic of the incorporated drug can be controlled. As with liposomes, technology also allows precision surface modification of nanospheres with polymeric and biological materials for specific applications or targeting to the desired locations in the body. Aquasomes (Carbohydrate-Ceramic Nanoparticles): These are spherical 60–300 nm particles used for drug and antigen delivery. The particle core is composed of nanocrystalline calcium phosphate or ceramic diamond, and is covered by a polyhydroxyl oligomeric film. Drugs and antigens are then adsorbed on to the surface of these particles [19]. In the present review, major emphasis was laid down on the use of nanomedicines in diagnosis, therapeutic and research and development processes. 1.2 Therapeutic Nanomedicine Targeting the delivery of drugs to diseased lesions is one of the important aspects of the drug delivery systems. With the development of nanotechnology, the integration of nanomaterial into cancer therapeutics is one of the rapidly advancing fields. Nanomaterials have ability to penetrate and spontaneously accumulate at biological sites by enhanced permeability and retention (EPR effect) [20]. The current generation of drugs is largely based on small molecules with a mass of 1000 Da or less that circulate systemically. However, there are several deleterious consequences seen with these low-molecular weight drugs in comparison to nanomedicines. Common deleterious consequences of systemic biodistribution include toxicity to nontarget tissues, difficulty in maintaining drug concentrations within therapeutic windows and rapid hepatic metabolism and excretion of drugs by the kidneys leading to reduced circulating time of the drugs, all of Page | 86
which can reduce efficacy. In addition, nanomedicine formulations also have proven advantage over low molecular-weight drugs in overcoming the different barriers encountered while delivering the drug to the target site. These barriers include chemical barriers like stability and solubility, anatomical barriers like vascular endothelium, cellular membrane, nuclear membrane and blood brain barrier, physiological barriers like renal filtration, hepatic degradation, high tumour cell density, drug efflux pumps and clinical barriers like low efficacy and high toxicity of drugs etc. [2]. Nanotechnologybased delivery systems could mitigate these problems by combining tissue or organ-specific targeting with therapeutic action thereby, can revolutionize the treatment of cancer. Nanoparticles used for anticancer drug delivery can be made from a variety of materials, including polymers, dendrimers, liposomes, carbon nanotubes and metals such as iron oxide and gold [21]. Cancer therapeutics generally implies both passive and active targeting. Passive targeting implies the passage of nanoparticle based drugs to the tumour site by extravasation from the angiogenic blood vessels which have gap junctions of around 600800 nm between adjacent endothelial cells whereas the blood vessels in normal tissues have tight junctions between the adjacent endothelial cells, thereby preventing nanoparticle drugs from extravasation. Thus the nanoparticle based drugs gain access to the tumour site via the hyperpermeable vasculature and thus the drug molecules get concentrated at the site of the tumour as there is very less lymphatic drainage found at the tumour site so the drug molecules can’t be escaped. This is often referred to as enhanced permeability and retention or the EPR effect [22, 23]. Tumours can be actively targeted by molecular recognization of cancer cells either via ligand-receptor or antigen-antibody interactions. Particles with more hydrophobic surfaces are actively taken up by reticuloendothelial system (RES). Therefore nanoparticles coated with hydrophilic polymers are. Apart from cancer, therapeutic nanomedicines are also used for some other inflammatory diseases such as rheumatoid arthritis and atherosclerosis. Nanomedicines gain access to these inflammatory diseases due to the leaky vasculature of these inflamed tissues [22]. Due to their size, shape and functionality, nanoparticle systems play a pivotal role in creation of DNA delivery vectors [24]. Even recently the nanoparticles have been employed as potential carriers for anti-hypertensive drugs, hormones etc. [25]. 1.3 Diagnostic Nanomedicine Over the last few years, the nanomedicine has been found to be quite effective in the field of medical diagnosis although the applications are quite Page | 87
few in comparison to low molecular weight diagnostic agents. Nanoparticle based medical formulations have been developed solely for diagnostic purpose or for assessing and improving the potential of therapeutic interventions. Although nanoparticle-based formulations have been employed widely in pre-clinical set-up e.g. in animal models ; clinically they are used only in a limited number of situations like Godomer-17 and Rosovist in estimating the perfusion of tumour blood vessels and coronary arteries, imaging of labelled stem cells and the visualization of primary and/or metastatic liver lesions etc. The fact that these are used in limited number of situations is because the intravenous (I/V) administered diagnostic agents have stringent pharmacokinetic (P/K) properties [2]. 1.4 Nano Based Tools in Research and Development a.
Applications in Process Development
The term process development refers to both synthesis of drugs, drug intermediates and to development of analytical tools for diagnostics. Of the several important methods, the most important tool in process development is miniaturization and automation in biological screening of compounds on nanoscale e.g. Nano Syn TestTM- System. The main feature of such type of system is to manipulate reactions in nano-size titre plates with a density of about 1000 wells/cm2 and the capability to handle nanolitre volumes [20]. b. Application in Product Development The term product development encompasses drug discovery as well as development of diagnostic tools. One of the most important nanotechnology tool for product development is the opportunity to convert existing drugs having poor water solubility and dissolution rate into readily water soluble dispersions by converting them into nano-size drugs. When the size of the drugs is reduced to nanometer range, the exposed surface area of the drug is increased and hence its ability to get absorbed also increases [26]. Conclusion In the recent years, research in nanomedicine mainly focused on targeted and site specific drug delivery. The ability of nanoparticles to target a particular site depends upon certain properties such as size of the particles, surface charge, surface modification and hydrophobicity. However, the biggest challenge nanomedicines are facing at present are meeting all the safety guidelines required for gaining clinical acceptance. Thus, the problems related to selective binding, targeted delivery and toxicity need to be addressed with utmost caution. In spite of all these challenges, nanotechnology has become closely related with cancer care today and has Page | 88
been applied in an evolutionary manner to improve the properties of cancer therapeutic, diagnostic and other health-care products. Futuristic agenda of nanomedicine involves providing solutions to many of modern medicine’s unsolved problems by focusing on personalised, targeted and regenerative medicine. References 1.
Whitesides GM. The ‘right’ size in nanobiotechnology. Nat. Biotech. 2003; 21:1161-1165.
2.
Rizzo LY et al. Recent Progress in Nanomedicine: Therapeutic, Diagnostic and Theranostic Applications. Curr Opin Biotechnol. 2013; 24(6).
3.
Krukemeyer MG, Krenn V, Huebner F, Wagner W, Resch R. History and possible uses of nanomedicine based on nanoparticles and nanotechnological progress. J Nanomed Nanotechnol. 2015; 6:336.
4.
Freitas RA. What is nanomedicine? Nanomed. 2005; 1:2-9.
5.
Arayne MS, Sultana N, Qureshi F. Review: Nanoparticles in delivery of cardiovascular drugs. Pak J Pharm Sci. 2007; 20:340-8.
6.
Mirza AZ, Siddiqui FA. Nanomedicine and drug delivery: A mini review. Int Nano Lett. 2014; 4:94.
7.
Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: A formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci. 2003; 18(2):113-20.
8.
Sahoo SK. Applications of nanomedicine. APBN. 2005; 9(20):1048-50.
9.
Research Media Ltd. British Society for Nanomedicine, 2013.
10. Toyama T, Matsuda H, Ishida I, Tani M, Kitaba S, Sano S et al. A case of toxic epidermal necrolysis-like dermatitis evolving from contact dermatitis of the hands associated with exposure to dendrimers. Contact Dermatitis. 2008; 59:122-3. 11. Jain K, Kesharwani P, Gupta U, Jain NK. Dendrimer toxicity: let’s meet the challenge. Inter J Pharmaceutics. 2010; 394:122-42. 12. Vinagradov SV, Bronich TK, Kabanov AV. Pluronic block copolymers: Novel functional molecules for gene therapy. Adv Drug Del Rev. 2002; 54:223-33. 13. Vauthier C, Labarre D, Ponchel G. Design aspects of poly(alkylcyanoacrylate) nanoparticles for drug delivery. J Drug Target. 2007; 15:641. Page | 89
14. Gelperina S, Kisich K, Iseman MD, Heifets L. The potential advantages of nanoparticle drug delivery systems in chemotherapy of tuberculosis. Am J Respir Crit Care Med. 2005; 172:1487-90. 15. Moghimi SM, Hunter AC, Murray JC. Long-circulating and targetspecific nanoparticles: Theory to practice. Pharmacol Rev. 2001; 53:283. 16. Jain RA. The manufacturing techniques of various drug loaded biodegradable poly (lactide-co-glycolide) (PLGA) devices. Biomaterials. 2000; 21:2475-90. 17. Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE. Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release. 2001; 70:1-20. 18. Stroh M, Zimmer JP, Duda DG, Levchenko TS, Cohen KS, Brown EB et al. Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo. Nat Med. 2005; 11:678-82. 19. Chen Y, Chi Y, Wen H, Lu Z. Sensitized luminescent terbium nanoparticles: preparation and time-resolved fluorescence assay for DNA. Anal Chem. 2007; 79:960-5. 20. Chen S, Zhang Q, Hou Y, Zhang J, Liang XJ. Nanomaterials in medicine and pharmaceuticals: nanoscale materials developed with less toxicity and more efficacy. Eur. J Nanomed. 2013; 5(2):61-79. 21. Dilipkumar Pal, Amit Kumar Nayak. Nanotechnology for targeted Delivery in Cancer Therapeutics. Int J of Pharma. Sc. Rev. and Res. 2010; 1:1-5. 22. Jain RK. Delivery of molecular and cellular medicine to solid tumours. J Control. Release. 1998; 53:49. 23. La Van DA, McGui re T, Langer R. Small-scale systems for in vivo drug delivery. Nature Biotechnol. 2003; 21:1184-1191. 24. Han G, Ghosh P, Rotello VM. Functionalized gold nanoparticles for drug delivery. Nanomedicine. 2007; 2:113-123. 25. Bala I, Hariharan S, Kumar MN. PLGA nanoparticles in drug delivery: The state of the art. Crit Rev Ther Drug Carrier System. 2004; 21:387422. 26. Kharb V et al., Pharm. Technol. 2006; 30(2):82.
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Chapter - 5 Autologous Platelet Rich Plasma Therapy in Orthopedics
Authors Madhan Jeyaraman Junior Resident, Department of Orthopedics, JJM Medical College, Davangere, karnataka, India Naveen Jeyaraman Junior Resident, Department of Orthopedics, Kasturba Medical College, Manipal, karnataka, India Prajwal GS Junior Resident, Department of Orthopedics, JJM Medical College, Davangere, karnataka, India
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Chapter - 5 Autologous Platelet Rich Plasma Therapy in Orthopedics Madhan Jeyaraman, Naveen Jeyaraman and Prajwal GS
Abstract Recent advances in cellular and molecular biology have led to the identification of specific cytokines that mediate cellular activities which becomes a powerful tool in management of orthopaedic disorders. Platelet rich plasma is the novel “Orthobiologic” agent for treating inflammatory and degenerative musculoskeletal disorders. Platelet rich plasma therapy aimed in rejuvenating the degenerating tissues by neoangiogensis and neoinnervation thus by increasing the texture and biology of the diseased tissues. This article outlines the guidelines for the usage of autologous platelet rich plasma therapy in musculoskeletal disorders. Keywords: Platelet rich plasma; Orthobiologic; Growth factors; transforming growth factor; Centrifugation Introduction Platelet Rich Plasma (PRP) is defined as a volume of plasma with an increased platelet concentrations of 4 to 6 times above normal values (approximately 106 / mL). The rationale for use of platelet rich plasma is to stimulate the natural healing cascade and tissue regeneration by a “Supra – Physiological” release of platelet derived factors at the site of treatment [1]. Structure of Platelets Platelets have no cell nucleus as they are fragments of cytoplasm that are derived from the megakaryocytes of the bone marrow, and then enter the circulation. These unactivated platelets are biconvex discoid (lens-shaped) structures with 2–3 µm in greatest diameter. The ratio of platelets to red blood cells in a healthy adult ranges from 1:10 to 1:20 [2]. Zones of Platelet A) Peripheral zone - Rich in glycoproteins required for platelet adhesion, activation, and aggregation. Page | 93
B) Sol-gel or structural zone - Rich in microtubules and microfilaments, allowing the platelets to maintain their discoid shape. C) Organelle zone - Rich in platelet granules. D) Membranous zone - Contains membranes derived from megakaryocytic smooth endoplasmic reticulum organized into a dense tubular system which is responsible for thromboxane A2 synthesis. Growth Factors of Platelets [2, 3] Growth Factors
Significance
Cell growth, generation and repair of blood Platelet derived growth factor (PDGF) vessels, collagen production Vascular endothelial growth factor (VEGF)
Neoangiogenesis, regeneration of endothelial cells
Transforming growth factor – β (TGFβ)
Growth of epithelial and endothelial cells, promotion of wound healing, collagen production
Keratinocyte growth factor (KGF)
Growth and regeneration of keratinocytes
Fibroblast growth factor (FGF)
Helps in tissue repair, cell growth, collagen production
Epidermal growth factor (EGF)
Promotion of epithelial cell growth, angiogenesis, promotion of wound healing
Platelet Dynamics [2] The intact endothelial lining inhibits platelet activation producing nitric oxide, endothelial-ADPase, and PGI2 (Prostacyclin). 1.
by
Adhesion
When the endothelial layer is disrupted, collagen and VWF anchor platelets to the subendothelium. Platelet GP1b-IX-V receptor binds with VWF; and GP VI receptor and integrin α2-β1 bind with collagen. 2.
Activation
Intracellular calcium concentration determines platelet activation status, as it is the second messenger that drives platelet conformational change and degranulation. Coupling Gs of protein to increase adenylate cyclase activity and increases the production of cAMP, further promoting the efflux of calcium and reducing intracellular calcium availability for platelet activation. Collagen mediated GP VI signaling, TXA2 production and PGI2 inhibition and metabolic flux of platelet eicosanoid pathway converts GPIIb/IIIa receptors to their active form to initiate aggregation. Page | 94
3.
Granule Secretion
Activated platelets secrete the contents of these granules through their canalicular systems to the exterior. Granules
Significance
α granules (alpha granules)
Contains P-selectin, platelet factor 4, transforming growth factor-β1, platelet-derived growth factor, fibronectin, Bthromboglobulin, vWF, fibrinogen, and coagulation factors V and XIII
δ granules (delta Contains ADP or ATP, calcium, and serotonin or dense granules) γ granules (gamma Contains hydrolytic enzymes (lysosomes) granules) λ granules (lambda Involved in clot resorption during later stages of vessel repair granules)
4.
Morphology Change
5.
Coagulation Facilitation
Platelet activation causes its membrane surface to become negatively charged. The intracellular signaling pathways moves negatively charged phospholipids from the inner to the outer platelet membrane surface. These phospholipids initiates the interaction between platelets and the coagulation cascade. Calcium ions are essential for the binding of these coagulation factors. 6.
Aggregation Role in aggregation
Tethering, translocation
Receptor interactions
GP Ib/V/IX – vWF
Platelet-platelet cohesion αIIbβ3 – fibronectin, vWF
Stabilization αIIbβ3 – fibrinogen, fibronectin Page | 95
Benefits of PRP
Increases the concentration of growth factor levels at the injury site.
Provides a provisional matrix or scaffold for healing.
Has anti-inflammatory & antimicrobial properties.
Processing and application patient side is simple and rapid.
Eliminates the risk of disease transmission.
Families of Platelet Concentrates – Based on Presence of Leukocytes and Fibrin Architecture [4] A) Pure Platelet Rich Plasma (P-PRP) or Leukocyte Poor Platelet Rich Plasma.
Contains plasma with high concentrate of platelets, low density fibrin network without leukocytes
Can be used as liquid solution or in activated gel form
B) Leukocyte and Platelet Rich Plasma (L-PRP).
Contains plasma with high concentrate of platelets and leukocytes, low density fibrin network without leukocytes
Can be used as liquid solution or in activated gel form
C) Pure Platelet Rich Fibrin (P-PRF) or Leukocyte Poor Platelet Rich Fibrin.
Contains high concentration of platelets without leukocytes with high density fibrin network
Exist in a strong activated gel form
D) Leukocyte and Platelet Rich Fibrin.
Contains high concentration of platelets with leukocytes with high density fibrin network
Exist in a strong activated gel form
Mechanism of Action of PRP Once growth factor binds to target cell receptor, it induces an intracellular signal transduction system and produces a biological response critical for chemotaxis, cell proliferation and osteoblastic differentiation. The molecular basis of platelet rich plasma is due to increased HGF and TNF-α activity by disrupting NF-κB-transactivating activity [5]. Uses of PRP in Orthopedics A) Ligament injuries – Strains and sprains of MCL and LCL injuries. Page | 96
B) Tendon injuries – Achilles tendinitis, Rotator cuff injuries, Quadriceps tendinitis & Patellar tendinitis. C) Overuse syndromes – Tennis elbow, Golfer’s elbow, plantar fasciitis. D) Muscle injuries – Tear of quadriceps, hamstrings, biceps, triceps and calves. E) Cartilage injuries – Osteoarthritis of hip, knee & shoulder, Periarthritis of shoulder, Patello-femoral chondrosis. F) Knee injuries – Anterior cruciate ligament (ACL) injuries and meniscal tears. G) Entrapment syndromes – Carpal tunnel syndrome. H) Spinal injuries – Lumbar spinal disc pain, SI joint pain. Contraindications of Platelet Rich Plasma Absolute Contraindications
Platelet dysfunction syndrome Critical thrombocytopenia Hemodynamic instability Septicemia Local infection at the site of the procedure Patient unwilling to accept risks
Relative Contraindications Consistent use of NSAIDs within 48 hours of procedure Corticosteroid injection at treatment site within 1 month Systemic use of corticosteroids within 2 weeks Tobacco use Recent fever or illness Leukemia & lymphoma of blood and bone cancers Hemoglobin < 10 g/dl Platelet count < 105/ul
Pre-Procedural Considerations 1.
Specific indication for PRP therapy should be emphasized which should be correlated with clinical and radiological examination prior to treatment.
2.
Appropriate patient education and discussion about PRP therapy.
3.
Informed consent to be taken prior to the initiation of procedure.
4.
Patient should not have taken analgesics 48 to 72 hours prior to PRP therapy.
Autologous PRP Preparation [6] A) Withdrawal of Blood from Patient
The patient is placed in a comfortable seated or recumbent position. Page | 97
Sterile single use needles and syringes should be used with appropriate handling and disposal.
Using aseptic technique, an appropriate amount of venous blood is obtained for the given procedure.
Single-stick draws are preferred to decrease chances of activation.
Using sterile technique, the venous blood is transferred to the vials. PRP should be obtained using a separating device designed for autologous blood.
Proper labelling of each vial should be completed to ensure no cross contamination or the sample being used on the wrong patient.
B) Autologous PRP Preparation
A 20 cc venous blood will yield 3 – 4 cc of PRP depending on the baseline platelet count of an individual.
PRP is prepared by a process known as differential centrifugation. In differential centrifugation, acceleration force is adjusted to sediment certain cellular constituents based on different specific gravity.
Methods of PRP preparation.
PRP Method (Double Centrifugation Method)
Buffy Coat Method
20 cc blood taken in vials with sodium citrate as anticoagulant ↓ First centrifugation of 3000 rpm for 15 minutes (Soft spin) ↓ Separate plasma and buffy coat from RBCs and transfer into sterile plain vials ↓ Second centrifugation of 5000 rpm for 15 minutes (Hard spin) ↓ Resultant plasma contains top 2/3rd part of platelet poor plasma and bottom 1/3rd part of platelet rich plasma
Whole blood should be stored at 20°C to 24°C before centrifugation. ↓ Centrifuge whole blood at a ‘high’ speed for 15 minutes ↓ Remove supernatant plasma from the top of the container and transfer the buffycoat layer to sterile plain tube ↓ Centrifuge at low speed to separate WBCs or use leucocyte filtration filter.
Activation of PRP
PRP can be activated exogenously by thrombin, calcium chloride or mechanical trauma and endogenously by collagen,
Once PRP is activated, a fibrin network (fibrinogen – fibrin
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complex) begins to form which solidifies the plasma and creating a fibrin clot or membrane which is also called as PRP gel.
Fig 1: Blue vials with RBC layer are the remains of first centrifugation and red vials with plasma contains platelet poor plasma (upper 2/3rd) & platelet rich plasma (lower 1/3rd)
PRP Injection Technique
The patient should be placed in an appropriate position to gain the access to the site of injection.
The pathological site is to be cleansed appropriately and sterile drapes should be used to create an aseptic field.
Before injecting PRP to the pathological site, 10% calcium chloride to the PRP in the ratio of 1:10
Once calcium chloride is added to PRP solution, under ultrasound guidance, at the point of maximum tenderness, the injection should be given to avoid activation of PRP which will form PRP gel.
Apply dressing and appropriate bandage to protect the needle entry site
Fig 2: PRP injection technique at the point of maximum tenderness for right interscapular fibrofasciitis
Post Injection Events Once PRP is activated with by thrombin or calcium chloride or calcium gluconate, a fibrin network begins to form, solidifying plasma and create a fibrin clot or membrane. A tetramolecular stable meshwork forms that Page | 99
enhances enmeshment of cells and growth factors. Activated PRP forms a gel like substance in the injected tissue which leads to rapid release of growth factors with 90% of prefabricated factors release within 10 minutes of injection [7]. The phases of activated PRP follows four phases namely a.
Inflammatory phase is characterized by increased vascular permeability, initiation of angiogenesis, stimulation of tenocyte proliferation and initiation of type III collagen synthesis over injection site which lasts for 48 – 72 hours
b.
Proliferative phase is characterized by accumulation of fibroblast proliferation and neoangiogenesis which lasts from 1 to 6 weeks. During this phase, water content and glycosaminoglycan concentration remains high.
c.
Remodelling phase commences approximately after 6 weeks and lasts till 10 weeks with decreased cellularity and decreased collagen and glycosaminoglycan synthesis
d.
Maturation phase is characterized by synthesis of type I collagen which lasts from 10 weeks to 6 months. In this phase, the metabolism of tenocyte remains high.
If the patient recurs with symptoms, the next dose of PRP injection should be given with an interval of 3 weeks. The time duration of 3 weeks is provided for the initiation of fibroblast proliferation and neoangiogenesis. Post Procedural Care
Monitor for post procedural complication – Vasovagal attack
Adequate immobilisation & counselling of post procedural activity
Post procedural pain must be combated with paracetamol or tramadol
Avoid NSAIDs following the procedure for minimum of 2 weeks since it interacts with cyclooxygenase pathway
Follow-Up
Follow up examination of patients are generally done 2 – 6 weeks after the procedure to monitor pain, function, injection site and to discuss concerns and future course.
Patient’s response should be recorded using validated outcome measures.
Tracking of patients for complications and other pertinent data
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Consideration for re-injection should be a patient centered decision and based on functional outcome. There is no endorsement for a specific number of injections at any site.
Future Prospects Further research on the amount of growth factors to be injected, dosage and protocol are necessary to increase the credibility and longevity of platelet rich plasma as a minimally invasive procedure to combat musculoskeletal disorders. Conclusion Percutaneous therapy of platelet rich plasma is the potential orthobiologic of choice for treating inflammatory and degenerative musculoskeletal disorders which improves the functional quality of life. References 1.
Menetrey J, Kasemkijwattana C, Day CS, Bosch P, Vogt M, Fu FH et al. Growth factors improve muscle healing in vivo. J Bone Joint SUrg Br. 2000; 82(1):131-7.
2.
Eduardo Anitua, Ramon Cugat, Mikel Sanchez. Platelet rich plasma in orthopaedics and sports medicine, Switzerland, Springer, First edition, Chapter. 2018; 1:13-28.
3.
Antoniades HN, Williams LT. Human platelet derived growth factor: Structure and functions. Fed Proc. 1983; 42:2630-4.
4.
Dohan Ehrenfest DM, Rasmusson L, Albrektsson T. Classification of platelet concentrates: From pure platelet rich plasma (PPRP) to leucocyte and platelet rich fibrin (LPRF) Trends Biotechnol. 2009; 27:158-67.
5.
Eduardo Anitua, Ramon Cugat, Mikel Sanchez. Platelet rich plasma in orthopaedics and sports medicine, Switzerland, Springer, First edition, Chapter. 2018; 3:47-64.
6.
Rachita Dhurat, Sukesh MS. Principles and Methods of Preparation of Platelet Rich Plasma: A Review and Author's Perspective. J Cutan Aesthet Surg. 2014; 7(4):189-197.
7.
Alsousou J, Thompson M, Hulley P, Noble A, Willett K. The biology of platelet rich plasma and its application in trauma and orthopaedic surgery: a review of literature. J Bone Joint Surg Br. 2009; 91(8):987-96.
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Chapter - 6 New Research Trends in Diabetes: The Islet Cell Transplantation in Type 1 Diabetics in India
Authors Dr. Sarmistha Sarkar Post Graduate Trainee (Jr-III), Dept. of Biochemistry, Jawaharlal Nehru Medical College, Sawangi (Meghe), DMIMS (DU), Wardha, Maharashtra, India Dr. Ajay Meshram Professor and Head, Dept. of Biochemistry, Jawaharlal Nehru Medical College, Sawangi (Meghe), DMIMS (DU), Wardha, Maharashtra, India
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Chapter - 6 New Research Trends in Diabetes: The Islet Cell Transplantation in Type 1 Diabetics in India Dr. Sarmistha Sarkar and Dr. Ajay Meshram
Abstract Insulin dependent type 1 diabetes (DM) is an auto-immune disease, characterized by the destruction of the insulin secreting beta cells of the pancreas. Different treatment modalities for type 1 DM available are Intensive Insulin Therapy, Pancreatic organ transplant, pancreatic beta cell transplantation. To combat type 1 DM, pancreatic islet transplantation is emerging a preferred option these days. In this process, islet cells are taken from the pancreas of a deceased/living donor & are injected into diabetic patients & these islets begin to produce & release insulin which let the type 1 diabetics live without their daily insulin injections. Immunosuppressant drugs are used to prevent transplant rejections. USA & Europe are well versed with this technique but it has not been adopted in India yet. A joint initiative by Asian Institute of Gastro enterology & University of Minnesota, an Indo-US bilateral workshop taken place in Hyderabad, aimed at procuring the knowledge about the concept of Islet cell transplantation & introducing this process in India has taken place. This workshop explains pancreatic islet transplantation can let diabetics live without using insulin injections for about 3-5 years depending on the patients & also explains the solutions with immuno-rejections. The Endocrinology Dept. of PGI is also planning to start this transplantation for treatment of those type 1 diabetics in whom insulin injections cannot control the blood sugar level. Islet cell transplantation has raised hope for a cure of diabetes for the past 3 decades. Through new innovative tools such as stem cell therapy, gene therapy, & immunomodulation there is a tremendous opportunity for translating bench work into the clinical arena such that the goal of successful long term functional islet graft survival is within reach. Challenges are to be popped with the better help of Govt. & Private organization more cases of pancreatic islet transplantation & research for prevention of rejections can be done in India. Page | 105
Keywords: Diabetes, type 1 diabetes, Islet cell transplantation, graft preparation, pancreatic beta cells, diabetes research. Introduction The term diabetes mellitus describes a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defect in insulin secretion, insulin action or both [1]. Diabetes Mellitus is most common endocrine disease. Diabetes mellitus is an ancient disease, yet remains today a worldwide threat with an alarming rise of prevalence and is creating a massive health burden. Diabetes is one of the most challenging health problems in the 21st century. Diabetes is a growing chronic disease, pandemic and one of the greatest threats to public health. The term diabetes mellitus describes a chronic, persistent hyperglycemic disorder, accompanied by other metabolic abnormalities. The metabolic derangement is frequently associated with permanent and irreversible functional and structural changes in the cells of the body, those of the vascular system, being particularly most susceptible. The common symptoms with diabetes include increased thirst, increased hunger, frequent urination and weight loss. If untreated or poorly controlled, diabetes can lead to acute life-threatening complications such as nonketotic hyperosmolar syndrome and diabetic ketoacidosis. The chronic hyperglycaemia of diabetes is associated with long term damage, dysfunction and failure of different organs, and these changes in turn lead to development of well-defined clinical entities, the so called complications. Diabetes leads to various complications such as coronary artery disease, peripheral vascular disease, stroke, neuropathy, diabetic nephropathy, retinopathy and diabetic foot. Long-term hyperglycaemia in diabetes leads to late chronic complications which are classified based on types of blood vessel involved. These include i)
macro-vascular complications (cerebrovascular cardiovascular disease and peripheral vascular disease);
ii) Micro-vascular neuropathy).
complications
(retinopathy,
disease,
nephropathy
and
Epidemiology of Diabetes Mellitus The global prevalence of diabetes mellitus is expected to increase from 4% in 1995 to 5.4% by the year 2025 [2]. Page | 106
The global increase in the prevalence of diabetes is due to population growth, aging, urbanization and an increase of obesity and physical inactivity [3, 5]. The World Health Organization (WHO) predicted net losses in national income from diabetes and cardiovascular disease of 336.6 billion in India between 2005 and 2015 [3, 6, 7]. According to The International Diabetes Federation (IDF) estimation India will have rise in people living with diabetes up to 87.0 million by 2030 from 50.8 million (2010),making it the 'Diabetes Capital' of the world [3, 8]. According to the International Diabetic Foundation, currently the disease affects >62 million Indians, which is >7.1% of India's adult population. IDF data reveal that India has more diabetics than the United States and ranked second in the world in diabetes prevalence, just behind China [9]. This prevalence is increasing not only in urban but also in rural area. According to the World Health Organization (WHO) criteria, the prevalence of known diabetes was 5.6% and 2.7% among urban and rural areas, respectively [10]. Types of Diabetes WHO classified Diabetes Mellitus according to their aetiologies namely Type 1, Type 2, gestational diabetes mellitus (GDM) and other specific types [11]. Other types of diabetes are diabetes with less common causes, e. g., genetic defects β cell function or drug-induced diabetes. For example, maturity-onset diabetes of the young (MODY) is a form of early-onset, noninsulin dependent diabetes. It compromises a group of monogenetic disorders with impaired β cell function and takes up approximately 1% of all forms of diabetes. Type I Diabetes T1DM accounts for 5-10% of all diabetes cases and results from immune-mediated destruction of insulin-secreting pancreatic β cells. T1DM is most commonly occurs in children, but it can be diagnosed at any age [12]. The incidence of T1DM is increasing globally despite the incidence varies considerably among different countries, from the lowest 0.1/100,000 in China to highest over 60/100,000 in Finland. Sweden has the second highest incidence of T1DM in children [12, 13].
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More than 90% newly diagnosed T1DM patients have one or more auto antibodies against β cell antigens, which is the key feature to distinguish T1DM and T2DM [12]. Lifetime treatment with exogenous insulin is required for the patients with T1DM [14]. Different treatment modalities for type I DM are:
Intensive Insulin Therapy,
Pancreatic organ transplant,
Pancreatic Islet cell transplantation.
In Type I DM, pancreatic islet transplantation is emerging a preferred option these days. In recent establishment of certain HLA alleles and this disease, type 1 DM patients are known to be genetically predisposed to diabetes [15]. Although the etiology of this disease is unclear, it is believed that environmental factors such as infections or allergens lead to cytotoxic T-cellmediated destruction of the β cells [16].
Fig 1: showing raise in blood glucose level in Type 1 Diabetes
Overview of Islet Transplantation Pancreatic Islets Pancreatic islets, also called islets of Langerhans, are tiny clusters of cells scattered throughout the pancreas. Pancreatic islets contain several types of cells, including beta cells that produce the hormone insulin. The pancreas also makes enzymes that help the body digest and use food. Page | 108
When the level of blood glucose, rises after a meal, the pancreas responds by releasing insulin into the bloodstream. Insulin helps cells throughout the body absorb glucose from the bloodstream and use it for energy. Diabetes develops when the pancreas does not make enough insulin, the body’s cells do not use insulin effectively, or both. As a result, glucose builds up in the blood instead of being absorbed by cells in the body. In type 1 diabetes, the beta cells of the pancreas no longer make insulin because the body’s immune system has attacked and destroyed them. A person who has type 1 diabetes must take insulin daily to live.
Fig 2: showing different hormones synthesize from human Pancreas
Pancreatic Islet Transplantation The two types of pancreatic islet transplantation are
1.
1.
allo-transplantation
2.
auto-transplantation Pancreatic Islet Allo-Transplantation is a procedure in which islets from the pancreas of a deceased organ donor are purified, processed, and transferred into another person. Pancreatic islet allotransplantation is currently labeled an experimental procedure until the transplantation technology is considered successful enough to be labeled therapeutic. Page | 109
For each pancreatic islet allo-transplant infusion, researchers use specialized enzymes to remove islets from the pancreas of a single, deceased donor. The islets are purified and counted in a lab. Transplant patients typically receive two infusions with an average of 400,000 to 500,000 islets per infusion. Once implanted, the beta cells in these islets begin to make and release insulin. Pancreatic islet allo-transplantation is performed in certain patients with type 1 diabetes whose blood glucose levels are difficult to control. The goals of the transplant are to help these patients achieve normal blood glucose levels with or without daily injections of insulin and to reduce or eliminate hypoglycemia unawareness-a dangerous condition in which a person with diabetes cannot feel the symptoms of hypoglycemia, or low blood glucose. When a person feels the symptoms of hypoglycemia, steps can be taken to bring blood glucose levels back to normal. Pancreatic islet allo-transplants are only performed at hospitals that have received permission from the U.S. Food and Drug Administration (FDA) for clinical research on islet transplantation. The transplants are often performed by a radiologist-a doctor who specializes in medical imaging. The radiologist uses X-rays and ultrasound to guide the placement of a thin, flexible tube called a catheter through a small incision in the upper abdomen-the area between the chest and hips-and into the portal vein of the liver. The portal vein is the major vein that supplies blood to the liver. The islets are then infused, or pushed, slowly into the liver through the catheter. Usually, the patient receives a local anesthetic and a sedative. In some cases, a surgeon performs the transplant using general anesthesia. Patients often need two or more transplants to get enough functioning islets to stop or reduce their need for insulin injections.
Fig 3: showing pancreatic islet allo-transplantation Page | 110
2.
Pancreatic islet auto-transplantation is performed following total pancreatectomy- the surgical removal of the whole pancreas-in patients with severe and chronic, or long lasting, pancreatitis that cannot be managed by other treatments. This procedure is not considered experimental. Patients with type 1 diabetes cannot receive pancreatic islet auto-transplantation. The procedure is performed in a hospital, and the patient receives general anesthesia. The surgeon first removes the pancreas and then extracts and purifies islets from the pancreas. Within hours, the islets are infused through a catheter into the patient’s liver. The goal is to give the body enough healthy islets to make insulin.
In the period from 1999 to 2004, 471 patients with type 1 diabetes have received islet transplants at 43 institutions worldwide [17]. History of Islet Transplantation The concept of islet transplantation is not new [18]. Investigators as early as the English surgeon Charles Pybus (1882– 1975) attempted to graft pancreatic tissue to cure diabetes. Most, however, credit the recent era of islet transplantation research to Paul Lacy's studies more than three decades ago. In 1967, Lacy’s group described a novel collagenase-based method (later modified by Dr. Camillo Ricordi, then working with Dr. Lacy) to isolate islets, paving the way for future in vitro and in vivo islet experiments [19]. Subsequent studies showed that transplanted islets could reverse diabetes in both rodents and non-human primates [20, 21]. In a summary of the 1977 Workshop on Pancreatic Islet Cell Transplantation in Diabetes, Lacy commented on the feasibility of islet cell transplantation as a therapeutic approach for the possible prevention of the complications of diabetes in man [22]. Improvements in isolation techniques and immunosuppressive regimens ushered in the first human islet transplantation clinical trials in the mid-1980s. The first successful trial of human islet allo-transplantation resulting in long-term reversal of diabetes was performed at the University of Pittsburgh in 1990 [23]. Yet despite continued Procedural improvements, only about 10% of islet recipients in the late 1990s achieved euglycemia (normal blood glucose). In 2000, Dr. James Shapiro and colleagues published a report describing seven consecutive patients who achieved euglycemia following islet transplantation using a steroid-free protocol and large numbers of donor islets, since referred to as the Edmonton protocol [24]. This protocol has been Page | 111
adapted by islet transplant centers around the world and has greatly increased islet transplant success. Rationale for Islet Transplantation Insulin therapy is lifesaving but it is not perfect. Because most of the people with Type I DM have abnormal blood sugar level despite best insulin plans. The Potential Advantage of Islet Transplantation over Insulin Administration is that 1.
The Islets would maintain normal blood sugar level under all conditions.
2.
This would not produce excess insulin, resulting in hypoglycemia.
The main aim is to infuse enough islets to control the blood glucose level removing the need for insulin injections. For an average-size person (70 kg), a typical transplant requires about one million islets, isolated from two donor pancreases. Because good control of blood glucose can slow or prevent the progression of complications associated with diabetes, such as nerve or eye damage, a successful transplant may reduce the risk of these complications. But a transplant recipient will need to take immunosuppressive drugs that stop the immune System from rejecting the transplanted islets. Islet Cell Isolation, Preparation for Graft and Transplantation 1.
Selection of the Donor
Donor selection has been repeatedly shown to be a critical factor in successful islet cell isolation and transplantation. Donors are selected based on body mass index (BMI), donor age, and retrieval by a local surgical team [25]. Although donors with high BMI are not routinely used in whole organ transplantation, paradoxically these organs generally provide higher islet yields compared with lean donors [25, 26]. The major obstacle in the isolation of islets from young donors is the inability of separating islets from the surrounding acinar tissue without injuring the islets themselves [26]. Low islet levels have also been shown to correlate with donors who have experienced prolonged hypotension, longer cold ischemia time, longer duration of cardiac arrest, and elevated serum creatinine [27]. 2.
Islet Preparation
Islet cell isolation from human pancreas has significantly improved over the past 3 decades. The landmark advance was the development of the Page | 112
semiautomatic method for controlled pancreatic digestion using a dissociation chamber (Ricordi Chamber), which has dramatically increased islet cell levels and is still the basis for current islet cell isolation technology [28].
This novel technique allows for islet separation from the exocrine tissue in a digestion chamber where a mechanically enhanced continuous enzymatic process occurs. As the pancreatic tissue is progressively digested, the released material is continuously being collected in a separate large volume of solution designed to inhibit further enzyme activity. 3.
Digestion
The enzymatic dissociation of islet cells from the surrounding acinar tissue by collagenase is the critical aspect of successful human islet transplantation [29, 30]. Roche Applied Science developed Liberase HI, which was a highly purified, low endotoxin enzyme blend of collagenase I and II as well as neutral protease thermolysin. This product consistently demonstrated high yields of excellent quality human islets when compared with previous crude blends of enzymes [31]. Unfortunately, concerns about the potential for prion disease was raised with Liberase HI because it was from media with brain-heart infusion broth [32] . Roche has developed a mammalian tissue-free Liberase MTF-S as an alternative to its original product [33]. In addition, there are two additional commercially available products that have both demonstrated comparable digestive capabilities: Serva Collagenase NB1 and Vitacyte collagenase HA [34, 35]. Today, ongoing research is being performed to identify the ideal alternative to Liberase HI, the previous gold standard. 4.
Purification
After complete digestion of the pancreatic tissue, it is critical to isolate the islet cells (which only represent 1 to 2% of the total tissue) through a purification step. This process allows for isolation of the islet cells and reduction of the volume of tissue that will ultimately be implanted in the patient. The semiautomated computerized COBE-2991 cell processor is the gold standard for islet cell purification because it allows for large-volume processing in a short time [36]. In addition, a critical feature is the ability to collect serial fractions to select those islet cells with the highest degree of purity. Finally, the toploading feature has the advantage of allowing the digested material to remain in physiological media and minimizes trauma from centrifugal forces.
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5.
Pretransplant Culturing
The process of human islet cell isolation generates sizable stress and trauma to the islet cells as demonstrated by the induction of apoptosis, necrosis, and prionflammatory cytokines and chemokines [37, 38]. Thus optimal culture conditions should allow isolated islet cells the oxygen and nutrients to recover and prevent further cell loss. Culturing islets prior to transplantation has practical advantages including time to arrange patient transportation, the logistics of coordinating islet cell infusion, patient precondition with immunosuppression, and microbiological testing of the isolate for contamination. Numerous media formulations and culture protocols are currently being used [39]. Further clinical research is necessary to optimize the pretransplant culturing process to improve β-cell mass and successful clinical islet cell transplantation. 6.
Islet Cell Infusion or Transplantation
In most centers, the islet preparations are implanted into the recipient's liver through the portal vein via a percutaneous transhepatic cannulation. The catheter can be placed under either initial sonographic followed by fluoroscopic guidance, or entirely by fluoroscopic guidance [40, 41]. Once the catheter's location has been confirmed, portal pressure is measured by an indirect pressure transducer. Subsequently, islet cells are gradually infused by gravity via a closed bag system. The infusion of islets occurs over 15 to 40 minutes depending on the volume of tissue to be infused and the changes in portal pressure that occur during islet infusion. The portal pressures are measured every 5 minutes by interrupting the infusion. If the portal pressure doubles, the infusion is held until the pressure returns toward baseline. Post infusion portography and pressures are obtained at the completion of the islet cell infusion just before establishing hemostasis. The entry tract is typically plugged with a hemostatic sealant. Technical details describing transhepatic sealing/closure are discussed in the current issue “Percutaneous Portal Vein Access and Transhepatic Tract Hemostasis [42] . The Overall Procedure is shown in A Flow Chart Selection of donor for the transplantation. Then Islet cell preparation done via semi automatic method for controlled Page | 114
pancreatic digestion. Islet separation is done via continuous enzymatic process in a digestion chamber. Released material collected continuously in a separated large volume of solution design to inhibit further enzyme activity. Collagenase is infused to separate the islet cells. Density gradient centrifugation is done. Purification is done to isolate the Islet cells. Pre transplant culturing is done to improve beta cell mass. Islet cell transplantation
Fig 4: showing the overall procedure of Islet cell transplantation Page | 115
Complications
Early complications of islet cell transplantation are related to the hepatic infusion and include bleeding, portal vein thrombosis, and hepatic infarct [43, 44].
Recent studies have identified risk factors for acute portal pressure rise including packed cell volume after purification, the number of transplanted cells, and the absence of purification stage [45, 46].
Recommended packed cell volume 24,000 done in US & >12,000 outside US.
Conclusions Islet cell transplantation has raised hope for a cure of diabetes for the past 3 decades. Other new innovative tools which also helpful are- stem cell therapy, gene therapy, immunomodulation. With better help of Govt. & Private organization more cases of pancreatic islet transplantation & prevention of rejections can be done in India. References 1.
Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications WHO/NCD/NCS/99.2 Original: English Distr: General.
Page | 119
2.
King H, Aubert RE, Herman WH. Global burden of diabetes, 19952025: prevalence, numerical estimates, and projections. Diabetes Care. 1998; 21:1414-1431.
3.
IDF Diabetes Atlas, 4th edition. International Diabetes Federation, 2009.
4.
Chan JC, Malik V, Jia W et al. Diabetes in Asia: Epidemiology, risk factors, and pathophysiology. JAMA. 2009; 301:2129-40.
5.
Ramachandran A, Wan Ma RC, Snehalatha C. Diabetes in Asia. Lancet. 2010; 375:408-18.
6.
Joshi SR, Das AK, Vijay VJ, Mohan V. Challenges in Diabetes Care in India: Sheer Numbers, Lack of Awareness and Inadequate Control, JAPI 56 JUNE, 2008, 443-450.
7.
Diabetes facts http://www.worlddiabetesfoundation.org/composite35.htm (accessed on 13/1/2012)
8.
The Average Age of Onset of Diabetes among Indians is a Decade Earlier than Other Races. Available on http://www.expresshealthcare.in/ 201110/diabeteswatch05.shtml. Accessed on January 13th 2012.
9.
http://www.diabeteshealth.com.
10. Mohan V, Pradeepa R. Epidemiology of diabetes in different regions of India. Health Administrator. 2009; 22:1-18. 11. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic Medicine. 1998; 15(7):539-53. 12. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014; 383(9911):69-82. 13. Patterson CC, Dahlquist GG, Gyürüs E, Green A, Soltész G. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study, Lancet. 2009; 373:2027-2033. 14. Gale EAM. How to survive diabetes. Diabetologia. 2009; 52(4):559-67. 15. Larsen CE, Alper CA. The genetics of HLA-associated disease. Curr Opin Immunol. 2004; 16(5):660-667. 16. Knip M. Environmental triggers and determinants of beta-cell autoimmunity and type 1 diabetes. Rev Endocr Metab Disord. 2003; 4(3):213-223. Page | 120
17. Shapiro A, Lakey J, Paty B, Senior P, Bigam D, Ryan E. Strategic opportunities in clinical islet transplantation. Transplantation. 2005; 79(10):1304-1307. doi:10.1097/01.TP.0000157300.53976.2A. PMID 15912095. 18. Piemonti L, Pileggi A. 25 Years of the Ricordi Automated Method for Islet Isolation. CellR4. 2013; 1(1):8-22. 19. Lacy P, Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 1967; 16(1):35-39. doi:10.2337/diab.16.1.35. PMID 5333500. 20. Kemp C, Knight M, Scharp D, Lacy P, Ballinger W. Transplantation of isolated pancreatic islets into the portal vein of diabetic rats. Nature. 1973; 244(5416):447. doi: 10.1038/244447a0. PMID 4200461. 21. Scharp D, Murphy J, Newton W, Ballinger W, Lacy P. Transplantation of islets of Langerhans in diabetic rhesus monkeys. Surgery. 1975; 77(1):100-105. PMID 122797. 22. Lacy P. Workshop on Pancreatic Islet Cell Transplantation in Diabetes sponsored by the National Institute of Arthritis, Metabolism, and Digestive Diseases and held at the National Institutes of Health in Bethesda, Maryland, on November 29 and 30, 1977. Diabetes. 1978; 27(4):427-429. doi:10.2337/diab.27.4.427. PMID 416985. 23. Tzakis A, Ricordi C, Alejandro R, Zeng Y, Fung J, Todo S et al. Pancreatic islet transplantation after upper abdominal exenteration and liver replacement. Lancet. 1990; 336(8712):402-405. doi: 10.1016/01406736(90)91946-8. PMC 2972674. PMID 1974944. 24. Shapiro A, Lakey J, Ryan E, Korbutt G, Toth E, Warnock G et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000; 343(4):230-238. doi: 10.1056/NEJM200007273430401. PMID 10911004. 25. Zeng Y, Torre MA, Karrison T, Thistlethwaite JR. The correlation between donor characteristics and the success of human islet isolation. Transplantation. 1994; 57(6):954-958. 26. Ricordi C. Quantitative and qualitative standards for islet isolation assessment in humans and large mammals. Pancreas. 1991; 6(2):242244. 27. Brandhorst H, Brandhorst D, Hering BJ, Federlin K, Bretzel RG. Body Page | 121
mass index of pancreatic donors: a decisive factor for human islet isolation. Exp Clin Endocrinol Diabetes. 1995; 103(2):23-26. 28. Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW. Automated method for isolation of human pancreatic islets. Diabetes. 1988; 37(4):413-420. 29. Kin T, Johnson PR, Shapiro AM, Lakey JR. Factors influencing the collagenase digestion phase of human islet isolation. Transplantation. 2007; 83(1):7-12. 30. Kin T, Zhai X, Murdoch TB, Salam A, Shapiro AM, Lakey JR. Enhancing the success of human islet isolation through optimization and characterization of pancreas dissociation enzyme. Am J Transplant. 2007; 7(5):1233-1241. 31. Olack BJ, Swanson CJ, Howard TK, Mohanakumar T. Improved method for the isolation and purification of human islets of Langerhans using Liberase enzyme blend. Hum Immunol. 1999; 60(12):1303-1309. 32. Alejandro R, Barton FB, Hering BJ, Wease S. Collaborative Islet Transplant Registry Investigators. Update from the Collaborative Islet Transplant Registry. Transplantation. 2008; 86(12):1783-1788. 33. Caballero-Corbalan J, Brandhorst H, Asif S, Korsgren O, Engelse M, de Koning E et al. Mammalian tissue-free liberase: a new GMP graded enzyme blend for human islet isolation. Transplantation. 2010; 90(3):332-333. 34. Caballero-Corbalán J, Friberg AS, Brandhorst H et al. Vitacyte collagenase HA: a novel enzyme blend for efficient human islet isolation. Transplantation. 2009; 88(12):1400-1402. 35. Szot GL, Lee MR, Tavakol MM et al. Successful clinical islet isolation using a GMP-manufactured collagenase and neutral protease. Transplantation. 2009; 88(6):753-756. 36. Goto M, Eich TM, Felldin M et al. Refinement of the automated method for human islet isolation and presentation of a closed system for in vitro islet culture. Transplantation. 2004; 78(9):1367-1375. 37. Abdelli S, Ansite J, Roduit R. et al. Intracellular stress signaling pathways activated during human islet preparation and following acute cytokine exposure. Diabetes. 2004; 53(11):2815-2823. 38. Bottino R, Balamurugan AN, Tse H et al. Response of human islets to isolation stress and the effect of antioxidant treatment. Diabetes. 2004; 53(10):2559-2568. Page | 122
39. Murdoch TB, McGhee-Wilson D, Shapiro AM, Lakey JR. Methods of human islet culture for transplantation. Cell Transplant. 2004; 13(6):605-617. 40. Venturini M, Angeli E, Maffi P et al. Technique, complications, and therapeutic efficacy of percutaneous transplantation of human pancreatic islet cells in type 1 diabetes: the role of US. Radiology. 2005; 234(2):617-624. 41. Baidal DA, Froud T, Ferreira JV, Khan A, Alejandro R, Ricordi C. The bag method for islet cell infusion. Cell Transplant. 2003; 12(7):809-813. 42. Saad W, Maddoff D. Percutaneous portal vein access and transhepatic tract hemostasis. Semin Intervent Radiol. 2012; 29(2):71-80. 43. Casey JJ, Lakey JR, Ryan EA et al. Portal venous pressure changes after sequential clinical islet transplantation. Transplantation. 2002; 74(7):913-915. 44. Ryan EA, Paty BW, Senior PA, Shapiro AM. Risks and side effects of islet transplantation. Curr Diab Rep. 2004; 4(4):304-309. 45. Moberg L, Johansson H, Lukinius A et al. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet. 2002; 360(9350):2039-2045. 46. Johansson H, Lukinius A, Moberg L et al. Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation. Diabetes. 2005; 54(6):17551762. 47. Kawahara T, Kin T, Kashkoush S, Gala-Lopez B, Bigam DL, Kneteman NM et al. Portal vein thrombosis is a potentially preventable complication in clinical islet transplantation. Am J Transplant. 2011; 11(12):2700-2707. 48. Kawahara T, Kin T, Shapiro AM. A comparison of islet auto transplantation with allotransplantation and factors elevating acute portal pressure in clinical islet transplantation. J Hepatobiliary Pancreat Sci. 2012; 19(3):281-288. 49. Johansson H, Goto M, Dufrane D et al. Low molecular weight dextran sulfate: a strong candidate drug to block IBMIR in clinical islet transplantation. Am J Transplant. 2006; 6(2):305-312. 50. Cabric S, Sanchez J, Lundgren T et al. Islet surface heparinization prevents the instant blood-mediated inflammatory reaction in islet transplantation. Diabetes. 2007; 56(8):2008-2015. Page | 123
51. Shapiro AJ, Lakey JT et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000; 343(4):230-238 52. Berney T, Secchi A. Rapamycin in islet transplantation: friend or foe? Transpl Int. 2009; 22(2):153-161. 53. Ryan EA, Paty BW, Senior PA et al. Five-year follow-up after clinical islet transplantation. Diabetes. 2005; 54(7):2060-2069. 54. Kenmochi T, Asano T, Maruyama M et al. Clinical islet transplantation in Japan. J Hepatobiliary Pancreat Surg. 2009; 16(2):124-130.
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