Martin J. London, MD

• Professor of Clinical Anesthesia
• University of California at San Francisco
• San Francisco, California

Many developmental changes occur between the end of the neonatal period and 18 months of age blood glucose test strips price effective 5 mg forxiga. The "baby fat" that accumulates under the skin during the first year begins to decrease diabetes symptoms for adults buy 10 mg forxiga fast delivery, and the plump infant becomes leaner diabetes type 2 what to eat discount forxiga 5mg with amex. One of Infancy the period of infancy begins abruptly at birth and lasts about 18 months diabetes test cvs cheap forxiga uk. Neonatology is the medical and nursing specialty concerned with the diagnosis and treatment of disorders of the newborn or neonate diabetes type 2 and headaches forxiga 5mg low price. Many of the changes that occur in the cardiovascular and respiratory systems at birth are necessary for sur- cut diabetes medications called thiazolidinediones buy discount forxiga 10mg online. This act separates the neonate from the placental blood supply and requires the infant to breathe to get the oxygen once supplied by the mother. Photograph showing the normal rounded curvature of the vertebral column in an infant. This permits the infant to follow a moving object with the eyes (2 months); lift the head and raise the chest (3 months); sit when well supported (4 months); crawl (10 months); stand alone (12 months); and run, although a bit stiffly (18 months). Many of the developmental changes that occur during this period are controlled by the secretion of sex hormones and are classified as secondary sex characteristics. Breast development is often the first sign of approaching puberty in girls, beginning about age 10. In girls the spurt in height begins between the ages of 10 and 12 and is nearly complete by age 14 or 15. In boys the period of rapid growth begins between 12 and 13 and is generally complete by age 16. Childhood Childhood extends from the end of infancy to sexual maturity or puberty - 12 to 14 years in girls and 14 to 16 years in boys. Overall, growth during early childhood continues at a rather rapid pace, but month-tomonth gains become less consistent. By the age of 6 years, the child appears more like a preadolescent than an infant or toddler. The child becomes less chubby, the potbelly becomes flatter, and the face loses its babyish look. The nervous and muscular systems continue to develop rapidly during the middle years of childhood; by 10 years of age the child has developed numerous motor and coordination skills. The deciduous teeth, which begin to appear at about 6 months of age, are lost during childhood, beginning at about 6 years of age. The permanent teeth, with the possible exception of the third molars, or wisdom teeth, all erupt by age 14. This period is marked by rapid and intense physical growth, which ultimately results in sexual maturity. The figure shows typical patterns of gain in height to adulthood for girls and boys. Notice the rapid gain in height during the first few years, a period of slower growth, and then another burst of growth during adolescence, finally ending at the beginning of adulthood. Examples include the maturation of bone, resulting in the full closure of the growth plates, and changes in the size and placement of other body components such as the sinuses. Normal balding patterns, for example, are determined at the time of fertilization by heredity but do not appear until maturity. As a general rule, adulthood is characterized by maintenance of existing body tissues. With the passage of years, the ongoing effort of maintenance and repair of body tissues becomes more and more difficult. As a person grows older, a gradual but cerConduction tain decline takes place in the functioning of every mavelocity of Liver nerve fiber jor organ system in the body. Insets show proportion of remaining function in the organs of illustration highlights the proportion of remaining funca person in late adulthood compared with that of a 20-year-old person. Some gerontologists believe that an important aging mechanism is the limit on cell reproduction. Thus the tissues of the dead cells are not replaced, causing body fail to maintain or repair themselves degeneration of tissues. Perhaps the normally, and many of the degenerative concells are not replaced because the surditions more commonly seen in elderly indirounding cells have reached their viduals appear. Most people with progeria die of cardiovascumechanism seems to operate in indilar disease within the first or second decade viduals with progeria, a rare, inherof life. Some gerontologists believe that nutrition, injury, disease, and other environmental factors affect the aging process. A few have even proposed that aging results from cellular changes caused by slow-acting "aging" viruses found in all living cells. Other gerontologists have proposed that aging is caused by "aging" genes - genes in which aging is "preprogrammed. Free radicals are highly reactive forms of oxygen that normally result from cellular activities, but may damage the cell. Although the causes and basic mechanisms of aging are yet to be understood, at least many of the signs of aging are obvious. The remainder of this chapter deals with a number of the more common degenerative changes that frequently characterize senescence, or older adulthood. Although advanced age brings with it the higher risk of many disorders, it also brings some biological advantages. Free-radical production by cells, one of many possible mechanisms of the aging processes, may increase as a person gets older, increasing the amount of cellular damage. Free radicals are highly reactive forms of oxygen that are normal by-products of cellular respiration in the mitochondria (shown) and other cell processes. As one ages, the number of free radicals increases as cellular efficiency decreases. Thus more cellular damage occurs, especially damage to cellular membranes, causing degeneration of the cell. Pigmentation changes and the thinning or loss of hair are also common problems associated with the aging process. Although some elderly individuals suffer from depression, especially when they become ill or separated from family, the average elderly person is happier than when they were younger. Special Senses the sense organs, as a group, all show a gradual decline in performance and capacity as a person ages. Most people are farsighted by age 65 because eye lenses become hardened and lose elasticity; the lenses cannot become curved to accommodate for near vision. This explains the increased need, with advancing age, for bifocals, or glasses that incorporate two lenses, to automatically accommodate for near and distant vision. Loss of transparency of the lens or its covering capsule is another common age-related eye change. If the lens actually becomes cloudy and significantly impairs vision, it is called a cataract and must be removed surgically. The incidence of glaucoma, the most serious agerelated eye disorder, increases with age. Glaucoma causes an increase in the pressure within the eyeball and, unless treated, often results in blindness. In many elderly people a very significant loss of hair cells in the organ of Corti (spiral organ of the inner ear) causes a serious decline in the ability to hear certain frequencies. In addition, the eardrum and attached ossicles become more fixed and less able to transmit mechanical sound waves. The resulting loss of appetite may be caused, at least in part, Skeletal System In older adulthood, bones undergo changes in texture, degree of calcification, and shape. Instead of clean-cut margins, older bones develop indistinct and shaggyappearing margins with spurs - a process called lipping. This type of degenerative change restricts movement because of the piling up of bone tissue around the joints. With advancing age, changes in calcification may result in reduction of bone size and in bones that are porous and subject to fracture. The lower cervical and thoracic vertebrae are the site of frequent compression fractures. The result is curvature of the spine and the shortened stature so typical of late adulthood. Degenerative joint diseases such as osteoarthritis are also common in elderly adults. However, many of the aging effects seen in the skeleton can be lessened by physical activity - especially if exercise starts earlier in life. Loss of bone mass and reduced mobility can be avoided or reduced by an ongoing program of physical activity coupled with good nutrition. Central Nervous System Advancing age brings with it the risk of dementia, the loss of memory and other functions of conscious thinking - and other degenerative conditions that affect the central nervous system. But even simple changes in lifestyle, regardless of modern medical wonders, can keep the effects of aging from creeping up too soon. Perhaps the three most important "low tech" methods for improving the quality of life as you age are healthful diet, exercise, and stress management. A healthful diet is not available to some individuals, but it is available to most of us. We are learning more every day about what kind of diet is best, even to the point of being able to manage specific diseases through diet. And last, even ancient and simple techniques of stress management such as meditation have been shown to help reduce the effects of aging and the diseases that often accompany aging such as heart disease and strokes. In short, we can usually stay "young" longer if we eat right, exercise, and relax. But when Belgium was about to be invaded by the Nazis, she decided to return home to Italy and work in seRita Levi-Montalcini (born 1909) cret. Her home laboratory was very crude, but in it she made some important discoveries about how the nervous system develops during embryonic growth. Her discovery of a chemical that regulates the growth of new nerves during early brain development has led to many different paths of investigation. For example, by learning more about growth regulators, we have gained knowledge about how the nervous system and also other tissues, organs, and systems of the body develop. Today many professions make use of the discoveries of embryology - the study of early development. These discoveries are important not only for health professionals involved in obstetrics and prenatal health care but also for those studying and practicing adult medicine. Even the fields of gerontology (study of aging) and geriatrics (treatment of the aged) have benefited from embryological research. The insights gained on how tissue development is regulated in the embryo have given scientists a better understanding of how to possibly stimulate damaged tissues in older adults to repair or regenerate themselves. Only about 40% of the taste buds present at age 30 remain in an individual at age 75. Cardiovascular System Degenerative heart and blood vessel disease is one of the most common and serious effects of aging. Fatty deposits build up in blood vessel walls and narrow the passageway for the movement of blood, much as the buildup of scale in a water pipe decreases flow and pressure. If fatty accumulations or other substances in blood vessels calcify, actual hardening of the arteries, or arteriosclerosis occurs. Hardening of arteries reduces their elasticity, which can contribute to abnormally high arterial pressure. With advancing years a generalized atrophy or wasting of muscle tissue takes place as the contractile muscle cells are replaced by connective tissue. This loss of muscle cells decreases the strength of the muscles associated with inspiration and expiration. Urinary System the number of nephron units in the kidney decreases by almost 50% between the ages of 30 and 75. Also, because less blood flows through the kidneys as an individual ages, there is a reduction in overall function and excretory capacity or the ability to produce urine. In the bladder, significant age-related problems often occur because of diminished muscle tone. Muscle atrophy (wasting) in the bladder wall results in decreased capacity and inability to empty or void completely. Reproductive Systems Although most men and women remain sexually active throughout their later years, mechanisms of the sexual response may change, and fertility declines. In men, erection may be more difficult to achieve and maintain, and urgency for sex may decline. Although men can continue to produce gametes as they age, women experience a cessation of reproductive cycling between the ages of 45 and 60 - menopause. Menopause results from a decrease in the cyclic production of gonadotropins from the pituitary, which in turn reduces estrogen secretion. Respiratory System In older adulthood the costal cartilages that connect the ribs to the sternum become hardened or calcified. This makes it difficult for the rib cage to expand and contract as it normally does during inspiration and expiration. In time the ribs gradually become "fixed" to the sternum, and chest movements become difficult. However, in addition to the cessation of menstrual cycles, the decrease in blood estrogen levels during this period accounts for a number of common and often troubling symptoms which include hot flashes, sleep disturbances, and dryness and thinning of the vaginal wall in many women. Fortunately, medications other than estrogen are also available to effectively treat or prevent most menopausal symptoms and other health problems, such as loss of bone mass, or osteoporosis (see Chapter 8), and heart disease, that increase in frequency in older women who have lower blood estrogen levels. As with any therapy, treatment for menopause-related symptoms requires careful, individualized risk-benefit analysis. Formation of new organs (organogenesis) and tissues (histogenesis) occurs from specific development of the primary germ layers 2. Each primary germ layer gives rise to definite structures such as the skin and muscles 3. Growth processes include cell differentiation, multiplication, growth, and rearrangement 4.

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However diabetes urine test order online forxiga, exercise physiologists have found that aerobic training increases the number of insulin receptors in target cells and the insulin affinity (attraction) of the receptors diabetic diet for 4 year old order forxiga 10mg online. This condition allows a small amount of insulin to have a greater effect than it would have otherwise had diabetes medications assistance programs purchase 10 mg forxiga overnight delivery. Not only is this form of treatment natural and cost-effective diabetes in dogs insulin costs generic forxiga 5mg, but it also helps reduce or prevent other problems such as obesity and heart disease diabete france cheap 10 mg forxiga with amex. Screening tests for all types of diabetes mellitus are based on the fact that the blood glucose level is elevated in this condition juvenile diabetes symptoms mayo clinic 10 mg forxiga with amex. Today, most screening is done with a simple test that requires only a drop of blood. Subjects with a high blood glucose level are suspected of having diabetes mellitus. In diabetes mellitus, excess glucose is filtered out of the blood by the kidneys and lost in the urine, producing the condition glycosuria. A quick look at these problems underscores the importance of insulin and insulin receptors in healthy bodies. During pregnancy, it produces chorionic gonadotropins, so called because they are tropic hormones secreted by cells of the chorion, the outermost membrane that surrounds the baby during development in the uterus. In addition to chorionic gonadotropins, the placenta also produces estrogen and progesterone. During the earliest weeks of pregnancy, the kidneys excrete large amounts of chorionic gonadotropins in the urine. This fact, discovered more than a half century ago, led to the development of early pregnancy tests. Each ovary contains two different kinds of glandular structures: the ovarian follicles and the corpus luteum. This hormone is also responsible for development of adult female body contours and initiation of the menstrual cycle. We shall save our discussion of the structure of these endocrine glands and the functions of their hormones for Chapter 23. It is named "pineal" because it resembles the pine nut (which looks like a small kernel of corn). The pineal gland is easily located in a child but becomes fibrous and encrusted with calcium deposits as a person ages. The pineal gland produces a number of hormones in very small quantities, with melatonin being the most significant. Melatonin inhibits the tropic hormones that affect the ovaries, and it is thought to be involved in regulating the onset of puberty and the menstrual cycle in women. The pineal gland uses information regarding changing light levels to adjust its output of melatonin; melatonin levels increase during the night and decrease during the day. Melatonin supplements are now widely used as an aid to induce sleep or to "reprogram" the sleep cycle as a treatment for jet lag. Abnormal secretion of or sensitivity to melatonin is implicated in a number of disorders. Patients with this condition exhibit signs of clinical depression only during the winter months, when nights are long. Apparently, unusually high melatonin levels associated with long winter nights cause psychological effects in these patients. The pineal gland seems to be tricked into responding as if the patient were experiencing a long summer day, thus secreting less melatonin (see Table 12-1). Male Sex Glands Some of the cells of the testes produce the male sex cells called sperm. Other cells in the testes, male reproductive ducts, and glands produce the liquid portion of the male reproductive fluid called semen. The interstitial cells in the testes secrete the male sex hormone called testosterone directly into the blood. Chapter 23 contains more information about the structure of the testes and the functions of testosterone. Other Endocrine Structures Continuing research into the endocrine system has shown that nearly every organ and system has an endocrine function. Until the early twentieth century, children with type 1 diabetes mellitus died a slow, horrible death as a result of their cells literally starving to death from lack of glucose. Chemist James Collip was able to purify the insulin sufficiently so that in 1921 their colleague, Scots physiologist John Macleod, could administer the insulin to a 14-year-old boy with diabetes. This breakthrough, for which Banting and Macleod received the 1923 Nobel Prize, was the start of a century of rapid progress in understanding and treating endocrine disorders. Because hormones affect so many different body functions, nearly every kind of health professional, from medical doctors to nurses to dietitians, needs to be aware of their functions. Of course, hormones and chemicals that influence hormone actions are often Charles Best (1899-1978) used in treatments, so pharmacologists and pharmacists also must have an excellent knowledge of endocrinology. Some scientists have applied principles of endocrinology in a variety of unexpected ways, including the development of early pregnancy test kits and ovulation test kits, to the use of synthetic hormones in healthy people to help them control their fertility. For example, ghrelin is secreted by epithelial cells lining the stomach and boosts appetite, slows metabolism, and reduces fat burning. A more recently discovered hormone is leptin, which is secreted by fat-storing cells throughout the body. Leptin seems to regulate how hungry or full we feel and how fat is metabolized by the body. Researchers are now looking at how leptin works with other hormones, such as ghrelin, in the hopes of finding ways to treat patients with obesity, diabetes mellitus, and other disorders involving fat storage. Hormones perform general functions of communication and control but a slower, longer-lasting type of control than that provided by nerve impulses C. Secondary effects may occur when steroid hormones bind to membrane receptors to rapidly trigger functional changes in the target cell Pituitary Gland A. Positive feedback - (uncommon) mechanisms that amplify physiological changes Mechanisms of Endocrine Disease (Table 12-1) A. Oxytocin - stimulates the pregnant uterus to contract; may initiate labor; causes glandular cells of the breast to release milk into ducts Thyroid Gland A. Calcitonin - decreases the blood calcium concentration by inhibiting breakdown of bone, which would release calcium into the blood D. Hyposecretion during early development may result in cretinism (retardation) and during adulthood in myxedema (characterized by edema and sluggishness) Hypothalamus A. After production in the hypothalamus, hormones pass along axons into the pituitary gland 3. The secretion and release of posterior pituitary hormones are controlled by nervous stimulation B. The hypothalamus controls many body functions related to homeostasis (temperature, appetite, and thirst) Parathyroid Glands A. Function of hormone - increases blood calcium concentration by increasing the breakdown of bone with the release of calcium into the blood Adrenal Glands A. Mineralocorticoids - increase blood sodium and decrease body potassium concentrations by accelerating kidney tubule reabsorption of sodium and excretion of potassium 4. Help maintain normal blood glucose concentration by increasing gluconeogenesis - the formation of "new" glucose from amino acids produced by the breakdown of proteins, mainly those in muscle tissue cells; also the conversion to glucose of fatty acids produced by the breakdown of fats stored in adipose tissue cells b. Play an essential part in maintaining normal blood pressure - make it possible for epinephrine and norepinephrine to maintain a normal degree of vasoconstriction, a condition necessary for maintaining normal blood pressure c. Act with epinephrine and norepinephrine to produce an antiinflammatory effect, to bring about normal recovery from inflammations of various kinds d. Produce antiimmunity, antiallergy effect; bring about a decrease in the number of lymphocytes and plasma cells and therefore a decrease in the amount of antibodies formed. Functions of hormones - help the body resist stress by intensifying and prolonging the effects of sympathetic stimulation; increased epinephrine secretion is the first endocrine response to stress D. Hypersecretion of glucocorticoids causes Cushing syndrome: moon face, hump on back, elevated blood sugar levels, frequent infections 2. Hypersecretion of adrenal androgens may result from a virilizing tumor and cause masculinization of affected women 3. Hyposecretion of cortical hormones may result in Addison disease: muscle weakness, reduced blood sugar, nausea, loss of appetite, and weight loss Pancreatic Islets A. Glucagon increases the blood glucose level by accelerating glycogenolysis in liver (conversion of glycogen to glucose) 2. Insulin decreases the blood glucose by accelerating the movement of glucose out of the blood into cells, which increases glucose metabolism by cells D. Glucose cannot enter cells and thus blood glucose levels rise, producing glycosuria (glucose in the urine) Female Sex Glands A. The ovaries contain two structures that secrete hormones - the ovarian follicles and the corpus luteum; see Chapter 23 1. The interstitial cells of testes secrete the male hormone testosterone; see Chapter 23 1. Called third eye because its influence on secretory activity is related to the amount of light entering the eyes C. Many organs (for example, the stomach, intestines, and kidneys) produce endocrine hormones 1. Fat-storing cells secrete leptin, which controls how full or hungry we feel Pineal Gland A. The endocrine system uses chemicals in the blood (hormones) rather than nerve impulses. Hormones can have a direct effect on almost every cell in the body, an impossible task for the nervous system. Use flash cards and online resources to learn the names of the hormones, what they do, and the names and locations of the glands that produce them. Remember that hormones released by the posterior pituitary gland are made in the hypothalamus. When studying the disorders of the endocrine system, make a chart that identifies the disorders as a hyposecretion or hypersecretion of a specific gland. This may be more difficult than you think because many of the disorders are named after people, so the names themselves are not helpful in explaining the disorders. Usually, if you know the normal function of the hormone, you should be able to figure out what effect on the body hyposecretion or hypersecretion would have. In your study group, discuss the hormone mechanisms and negative feedback loops involved in hormone regulation. The photocopy and the chapter outline summary at the end of the chapter would be a good way to organize almost all the information in the chapter. Go over the chart of endocrine disorders and the questions at the end of the chapter, and discuss possible test questions. Define or explain the following terms: hormone, target organ, hypersecretion, and hyposecretion. Explain and give an example of a negative feedback loop for the regulation of hormone secretion. Explain and give an example of a positive feedback loop for the regulation of hormone secretion. Name the four tropic hormones released by the anterior pituitary gland and briefly explain their functions. Gigantism and acromegaly have the same cause; what is the cause and what causes the difference in effect between the two conditions? Describe the antagonistic effects of calcitonin and parathyroid hormone in the regulation of calcium. Explain why a secondary messenger system is needed for nonsteroid hormones but not for steroid hormones. Why is a goiter usually more of a dietary problem rather than an endocrine problem? If a person diagnosed with diabetes mellitus were found to be producing a normal amount of insulin, what other cause could explain the diabetes? A cell or body organ that has receptors for a hormone that triggers a reaction is called a. The hormone receptors for a nonsteroid hormone are located in the, whereas the receptors for a steroid hormone are located in the. Which of the following hormones is released by the anterior pituitary gland and stimulates breast development during pregnancy necessary for eventual milk production? Which hormone released by the posterior pituitary gland stimulates the contraction of the pregnant uterus? What is the chemical process by which the glucose stored in the liver cells in the form of glycogen is converted to glucose? Glycogenolysis Match each hormone in Column A with its function or source in Column B. George, the chief executive officer of a major institution, was jogging around his summer home when he became distressed at what seemed to be an irregularity of his heart rhythm. His assistants immediately rushed George to a hospital, where he was diagnosed as having atrial fibrillation (uncoordinated contractions of the upper heart chambers). George was even more distressed to hear that he had a specific heart condition, fearing it might disrupt his very active lifestyle. His physicians informed him that the overactivity of his heart - and perhaps other organs - was caused by hyperthyroidism. What therapy is likely to help her regain control of her metabolism and thus avoid possible tissue or organ damage? Lynn has told you that her condition, if untreated, results in "starvation" of cells in her body. This condition is characterized by hyperglycemia (elevated blood glucose), so you might wonder how the cells could starve if they have an excess of nutrients available. Describe the primary functions and composition of blood, including the characteristics of blood tissue and plasma, and identify the most important function of each of the formed elements of blood. Have you ever thought of what would happen if the transportation ceased in your city or town?

The prenatal period begins at conception and ends at birth; the postnatal period begins at birth and continues until death diabetes type 2 medication metformin side effects buy 10mg forxiga with amex. Although important periods in our lives such as childhood and adolescence are often remembered as a series of individual and isolated events diabetes in dogs management order 10 mg forxiga fast delivery, they are in reality part of an ongoing and continuous process diabetic bracelets order forxiga online now. In reviewing the many changes that occur during the cycle of life from conception to death diabetes prevention strategies order generic forxiga on line, it is often convenient to isolate certain periods such as infancy or adulthood for study diabetes insipidus complications discount 10 mg forxiga mastercard. It is important to remember new zealand type 2 diabetes statistics generic forxiga 5 mg amex, however, that life is not a series of stop-and-start events or individual and isolated periods of time. Instead, it is a biological process that is characterized by continuous modification and change. Study of development during the prenatal period is followed by a discussion of the birth process and a review of changes occurring during infancy and adulthood. Finally some important changes that occur in the individual organ systems of the body as a result of aging are discussed. The fertilized ovum or zygote is genetically complete; it represents a new single-celled offspring. Time and nourishment are all that is needed for expression of characteristics such as sex, body build, and skin color that were determined at the time of fertilization. After union between a sperm cell and the ovum has occurred, the cycle of life begins. This scanning electron micrograph shows spermatozoa attaching themselves to the surface of an ovum. The period of prenatal development continues until the birth of the child about 39 weeks later. The science of the development of the offspring before birth is called embryology. It is a story of biological marvels, describing the means by which a new human life is started and the steps by which a single microscopic cell is transformed into a complex human being. Fertilization to Implantation After ovulation the discharged ovum first enters the abdominal cavity and then finds its way into the uterine (fallopian) tubes. Recall from Chapter 23 that each uterine tube extends outward from the uterus for about 10 cm. Sperm cells that are deposited in the vagina must enter and "swim" through the uterus and through the uterine tube to meet the ovum. While in the tube, the ovum is fertilized by a sperm to form the single-celled zygote. After a few days of rapid mitotic division, a ball of cells called a morula is formed. The cells of the morula continue to divide, and by the time the developing embryo reaches the uterus, it is a hollow ball of cells called a blastocyst. During the 10 days from the time of fertilization to the time when the blastocyst completes implantation in the uterine lining, few nutrients from the mother are available. One of the specializations of the ovum is its incredible store of nutrients that help support this embryonic development until implantation has occurred. As the blastocyst develops, it forms a structure with two cavities, the yolk sac and amniotic cavity. The solid mass of cells shown in D forms the morula - an early stage in embryonic development. In these animals the yolk sac digests the yolk and provides the resulting nutrients to the embryo. Because uterine fluids provide nutrients to the developing embryo in humans until the placenta develops, the function of the yolk sac is not a nutritive one. The amniotic cavity becomes a fluid-filled, shockabsorbing sac, sometimes called the bag of waters, in which the embryo floats during development. The placenta is a unique structure that has a temporary but very important series of functions during pregnancy. Placental tissue normally separates the maternal blood, which fills the lacunae of the placenta, from the fetal blood so that no intermixing occurs. Unfortunately, toxic substances, such as alcohol and some infectious organisms, may penetrate this protective placental barrier and injure the developing baby. The hollow blastocyst implants itself in the uterine lining about 10 days after ovulation. Until the placenta is functional, nutrients are obtained by diffusion from uterine fluids. Notice the developing chorion and how the blastocyst eventually forms a yolk sac and amniotic cavity. To learn more about fertilization and implantation, go to AnimationDirect online at evolve. In the " case of in vitro fertilization, it refers to the glass laboratory dish where an ovum and sperm are mixed and where fertilization occurs. After it is in the abdominal cavity, the device allows the physician to view the ovary and then puncture and "suck up" an ovum from a mature follicle. Over the years refinements to this technique have been made and less invasive procedures, such as the insertion of a needle through the vaginal wall, are currently being used. If implantation is successful, growth will continue and the subsequent pregnancy will progress. In the most successful fertility clinics in the United States, a normal term birth will occur in about 30% of in vitro fertilization attempts. With the advent of genomics (see Chapter 25), we are now able to check embryos for genetic disorders before implanting them. However, the controversial practice of selecting embryos for gender has caused ethicists to debate whether the screening of embryos is appropriate medical practice. The close placement of the fetal blood supply and the maternal blood in the lacunae of the placenta permits diffusion of nutrients and other substances. B, Photograph of a normal, full-term placenta (fetal side) showing the branching of the placental blood vessels. Periods of Development the length of pregnancy (about 39 weeks) - called the gestation period - is divided into three 3-month segments called trimesters. A number of terms are used to describe development during these periods known as the first, second, and third trimesters of pregnancy. After about 3 days of constant cell division, the solid mass of cells, identified earlier as the morula, enters the uterus. Continued development transforms the morula into the hollow blastocyst, which then implants into the uterine wall. Actually, the length of gestation (the amount of time one is pregnant) is defined in different ways in different situations and can vary from one pregnancy to another. In practice, any pregnancy of less than 37 weeks (259 days) is said to be premature, and any lasting more than 42 weeks (294 days) is said to be postmature. So as with many statistics regarding human function, what is "normal" can be spoken of only in generalities and averages. The embryonic phase of development extends from the third week after fertilization until the end of week 8 of gestation. During this period in the first trimester, the term embryo is used to describe the developing offspring. The fetal phase is used to indicate the period of development extending from week 9 to week 39. The facial features of the fetus are apparent, the limbs are complete, and gender can be identified. Formation of the Primary Germ Layers At the very beginning of the embryonic stage, all the cells are stem cells. Stem cells are unspecialized cells that reproduce to form specific lines of specialized cells. At this stage, they have their highest "stemness" or potency - that is, they are capable of producing many different kinds of cells in the body. Some stem cells remain throughout development and maturity such as the hematopoietic stem cells found in adult bone marrow. Adult stem cells replace the specialized cells in a tissue and thus ensure stable, functional populations of the cell types needed for survival. Early in the first trimester of pregnancy, three layers of stem cells develop that embryologists call the primary germ layers (Table 24-1). Each layer gives rise to definite structures such as the skin, nervous tissue, muscles, or digestive organs. The fascinating story of histogenesis and organogenesis in human development is long and complicated; its telling belongs to the science of embryology. Development of structure and function go hand in hand, and from 4 months of gestation, when every organ system is complete and in place, until term (about 280 days), fetal development is mainly a matter of growth. Histogenesis and Organogenesis the study of how the primary germ layers develop into many different kinds of tissues is called histogenesis. The way that those tissues arrange themselves into organs is called organogenesis. The red areas show when teratogens are most likely to cause major birth defects, and the yellow areas show when minor defects are more likely to arise. Birth or Parturition the process of birth, or parturition, is the point of transition between the prenatal and postnatal periods of life. As pregnancy draws to a close, the uterus becomes "irritable" and, ultimately, muscular contractions begin and cause the cervix to dilate or open, thus permitting the fetus to move from the uterus through the vagina, or "birth canal," to the exterior. When contractions occur, the amniotic sac or "bag of waters" ruptures, and labor begins. A breech birth is one in which the fetus fails to turn head downward and consequently the feet are born first. Often called simply a C-section, it is a surgical procedure in which the newborn is delivered through an incision in the abdomen and uterine wall. The procedure may be done when abnormal conditions of the mother or fetus (or both) make normal vaginal delivery hazardous or impossible. Stage one - period from onset of uterine contractions until dilation of the cervix is complete. Stage two - period from the time of maximal cervical dilation until the baby exits through the vagina. The time required for normal vaginal birth varies widely and may be influenced by many variables, including whether the woman has previously had a child. In most cases, stage one of labor lasts from 6 to 24 hours, and stage two lasts from a few minutes to an hour. Delivery of the placenta (stage three) normally occurs within 15 minutes after the birth of the baby. To assess the general condition of a newborn, a system that scores five health criteria is often used. Cervix Rectum Placenta 2 the fetus moves into the opening of the birth canal, and the cervix begins to dilate. To learn more about the three stages of birth, go to AnimationDirect online at evolve. A Identical twins B Fraternal twins Fertilization Blastocyst stage Multiple Births the term multiple births refers to the birth of two or more infants from the same pregnancy. The birth of twins is more common than the birth of triplets, quadruplets, or quintuplets. Multiple-birth babies are often born prematurely, so they are at a greater than normal risk of complications in infancy. However, premature infants that have modern medical care available have a much lower risk of complications than without such care. Twinning, or double births, can result from at least two different natural processes: 1. Identical (monozygotic) twins result from the splitting of embryonic tissue from the same zygote early in development. Because they develop from the same fertilized egg, identical twins have the same genetic code. A, Identical twins develop when embryonic tissue from a single zygote splits to form two individuals. Notice that the placenta and the part of the amnion separating the amniotic cavities are shared by the twins. B, Fraternal twins develop when two ova are fertilized at about the same time, producing two separate zygotes. Different environmental factors and personal experiences lead to individuality even in genetically identical twins. Ultimately, the presence of stem cells is required for bone marrow to produce blood cells. The fact that umbilical cord blood is rich in these stem cells has great clinical significance. In the past, if the stem cells in the bone marrow of a child were destroyed as a result of leukemia or by chemotherapy, death would result unless a bone marrow transplant was possible to provide replacement stem cells. The stem cells obtained from cord blood are as effective as those obtained from traditional bone marrow and are easier to match to the recipient. Thousands of cord blood transfusions have been performed worldwide to provide stem cells for treatment of numerous genetic diseases, leukemia, sickle cell anemia, lymphoma, and other types of cancer. As cord blood donations increase and supplies become more readily available, cord blood transfusions may eliminate or reduce the need for obtaining bone marrow as a source of stem cells, particularly for use in treating children. After the umbilical cord is cut after birth, the blood that remains in the cord is simply drained into a sterile bag (see illustration), frozen, and then stored in liquid nitrogen in one of the numerous cord-blood centers in the United States.

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Because Nanoneurology and Nanoneurosurgery 35 of these features diabetes prevention is better than cure purchase forxiga 10 mg fast delivery, they can be implanted without breaking diabetes symptoms pee order forxiga discount, move when the brain moves diabetes test strips target buy 10mg forxiga mastercard, which reduces local tissue injury blood sugar insulin chart purchase generic forxiga online, and are small enough to minimize host inflammatory response blood sugar readings chart trusted forxiga 5mg. In spite of decades of intense effort diabetes type 2 quotes order forxiga with a mastercard, there is still no effective neuroprotection medication for humans in clinical practice. In particular, hydroxyl-functionalized C-60 fullerenes called fullerenols have shown neuroprotection efficacy in preclinical models through glutamate receptor blockade and antioxidation activity (Silva 2005). The glutamate receptor antagonism leads to less glutamate-induced increase in intracellular calcium, which results in less excitotoxic and apoptotic cell death. The antioxidation effect is achieved through potentiation of the degradation of superoxide anions to oxygen and hydrogen peroxide. Nanoparticles can be constructed that will specifically bind to targeted tumor cells. Thus, a single class of nanoparticles can specifically mark, kill, and remark tumors. Current therapy is neurosurgical resection with radiation therapy and chemotherapy with temozolomide; however, this improves survival by only a few months. By tagging the nanoparticles with a fluorescent marker, the tumor will be illuminated. Self-assembling peptide nanofiber scaffolds are recent innovations and have been shown to permit axons to grow through a site of injury, thereby allowing restoration of function, such as vision (Ellis-Behnke et al. In an ionic environment, these amphiphiles will orient such that their hydrophobic ends will be in the center and their hydrophilic ends will be on the surface (Webber et al. While not yet nanosized, several miniaturized robotic systems for image-guided surgeries are in use. The StealthStation system is utilized for brain, spinal, orthopedic, and ear/nose/throat surgeries. The challenge lies in fully transitioning these applications to practical medicine as they pertain to the nervous system. Nanomedicine will remove the traditional boundaries separating the medical specialties of surgery, medicine, and radiology. As the scale of technical manipulation is reduced, so will the need to perform large open craniotomy tissue resection procedures. As technology becomes more focused on the cellular and subcellular levels, imaging will become more functionally based. When interventions are more specific, their applications are more clearly defined. So, for neurosurgeons, neurologists, and neuroradiologists, a time may come when the three specialties become one. Perhaps they will be referred to as neuromedical physicians, who, through neuronanomedicine, can diagnose, treat, and cure - all at the same time. Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma. Nano neuro knitting: Peptide nanofiber scaffold for brain repair and axon regeneration with functional return of vision. Nanotechnologies and regenerative medical approaches for space and terrestrial medicine. Use of prebiotics in oral delivery of bioactive compounds: a nanotechnology perspective. Vapor bubble generation around gold nano-particles and its application to damaging of cells. Masking and triggered unmasking of targeting ligands on nanocarriers to improve drug delivery to brain tumors. Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system. Nanotechnology approaches for the regeneration and neuroprotection of the central nervous system. Encapsulation of methylene blue in polyacrylamide nanoparticle platforms protects its photodynamic effectiveness. Because there has been confusion concerning the nomenclature of nanoparticles, a comprehensive definition for pharmaceutical purposes defines nanoparticles as ". They consist of macromolecular materials in which the active principle (drug or biologically active material) is dissolved, entrapped, encapsulated and/or to which the active principle is adsorbed or attached" (Kreuter 2007, p. Nanoparticles have been further categorized into seven different platforms: polymeric nanoparticles, polymeric nanoconjugates, micelles, peptides and proteins, metal complexes, carbon nanoplatforms, and dendrimers (Kateb et al. The structure of a nanosphere consists 39 40 the Textbook of Nanoneuroscience and Nanoneurosurgery of a matrix in which the drug is physically and uniformly dispersed, either at the sphere surface or encapsulated within the vesicle. Nanocapsules confine the drug to a central cavity consisting of a liquid core surrounded by a polymer matrix (Leary et al. The cyclic diester of lactic acid can polymerize using the anionic ringopening addition mechanism, creating materials that can then be cast into strong films or spun into fibers (Kulkarni et al. Lactic acid and glycolic acid have nearly identical molecular structures, with lactic acid bearing an additional methylene group at the beta carbon position. The copolymer ratio of lactic acid to glycolic acid affects the rate of degradation; higher lactic acid concentration decreases the rate of degradation due to decreased water imbibition. The size of the spheres is also a principle determinant of the rate of polymer degradation and drug release. As the size of the particle increases, the surface area/volume ratio decreases, resulting in a slower rate of drug release. Increased molecular weight is also a factor in retarding the erosion process (Pai et al. Polymeric nanoparticles have received a great deal of attention due to their stability and ease of surface modification. The most important features of polymeric nanoparticles are their size and surface chemistry. Nanoparticle size affects the concentration profile in blood vessels, the mechanism of clearance (Table 3. A nanosphere consists of a matrix in which the drug is physically and uniformly dispersed, either at the sphere surface or encapsulated within the vesicle. Furthermore, polysorbate inhibits the effects of the p-glycoprotein activity in glioma cell lines (Chavanpatil et al. Controlled drug release from polymeric nanoparticles is governed by surface or bulk erosion, diffusion through the polymer matrix, swelling followed by diffusion, and changes in local environment, such as changes in pH (Peer et al. The functional modules contained within and on the surface of a nanoconjugate serve to efficiently deliver, protect, and target the drug payload. Surface moieties such as monoclonal antibodies and peptides directed against cell surface antigens unique to a given cell population or overexpressed in tumors are used to drive cellular uptake via the endosomal pathway (Ljubimova et al. Polymeric nanoconjugates significantly differ from polymeric nanoparticles because they contain a covalently linked payload. Nanocarrier formulations that do not contain covalent linkages, such as polymeric nanoparticles, are susceptible to damage, which leads to premature leakage and release of their payload, which could potentially result in toxicity to healthy tissue (Ljubimova et al. Furthermore, polymeric nanoparticles rely on passive targeting, whereas polymeric nanoconjugates may exploit both active and passive targeting. Effective delivery of nanoparticles to target tissue through the blood stream requires nanoparticles to escape the scavenging effect of the reticuloendothelial system by virtue of their small size (size evasion) and to avoid binding to plasma proteins (surface evasion). Active targeting is achieved by attaching agents to the surface of a nanocarrier that bind to a specific cell type. Current strategies for intravascular delivery employ a system composed of the ligand or antibody as a targeting moiety, a polymer or lipid as the carrier, and a sophisticated payload delivery system that enables drug release and endosomal escape (Ljubimova et al. An alternative but more invasive delivery strategy is intratumoral delivery, in which a catheter is placed within the tumor, nanoparticles are infused directly into the target organ or tumor tissue, and nanoparticles spread through the extracellular space to reach the cells of interest (Sahoo et al. A benzothiazole dye that exhibits enhanced fluorescence upon binding to amyloid fibrils (Khurana et al. Successful delivery of Th-T-loaded nanocapsules, prepared by the polymerization of styrene, delivered by direct intrahippocampal injection into the brains of mice has been reported (Hartig et al. Currently this drug is given orally, requiring frequent dosing because of its restricted entry into the brain due to its hydrophilicity. A variety of cholinergic side effects result from such frequent dosing, including bradycardia, nausea, dyspepsia, vomiting, and anorexia. A cremophor-free albumin-bound nanoparticle formulation of paclitaxel that eliminates the cremophor-associated infusion toxicities and requirement for pretreatment steroid medication. The results showed that Abraxane was very well tolerated and should be further evaluated in a randomized setting in both adjuvant and neoadjuvant trials. To avoid this cardiotoxicity, targeting moieties on nanoparticles with the amide linkage formulation must avoid nonspecific binding to myocardial cells. Chronic infusions are unfortunately associated with complications including catheter-related vasculitis and sepsis (Desai et al. The nanoparticle formulation of paclitaxel serves as the paradigm for improving drug delivery of existing pharmaceuticals with nanotechnology. Paclitaxel [(2,4,5,7,10,13)-4,10-bis(acetyloxy)13-[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy-1,7-dihydroxy-9-oxo-5,20epoxytax-11-en-2-yl benzoate] is a clinical anticancer agent with activity against breast, lung, ovarian, and head and neck cancer. Paclitaxel binds the subunit of tubulin, which hyperstabilizes the microtubule structure of the cell and destroys its ability to use its cytoskeleton in a flexible manner. These solubilizing agents have been implicated as the cause of serious adverse side effects such as hypersensitivity reactions and peripheral neuropathy (Szebeni et al. The nanoparticle colloidal suspension is prepared by high-pressure homogenization of paclitaxel in the presence of serum albumin (Petrelli et al. After intravenous injection, the nanoparticles dissolve into smaller particles with a mean size of 10 nm, similar in size to that of endogenous serum albumin. Current models show that nab-P has ready bioavailability after intravenous infusion and accumulates in tumors via transcytosis (Petrelli et al. Abraxane is indicated for treating breast cancer after failure of combination chemotherapy or relapse within 6 months of adjuvant chemotherapy ("Abraxane" 2008). Abraxane was very well tolerated in this trial, which supports its further evaluation in a randomized setting in both adjuvant and neoadjuvant trials (Robidoux et al. Active targeting with polymeric nanoconjugates is a promising method that can be individually tailored to patients with a variety of diseases. An antibody to the vascular endothelial transferrin receptor (TfR) is the targeting module that facilitates passage of polycephin across the blood­tumor barrier and into the tumor. The nanoconjugate binds to the TfR on the surface of tumor endothelial cells, undergoes transcytosis, subsequently interacts with the tumor cell TfR, and enters the endosome of the tumor cell. Active targeting increases specificity and decreases the toxic effects that conventional systemically administered drugs have on healthy tissue. In active targeting, nanocarriers are internalized through receptors on specific cells that mediate their endocytosis (Table 3. After entering the target cell, polymeric nanoconjugates that have been engineered to bypass multidrug resistance transporters can overcome drug resistance, a bane of conventional chemotherapy (Lee et al. Polymeric implants slowly release drugs locally into the extracellular space of the tumor or brain. Drug distributes by diffusion around the implant, which limits therapeutic drug levels to tissues within 1­2 mm of the implant. Delivery of a therapeutic concentration of drug throughout a larger volume of target tissue can be achieved using the convection-enhanced delivery technique (Bobo et al. Nanoparticles have been distributed widely throughout the brain using the convection-enhanced delivery technique (Hadjipanayis et al. Local drug delivery requires invasive methods to place a slow-release polymer or an intracerebral catheter for convectionenhanced delivery. Although entering the brain can be achieved with little risk of permanent disability, the necessity of performing a surgical procedure and of staying in the hospital during an infusion makes local brain delivery more invasive and costly than systemic delivery, in which drug(s) can be administered during an outpatient visit. This nanoparticle provided efficiency of biodistribution two orders of magnitude greater when compared to other nanoparticle drug carriers (Vergoni et al. Successful entry of drugs into the brain via intranasal administration of a liposomal formulation of rivastigmine has been reported (Arumugam et al. A multilamellar liposomal formulation of rivastigmine administered intranasally reaches concentrations in the brain that are 10 times that of free drug administered intranasally and 5 times greater than with oral delivery of rivastigmine. The pharmacokinetic profile of this liposomal 46 the Textbook of Nanoneuroscience and Nanoneurosurgery formulation exhibited "burst"-type kinetics, with 56% of the rivastigmine payload being delivered within 6 h of administration. Presumably, the remainder of the payload was not released because drug concentrations equilibrated at the donor and recipient sites and prevented further drug release. Oral administration of nanoparticles may increase drug levels by avoiding presystemic hepatic metabolism. Transdermal drug delivery is a noninvasive method to provide steady and sustained drug levels (Cevc and Vierl 2010). Diseased tissues should be detected with greater sensitivity than present magnetic resonance techniques allow because the nanoconjugate-bound agents increase T1 signal and contrast both immediately and on a delayed basis from prolonged retention of gadolinium. This formulation contains a large number of potential binding sites for targeting molecules, creating the possibility of tissue-specific imaging; the oligonucleotide sequence can be modified to enhance binding to various subcellular organelles. Polymeric nanoparticles may also increase the sensitivity of laboratory diagnostics. They have been engineered to exhibit fluorescence upon binding disease-specific markers. To date, there have been few studies reporting specific in vivo toxicity of nanopolymers and nanoconjugates. The central goal to be achieved through these technologies is to increase the specificity of therapeutics and diagnostics and to limit toxicity in healthy tissues. Nanopolymers and Nanoconjugates for Central Nervous System Diagnostics and Therapies 47 Alyautdin, R. Delivery of loperamide across the blood­brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles.

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